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1.  Pharmacogenomics: The promise of personalized medicine 
AAPS PharmSci  2000;2(1):29-41.
Pharmacogenetics and pharmacogenomics deal with the genetic basis underlying variable drug response in individual patients. The traditional pharmacogenetic approach relies on studying sequence variations in candidate genes suspected of affecting drug response. On the other hand, pharmacogenomic studies encompass the sum of all genes, i.e., the genome. Numerous genes may play a role in drug response and toxicity, introducing a daunting level of complexity into the search for candidate genes. The high speed and specificity associated with newly emerging genomic technologies enable the search for relevant genes and their variants to include the entire genome. These new technologies have essentially spawned a new discipline, termed pharmacogenomics, which seeks to identify the variant genes affecting the response to drugs in individual patients. Moreover, pharmacogenomic analysis can identify disease susceptibility genes representing potential new drug targets. All of this will lead to novel approaches in drug discovery, an individualized application of drug therapy, and new insights into disease prevention. Current concepts in drug therapy often attempt treatment of large patient populations as groups, irrespective of the potential for individual, genetically-based differences in drug response. In contrast, pharmacogenomics may help focus effective therapy on smaller patient subpopulations which although demonstrating the same disease phenotype are characterized by distinct genetic profiles. Whether and to what extent this individual, genetics-based approach to medicine results in improved, economically feasible therapy remain to be seen.
To exploit these opportunities in genetic medicine, novel technologies will be needed, legal and ethical questions must be clarified, health care professionals must be educated, and the public must be informed about the implications of genetic testing in drug therapy and disease management.
doi:10.1208/ps020104
PMCID: PMC2750999  PMID: 11741220
Pharmacogenomics
2.  Pharmacogenetics: implementing personalized medicine 
Pharmacogenetics and pharmacogenomics have been widely recognized as fundamental steps toward personalized medicine. They deal with genetically determined variants in how individuals respond to drugs, and hold the promise to revolutionize drug therapy by tailoring it according to individual genotypes.
The clinical need for novel approaches to improve drug therapy derives from the high rate of adverse reactions to drugs and their lack of efficacy in many individuals that may be predicted by pharmacogenetic testing.
Significant advances in pharmacogenetic research have been made since inherited differences in response to drugs such as isoniazid and succinylcholine were explored in the 1950s. The clinical utility and applications of pharmacogenetics and pharmacogenomics are at present particularly evident in some therapeutic areas (anticancer, psycotrophic, and anticoagulant drugs).
Recent evidence derived from several studies includes screening for thiopurine methyl transferase or uridine 5'-diphosphoglucuronosyl-transferase 1A1 gene polymorphisms to prevent mercaptopurine and azathioprine or irinotecan induced myelosuppression, respectively. Also there is a large body of information concerning cytochrome P450 gene polymorphisms and their relationship to drug toxicity and response. Further examples include screening the presence of the HLA-B*5701 allele to prevent the hypersensitivity reactions to abacavir and the assessment of the human epidermal growth factor receptor (HER-2) expression for trastuzumab therapy of breast cancer or that of KRAS mutation status for cetuximab or panitumumab therapy in colorectal cancer.
Moreover, the application of pharmacogenetics and pharmacogenomics to therapies used in the treatment of osteoarticular diseases (e.g. rheumatoid arthritis, osteoporosis) holds great promise for tailoring therapy with clinically relevant drugs (e.g. disease-modifying antirheumatic drugs, vitamin D, and estrogens).
Although the classical candidate gene approach has helped unravel genetic variants that influence clinical drug responsiveness, gene-wide association studies have recently gained attention as they enable to associate specific genetic variants or quantitative differences in gene expression with drug response.
Although research findings are accumulating, most of the potential of pharmacogenetics and pharmacogenomics remains to be explored and must be validated in prospective randomized clinical trials.
The genetic and molecular foundations of personalized medicine appear solid and evidence indicates its growing importance in healthcare.
PMCID: PMC2781211  PMID: 22461093
pharmacogenetics, drug effects, drug metabolism, drug therapy, antineoplastic agents.
3.  Assessing the cost-effectiveness of pharmacogenomics 
AAPS PharmSci  2000;2(3):80-90.
The use of pharmacogenomics to individualize drug therapy offers the potential to improve drug effectiveness, reduce adverse side effects, and provide cost-effective pharmaceutical care. However, the combinations of disease, drug, and genetic test characteristics that will provide clinically useful and economically feasible therapeutic interventions have not been clearly elucidated. The purpose of this paper was to develop a framework for evaluating the potential cost-effectiveness of pharmacogenomic strategies that will help scientists better understand the strategic implications of their research assist in the design of clinical trials, and provide a guide for health care providers making reimbursement decisions. We reviewed concepts of cost-effectiveness analysis and pharmacogenomics and identified 5 primary characteristics that will enhance the cost-effectiveness of pharmacogenomics: 1) there are severe clinical or economic consequence that are avoided through the use of pharmacogenomics, 2) monitoring drug response using current methods is difficult, 3) a well-established association between genotype and clinical phenotype exists, 4) there is a rapid and relatively inexpensive genetic test, and 5) the variant gene is relatively common. We use this framework to evaluate several examples of pharmacogenomics. We found that pharmacogenomics offers great potential to improve patients' health in a cost-effective manner. However, pharmacogenomics will not be applied to all currently marketed drugs, and careful evaluations are needed on a case-by-case basis before investing resources in research and development of pharmacogenomic-based therapeutics and making reimbursement decisions.
doi:10.1208/ps020329
PMCID: PMC2761139  PMID: 11741245
4.  Peripheral vs. Central Sex Steroid Hormones in Experimental Parkinson’s Disease 
The nigrostriatal dopaminergic (NSDA) pathway degenerates in Parkinson’s disease (PD), which occurs with approximately twice the incidence in men than women. Studies of the influence of systemic estrogens in females suggest sex hormones contribute to these differences. In this review we analyze the evidence revealing great complexity in the response of the healthy and injured NSDA system to hormonal influences, and emphasize the importance of centrally generated estrogens. At physiological levels, circulating estrogen (in females) or estrogen precursors (testosterone in males, aromatized to estrogen centrally) have negligible effects on dopaminergic neuron survival in experimental PD, but can modify striatal dopamine levels via actions on the activity or adaptive responses of surviving cells. However, these effects are sexually dimorphic. In females, estradiol promotes adaptive responses in the partially injured NSDA pathway, preserving striatal dopamine, whereas in males gonadal steroids and exogenous estradiol have a negligible or even suppressive effect, effectively exacerbating dopamine loss. On balance, the different effects of gonadal factors in males and females contribute to sex differences in experimental PD. Fundamental sex differences in brain organization, including the sexually dimorphic networks regulating NSDA activity are likely to underpin these responses. In contrast, estrogen generated locally appears to preserve striatal dopamine in both sexes. The available data therefore highlight the need to understand the biological basis of sex-specific responses of the NSDA system to peripheral hormones, so as to realize the potential for sex-specific, hormone-based therapies in PD. Furthermore, they suggest that targeting central steroid generation could be equally effective in preserving striatal dopamine in both sexes. Clarification of the relative roles of peripheral and central sex steroid hormones is thus an important challenge for future studies.
doi:10.3389/fendo.2011.00082
PMCID: PMC3355917  PMID: 22649388
nigrostriatal pathway; estrogen; Parkinson’s disease; central vs. gonadal steroids; sex
5.  Environmental Sex Determination in the Branchiopod Crustacean Daphnia magna: Deep Conservation of a Doublesex Gene in the Sex-Determining Pathway 
PLoS Genetics  2011;7(3):e1001345.
Sex-determining mechanisms are diverse among animal lineages and can be broadly divided into two major categories: genetic and environmental. In contrast to genetic sex determination (GSD), little is known about the molecular mechanisms underlying environmental sex determination (ESD). The Doublesex (Dsx) genes play an important role in controlling sexual dimorphism in genetic sex-determining organisms such as nematodes, insects, and vertebrates. Here we report the identification of two Dsx genes from Daphnia magna, a freshwater branchiopod crustacean that parthenogenetically produces males in response to environmental cues. One of these genes, designated DapmaDsx1, is responsible for the male trait development when expressed during environmental sex determination. The domain organization of DapmaDsx1 was similar to that of Dsx from insects, which are thought to be the sister group of branchiopod crustaceans. Intriguingly, the molecular basis for sexually dimorphic expression of DapmaDsx1 is different from that of insects. Rather than being regulated sex-specifically at the level of pre–mRNA splicing in the coding region, DapmaDsx1 exhibits sexually dimorphic differences in the abundance of its transcripts. During embryogenesis, expression of DapmaDsx1 was increased only in males and its transcripts were primarily detected in male-specific structures. Knock-down of DapmaDsx1 in male embryos resulted in the production of female traits including ovarian maturation, whereas ectopic expression of DapmaDsx1 in female embryos resulted in the development of male-like phenotypes. Expression patterns of another D. magna Dsx gene, DapmaDsx2, were similar to those of DapmaDsx1, but silencing and overexpression of this gene did not induce any clear phenotypic changes. These results establish DapmaDsx1 as a key regulator of the male phenotype. Our findings reveal how ESD is implemented by selective expression of a fundamental genetic component that is functionally conserved in animals using GSD. We infer that there is an ancient, previously unidentified link between genetic and environmental sex determination.
Author Summary
Sex determination is a fundamental biological process that can be broadly divided into two major categories. In genetic sex determination (GSD), sex-specific differentiation results from intrinsic genetic differences between males and females, whereas environmental sex determination (ESD) relies on environmental signals to induce male or female sex determination. In contrast to model organisms that utilize GSD system, environmental sex-determining organisms are poor genetic models. Therefore, although candidate genes involved in ESD have been found in vertebrates, their functions have remained largely unknown, impairing our understanding of ESD and making the comparison of sex-determining genes between both systems difficult. Here, we report the identification of a gene responsible for the production of males during environmental sex determination in the crustacean Daphnia. This gene is homologous to the Doublesex gene that is functionally conserved in animals that use GSD. Expression of Doublesex was increased primarily in male-specific structures. Gain- and loss-of-function analyses established that Daphnia Doublesex gene is a major effector that regulates the male phenotype in Daphnia. We infer that there is an ancient, previously unidentified link between genetic and environmental sex determination.
doi:10.1371/journal.pgen.1001345
PMCID: PMC3063754  PMID: 21455482
6.  The Role of the Pediatric Pharmacist in Personalized Medicine and Clinical Pharmacogenomics for Children 
With the initiatives by the National Institutes of Health and the Food and Drug Administration, pharmacogenomics has now moved from the laboratory to the patient bedside. Over 100 drug-products now contain pharmacogenomic information as part of their labeling. Many of these are commonly used in the pediatric population. Direct-to-consumer genetic test kits also require intervention and guidance from healthcare professionals. This increased trend towards personalized medicine mandates that healthcare professionals develop a working knowledge about pharmacogenomics and its application towards patient care. Because pharmacogenomic testing can provide patient-specific predictors for response to and safety of medications, pharmacists are positioned to play an active role in pharmacogenomic testing, clinical interpretation of results, and recommendations for individualization of drug therapy. Opportunities for pharmacists exist in both inpatient and outpatient settings, such as pharmacist-managed clinical pharmacogenomics consultation services and educating patients and families about pharmacogenomic testing. In addition to clinical roles, pharmacists may also be involved in genetically-influenced drug discovery and development. Given the potential for genetic and age-dependent factors to influence drug selection and dosing, pediatric pharmacists should be involved in the development of dosing recommendations and interprofessional practice guidelines regarding pharmacogenomic testing in pediatric patients. Opportunities to become knowledgeable and competent in pharmacogenomics span from coursework as part of the pharmacy curriculum to postgraduate education (e.g., residencies, fellowships, continuing education). However, there exists a need for additional postgraduate learning opportunities for practicing pharmacists. As a result, the Pediatric Pharmacy Advocacy Group (PPAG) acknowledges a need for increased education of both student and practicing pharmacists, with consideration of special patient populations, such as infants and children. PPAG endorses and advocates for the involvement of pediatric pharmacists in pharmacogenomic testing and in using those results to provide safe and effective medication use in pediatric patients of all ages. Additionally, PPAG strongly encourages pediatric pharmacists to take responsibility for educating patients and their families about the importance of pharmacogenomic testing and its role in the safe and effective use of medications.
doi:10.5863/1551-6776-16.2.118
PMCID: PMC3208440  PMID: 22477836
pediatrics; personalized medicine; pharmacist; pharmacogenomics; testing
7.  An Evolutionarily Conserved Sexual Signature in the Primate Brain 
PLoS Genetics  2008;4(6):e1000100.
The question of a potential biological sexual signature in the human brain is a heavily disputed subject. In order to provide further insight into this issue, we used an evolutionary approach to identify genes with sex differences in brain expression level among primates. We reasoned that expression patterns important to uphold key male and female characteristics may be conserved during evolution. We selected cortex for our studies because this specific brain region is responsible for many higher behavioral functions. We compared gene expression profiles in the occipital cortex of male and female humans (Homo sapiens, a great ape) and cynomolgus macaques (Macaca fascicularis, an old world monkey), two catarrhine species that show abundant morphological sexual dimorphism, as well as in common marmosets (Callithrix Jacchus, a new world monkey) which are relatively sexually monomorphic. We identified hundreds of genes with sex-biased expression patterns in humans and macaques, while fewer than ten were differentially expressed between the sexes in marmosets. In primates, a general rule is that many of the morphological and behavioral sexual dimorphisms seen in polygamous species, such as macaques, are typically less pronounced in monogamous species such as the marmosets. Our observations suggest that this correlation may also be reflected in the extent of sex-biased gene expression in the brain. We identified 85 genes with common sex-biased expression, in both human and macaque and 2 genes, X inactivation-specific transcript (XIST) and Heat shock factor binding protein 1 (HSBP1), that were consistently sex-biased in the female direction in human, macaque, and marmoset. These observations imply a conserved signature of sexual gene expression dimorphism in cortex of primates. Further, we found that the coding region of female-biased genes is more evolutionarily constrained compared to the coding region of both male-biased and non sex-biased brain expressed genes. We found genes with conserved sexual gene expression dimorphism in the occipital cortex of humans, cynomolgus macaques, and common marmosets. Genes within sexual expression profiles may underlie important functional differences between the sexes, with possible importance during primate evolution.
Author Summary
The contribution of genetics versus environment to behavioral differences between the sexes is a fundamental question in neuroscience. We hypothesized that some differences between the sexes might be partially explained by sexually dependent gene expression differences in the brain. We further speculated that if differences in gene expression between males and females are functionally important, they may be conserved in the evolution of primates. To test these hypotheses, we measured gene expression in the brains of male and female primates from three species: humans (Homo sapiens), macaques (Macaca fascicularis), and marmosets (Callithrix jacchus). Our results point to a conserved signature of sexual gene expression dimorphism in the brains of primates. Interestingly, we found that genes with conserved sexual gene expression dimorphism in the brain also evolve under more evolutionary constraint, compared with other genes, suggesting that they may have important roles during evolution of sex in primates. Moreover, we found higher evolutionary constrains in the coding regions of female-biased genes as compared to both male-biased and non sex-biased brain expressed genes. The study of sex dimorphic genes may in the future shed light on the basis of psychiatric diseases with differences in prevalence between the sexes.
doi:10.1371/journal.pgen.1000100
PMCID: PMC2413013  PMID: 18566661
8.  Pharmacogenomics of pediatric asthma 
Indian Journal of Human Genetics  2010;16(3):111-118.
CONTEXT:
Asthma is a complex disease with multiple genetic and environmental factors contributing to it. A component of this complexity is a highly variable response to pharmacological therapy. Pharmacogenomics is the study of the role of genetic determinants in the variable response to therapy. A number of examples of possible pharmacogenomic approaches that may prove of value in the management of asthma are discussed below.
EVIDENCE ACQUISITION:
A search of PubMed, Google scholar, E-Medicine, BMJ and Mbase was done using the key words “pharmacogenomics of asthma”, “pharmacogenomics of β-agonist, glucocorticoids, leukotriene modifiers, theophylline, muscarinic antagonists in asthma”.
RESULTS:
Presently, there are limited examples of gene polymorphism that can influence response to asthma therapy. Polymorphisms that alter response to asthma therapy include Arg16Gly, Gln27Glu, Thr164Ile for β-agonist receptor, polymorphism of glucocorticoid receptor gene, CRHR1 variants and polymorphism of LTC4S, ALOX5. Polymorphic variants of muscarinic receptors, PDE4 and CYP450 gene variants.
CONCLUSION:
It was concluded that genetic variation can improve the response to asthma therapy. However, no gene polymorphism has been associated with consistent results in different populations. Therefore, asthma pharmacogenomic studies in different populations with a large number of subjects are required to make possible tailoring the asthma therapy according to the genetic characteristic of individual patient.
doi:10.4103/0971-6866.73398
PMCID: PMC3009420  PMID: 21206697
Asthma; pharamacogenomics; polymorphism; variability in response
9.  A Population-Based Study on Alcohol and High-Risk Sexual Behaviors in Botswana 
PLoS Medicine  2006;3(10):e392.
Background
In Botswana, an estimated 24% of adults ages 15–49 years are infected with HIV. While alcohol use is strongly associated with HIV infection in Africa, few population-based studies have characterized the association of alcohol use with specific high-risk sexual behaviors.
Methods and Findings
We conducted a cross-sectional, population-based study of 1,268 adults from five districts in Botswana using a stratified two-stage probability sample design. Multivariate logistic regression was used to assess correlates of heavy alcohol consumption (>14 drinks/week for women, and >21 drinks/week for men) as a dependent variable. We also assessed gender-specific associations between alcohol use as a primary independent variable (categorized as none, moderate, problem and heavy drinking) and several risky sex outcomes including: (a) having unprotected sex with a nonmonogamous partner; (b) having multiple sexual partners; and (c) paying for or selling sex in exchange for money or other resources. Criteria for heavy drinking were met by 31% of men and 17% of women. Adjusted correlates of heavy alcohol use included male gender, intergenerational relationships (age gap ≥10 y), higher education, and living with a sexual partner. Among men, heavy alcohol use was associated with higher odds of all risky sex outcomes examined, including unprotected sex (AOR = 3.48; 95% confidence interval [CI], 1.65 to 7.32), multiple partners (AOR = 3.08; 95% CI, 1.95 to 4.87), and paying for sex (AOR = 3.65; 95% CI, 2.58 to 12.37). Similarly, among women, heavy alcohol consumption was associated with higher odds of unprotected sex (AOR = 3.28; 95% CI, 1.71 to 6.28), multiple partners (AOR = 3.05; 95% CI, 1.83 to 5.07), and selling sex (AOR = 8.50; 95% CI, 3.41 to 21.18). A dose-response relationship was seen between alcohol use and risky sexual behaviors, with moderate drinkers at lower risk than both problem and heavy drinkers.
Conclusions
Alcohol use is associated with multiple risks for HIV transmission among both men and women. The findings of this study underscore the need to integrate alcohol abuse and HIV prevention efforts in Botswana and elsewhere.
Alcohol use is associated with multiple risks for HIV transmission in men and women. The findings underscore the need to integrate alcohol abuse and HIV prevention efforts in Botswana and elsewhere.
Editors' Summary
Background.
Human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS), is most commonly spread through unprotected sex with an infected partner. HIV enters the body through the lining of the sex organs, rectum, or mouth, and destroys immune system cells, leaving the infected person susceptible to other viruses and bacteria. Although HIV education and prevention campaigns emphasize the importance of safe sex in reducing HIV transmission, people continue to become infected by having unprotected sex (that is, not using a condom) with either a nonmonogamous partner or multiple sexual partners, or in situations where they are paying for or selling sex. Research in different populations suggested that heavy alcohol use is associated with risky sexual behaviors. This is because alcohol relaxes the brain and body, reduces inhibitions, and diminishes risk perception. Drinking alcohol may further increase the risk of becoming infected with HIV through its suppressive effects on the immune system.
Why Was This Study Done?
Alcohol abuse is widespread in sub-Saharan Africa where most HIV infections occur and has been associated with risky sexual behaviors. It may therefore be one of the most common, potentially modifiable HIV risk factors in this region. However, research to date has concentrated on the association between alcohol consumption and risky sex in people attending HIV-treatment clinics or recruited at beer halls, and these populations may not be representative of the general population of sub-Saharan Africa. In this study, the researchers have investigated the potential role of alcohol in perpetuating the HIV epidemic by undertaking a population-based study on alcohol use and high-risk sexual behaviors in Botswana. Nearly a quarter of adults are infected with HIV here, and alcohol abuse is also common, particularly in the townships.
What Did the Researchers Do and Find?
The researchers recruited a random cross-section of people from the five districts of Botswana with the highest number of HIV-infected individuals and interviewed all 1,268 participants using a questionnaire. This included general questions about the participants (for example, their age and marital status) and questions about alcohol use, sexual behavior, and knowledge of HIV. Overall, 31% of the men in the study and 17% of the women were heavy drinkers—more than 21 drinks/week for men, 14 for women; a drink is half a pint of beer or a glass of wine. Heavy alcohol use was associated with being male, being in an intergenerational relationship (at least 10 years age difference between partners; intergenerational sex facilitates the continued spread of HIV in sub-Saharan Africa), having had more education, and living with a sexual partner. Among men, those who drank heavily were three to four times more likely to have unprotected sex or multiple partners or to pay for sex than nondrinkers. Among women, there was a similar association between heavy drinking and having unprotected sex or multiple partners, and heavy drinkers were eight times as likely to sell sex as nondrinkers. For both men and women, the more they drank, the more likely they were to have risky sex. The study did not address behavior among same-sex partnerships.
What Do These Findings Mean?
This study indicates that heavy alcohol consumption is strongly and consistently associated with sexual risk behaviors in both men and women in Botswana. Because of the study design, it does not prove that heavy alcohol use is the cause of such behaviors but provides strong circumstantial evidence that this is the case. It is possible that these results may not apply to neighboring African countries—Botswana is unique in being relatively wealthy and in its government being strongly committed to tackling HIV. Nevertheless, taken together with the results of other studies, this research strongly argues for the need to deal with alcohol abuse within HIV prevention programs in sub-Saharan Africa. Strategies to do this could include education campaigns that target both alcohol use and HIV in schools and in social venues, including beer halls. But, stress the researchers, any strategy that is used must consider the cultural and social significance of alcohol use (in Botswana, alcohol use is a symbol of masculinity and high socioeconomic status) and must simultaneously tackle not only the overlap between alcohol use and risky sexual behavior but also the overlap between alcohol and other risk behaviors such as intergenerational sex.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030392.
US National Institute of Allergy and Infectious Diseases factsheet on HIV infection and AIDS
US Department of Health and Human Services information on AIDS
US Centers for Disease Control and Prevention information on HIV/AIDS
US National Institute on Alcohol Abuse and Alcoholism patient information on alcohol and HIV/AIDS]
Aidsmap, information on HIV and AIDS provided by the charity NAM,which includes some information on HIV infections and alcohol
AVERT information on HIV and AIDS in Botswana
doi:10.1371/journal.pmed.0030392
PMCID: PMC1592342  PMID: 17032060
10.  Pharmacogenomics Bias - Systematic distortion of study results by genetic heterogeneity 
Background
Decision analyses of drug treatments in chronic diseases require modeling the progression of disease and treatment response beyond the time horizon of clinical or epidemiological studies. In many such models, progression and drug effect have been applied uniformly to all patients; heterogeneity in progression, including pharmacogenomic effects, has been ignored.
Objective
We sought to systematically evaluate the existence, direction and relative magnitude of a pharmacogenomics bias (PGX-Bias) resulting from failure to adjust for genetic heterogeneity in both treatment response (HT) and heterogeneity in progression of disease (HP) in decision-analytic studies based on clinical study data.
Methods
We performed a systematic literature search in electronic databases for studies regarding the effect of genetic heterogeneity on the validity of study results. Included studies have been summarized in evidence tables.
In the case of lacking evidence from published studies we sought to perform our own simulation considering both HT and HP. We constructed two simple Markov models with three basic health states (early-stage disease, late-stage disease, dead), one adjusting and the other not adjusting for genetic heterogeneity. Adjustment was done by creating different disease states for presence (G+) and absence (G-) of a dichotomous genetic factor. We compared the life expectancy gains attributable to treatment resulting from both models and defined pharmacogenomics bias as percent deviation of treatment-related life expectancy gains in the unadjusted model from those in the adjusted model. We calculated the bias as a function of underlying model parameters to create generic results.
We then applied our model to lipid-lowering therapy with pravastatin in patients with coronary atherosclerosis, incorporating the influence of two TaqIB polymorphism variants (B1 and B2) on progression and drug efficacy as reported in the DNA substudy of the REGRESS trial.
Results
We found four studies that systematically evaluated heterogeneity bias. All of them indicated that there is a potential of heterogeneity bias. However, none of these studies explicitly investigated the effect of genetic heterogeneity. Therefore, we performed our own simulation study.
Our generic simulation showed that a purely HT-related bias is negative (conservative) and a purely HP-related bias is positive (liberal). For many typical scenarios, the absolute bias is smaller than 10%. In case of joint HP and HT, the overall bias is likely triggered by the HP component and reaches positive values >100% if fractions of „fast progressors" and „strong treatment responders" are low.
In the clinical example with pravastatin therapy, the unadjusted model overestimated the true life-years gained (LYG) by 5.5% (1.07 LYG vs. 0.99 LYG for 56-year-old men).
Conclusions
We have been able to predict the pharmacogenomics bias jointly caused by heterogeneity in progression of disease and heterogeneity in treatment response as a function of characteristics of patients, chronic disease, and treatment. In the case of joint presence of both types of heterogeneity, models ignoring this heterogeneity may generate results that overestimate the treatment benefit.
PMCID: PMC3011301  PMID: 21289909
11.  Pharmacogenomics Discovery and Implementation in GWAS Era 
Clinical response to therapeutic treatments often varies among individual patients, ranging from beneficial effect to even fatal adverse reaction. Pharmacogenomics holds the promise of personalized medicine through elucidating genetic determinants responsible for pharmacological outcomes (e.g., cytotoxicities to anti-cancer drugs) and therefore guide the prescription decision prior to drug treatment. Besides traditional candidate gene-based approaches, technical advances have begun to allow application of whole-genome approaches to pharmacogenomic discovery. In particular, comprehensive understanding of human genetic variation provides the basis for applying GWAS (genome-wide association studies) in pharmacogenomic research to identify genomic loci associated with pharmacological phenotypes (e.g., individual dose requirement for warfarin). We therefore briefly reviewed the background for pharmacogenetic/pharmacogenomic research, with statins and warfarin as examples for the GWAS discovery and their clinical implementation. In conclusion, with some challenges, whole-genome approaches such as GWAS have allowed unprecedented progress in identifying genetic variants associated with pharmacological phenotypes, as well as provided foundation for the next wave of pharmacogenomic discovery utilizing sequencing-based approaches. Furthermore, investigation of the complex interactions among genetic, and epigenetic factors on the whole-genome scale will become the post-GWAS research focus for pharmacologic complex traits.
doi:10.1002/wsbm.1199
PMCID: PMC3527666  PMID: 23188748
Pharmacogenomics; GWAS
12.  Are HIV Epidemics among Men Who Have Sex with Men Emerging in the Middle East and North Africa?: A Systematic Review and Data Synthesis 
PLoS Medicine  2011;8(8):e1000444.
A systematic review by Laith Abu-Raddad and colleagues collates and analyzes the epidemiology of HIV among men who have sex with men in Middle Eastern and North African countries.
Background
Men who have sex with men (MSM) bear a disproportionately higher burden of HIV infection than the general population. MSM in the Middle East and North Africa (MENA) are a largely hidden population because of a prevailing stigma towards this type of sexual behavior, thereby limiting the ability to assess infection transmission patterns among them. It is widely perceived that data are virtually nonexistent on MSM and HIV in this region. The objective of this review was to delineate, for the first time, the evidence on the epidemiology of HIV among MSM in MENA.
Methods and Findings
This was a systematic review of all biological, behavioral, and other related data on HIV and MSM in MENA. Sources of data included PubMed (Medline), international organizations' reports and databases, country-level reports and databases including governmental and nongovernmental organization publications, and various other institutional documents. This review showed that onsiderable data are available on MSM and HIV in MENA. While HIV prevalence continues at low levels among different MSM groups, HIV epidemics appear to be emerging in at least few countries, with a prevalence reaching up to 28% among certain MSM groups. By 2008, the contribution of MSM transmission to the total HIV notified cases increased and exceeded 25% in several countries. The high levels of risk behavior (4–14 partners on average in the last six months among different MSM populations) and of biomarkers of risks (such as herpes simplex virus type 2 at 3%–54%), the overall low rate of consistent condom use (generally below 25%), the relative frequency of male sex work (20%–76%), and the substantial overlap with heterosexual risk behavior and injecting drug use suggest potential for further spread.
Conclusions
This systematic review and data synthesis indicate that HIV epidemics appear to be emerging among MSM in at least a few MENA countries and could already be in a concentrated state among several MSM groups. There is an urgent need to expand HIV surveillance and access to HIV testing, prevention, and treatment services in a rapidly narrowing window of opportunity to prevent the worst of HIV transmission among MSM in the Middle East and North Africa.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS first emerged in the early 1980s among gay men living in the US. But, as the disease rapidly spread, it became clear that AIDS also affects heterosexual men and women. Now three decades on, more than 30 million people are infected with HIV, the virus that causes AIDS. HIV is most often spread by having unprotected sex with an infected partner and, globally, most sexual transmission of HIV now occurs during heterosexual sex. However, 5%–10% of all new HIV infections still occur in men who have sex with men (MSM, a term that encompasses homosexual, bisexual, and transgender men, and heterosexual men who sometimes have sex with men). In some countries, male-to-male sexual contact remains the most important transmission route. Moreover, although the global prevalence of HIV infection (the proportion the world's population infected with HIV) has stabilized, the prevalence of HIV infection among MSM seems to be increasing in multiple countries and new and resurgent HIV epidemics among MSM populations are being frequently reported.
Why Was This Study Done?
In the US and the UK, the MSM population is visible and has helped to raise awareness about the risks of HIV transmission through male-to-male sexual contact. In many other countries, MSM are much less visible, fearing discrimination, stigmatization (being considered socially unacceptable) or arrest. In the Middle East and North Africa (MENA, a geographical region that encompasses countries that share historical, socio-cultural, linguistic and religious characteristics), MSM are the most hidden HIV risk group. Consequently, very little is known about HIV transmission patterns among MSM in MENA. Indeed, it is widely thought that there is virtually no information available on the epidemiology (causes, distribution, and control) of HIV among MSM in this region. In this systematic review and data synthesis, the researchers use predefined search criteria to identify all the published and unpublished data on the epidemiology of HIV among MSM in MENA and combine (synthesize) these data to produce a coherent picture of the HIV epidemic in this potentially key group of people for HIV transmission in this region.
What Did the Researchers Do and Find?
The researchers identified 26 articles and 51 other country-level reports and sources of data that included data on the prevalence of male-to-male sexual contact, HIV transmission, levels of high-risk behavior, and the extent of knowledge about HIV among MSM in MENA. The prevalence of HIV infection among MSM was low in most countries but high in others. For example, the infection rate in Pakistan was 27.6% among one MSM group. Importantly, there was some evidence of increasing HIV prevalence and emerging epidemics among MSM in the region. Thus, by 2008, MSM transmission was responsible for more than a quarter of notified cases of HIV in several countries. Worryingly, MSM were involved in several types of HIV-related high risk behavior. For example, they had, on average, between 4 and 14 sexual partners in the past six months, their rates of consistent condom use were generally below 25% and, in some countries, MSM frequently reported injecting drug use, another common mode of HIV transmission. In addition, 20%–75.5% of MSM exchanged sex for money and contact between MSM and female sex workers and other female sexual partners was often common. Finally, although the level of basic knowledge about HIV/AIDS was high, the level of comprehensive knowledge was limited with a high proportion of MSM perceiving their risk of contracting HIV as low.
What Do These Findings Mean?
These findings indicate that there is considerable and increasing data about HIV transmission and risk behavior among MSM in MENA. However, the quality of this evidence varies greatly. Little has been collected over time in individual populations and, because only the visible part of the MSM populations in many MENA countries has been sampled, these findings may not be representative of all MSM in this region. Nevertheless, these findings suggest that HIV epidemics are emerging among MSM in several MENA countries. Importantly, the high levels of risk behaviors practiced by many MSM in MENA mean that MSM could become the pivotal risk group for HIV transmission in this region in the next decade. There is, therefore, an urgent need to expand HIV surveillance and access to HIV testing, prevention and treatment services among MSM in this region to limit the size of the HIV epidemic.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000444.
Information about the status of the HIV epidemic in the Middle East and North Africa can be found in the World Bank/UNAIDS/WHO report Characterizing the HIV/AIDS epidemic in the Middle East and North Africa: Time for strategic action
Information about the global HIV epidemic among men who have sex with men can be found in the World Bank report The Global HIV Epidemics among Men Who Have Sex with Men
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including information on HIV transmission and transmission in gay men and other MSM and on safer sex
Information is available from Avert, an international AIDS charity, on all aspects of HIV/AIDS, including information on HIV, AIDS and men who have sex with men and on HIV and AIDS prevention (in English and Spanish)
The US Centers for Disease Control and Prevention also have information about HIV/AIDS among men who have sex with men (in English and Spanish)
doi:10.1371/journal.pmed.1000444
PMCID: PMC3149074  PMID: 21829329
13.  Sex-Specific Differences in Hemodialysis Prevalence and Practices and the Male-to-Female Mortality Rate: The Dialysis Outcomes and Practice Patterns Study (DOPPS) 
PLoS Medicine  2014;11(10):e1001750.
In this study, Port and colleagues describe hemodialysis prevalence and patient characteristics by sex, compare men-to-women mortality rate with data from the general population, and evaluate sex interactions with mortality. The results show that women's survival advantage was markedly diminished in hemodialysis patients.
Please see later in the article for the Editors' Summary
Background
A comprehensive analysis of sex-specific differences in the characteristics, treatment, and outcomes of individuals with end-stage renal disease undergoing dialysis might reveal treatment inequalities and targets to improve sex-specific patient care. Here we describe hemodialysis prevalence and patient characteristics by sex, compare the adult male-to-female mortality rate with data from the general population, and evaluate sex interactions with mortality.
Methods and Findings
We assessed the Human Mortality Database and 206,374 patients receiving hemodialysis from 12 countries (Australia, Belgium, Canada, France, Germany, Italy, Japan, New Zealand, Spain, Sweden, the UK, and the US) participating in the international, prospective Dialysis Outcomes and Practice Patterns Study (DOPPS) between June 1996 and March 2012. Among 35,964 sampled DOPPS patients with full data collection, we studied patient characteristics (descriptively) and mortality (via Cox regression) by sex. In all age groups, more men than women were on hemodialysis (59% versus 41% overall), with large differences observed between countries. The average estimated glomerular filtration rate at hemodialysis initiation was higher in men than women. The male-to-female mortality rate ratio in the general population varied from 1.5 to 2.6 for age groups <75 y, but in hemodialysis patients was close to one. Compared to women, men were younger (mean = 61.9±standard deviation 14.6 versus 63.1±14.5 y), were less frequently obese, were more frequently married and recipients of a kidney transplant, more frequently had coronary artery disease, and were less frequently depressed. Interaction analyses showed that the mortality risk associated with several comorbidities and hemodialysis catheter use was lower for men (hazard ratio [HR] = 1.11) than women (HR = 1.33, interaction p<0.001). This study is limited by its inability to establish causality for the observed sex-specific differences and does not provide information about patients not treated with dialysis or dying prior to a planned start of dialysis.
Conclusions
Women's survival advantage was markedly diminished in hemodialysis patients. The finding that fewer women than men were being treated with dialysis for end-stage renal disease merits detailed further study, as the large discrepancies in sex-specific hemodialysis prevalence by country and age group are likely explained by factors beyond biology. Modifiable variables, such as catheter use, showing significant sex interactions suggest interventional targeting.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Throughout life, the kidneys filter waste products (from the normal breakdown of tissues and from food) and excess water from the blood to make urine. Chronic kidney disease—an increasingly common condition globally—gradually destroys the kidney's filtration units (the nephrons). As the nephrons stop working, the rate at which the blood is filtered (the glomerular filtration rate) decreases, and waste products build up in the blood, eventually leading to life-threatening end-stage kidney (renal) disease. Symptoms of chronic kidney disease, which rarely occur until the disease is advanced, include tiredness, swollen feet and ankles, and frequent urination, particularly at night. Chronic kidney disease cannot be cured, but its progression can be slowed by controlling diabetes and other conditions that contribute to its development. End-stage kidney disease is treated by regular hemodialysis (a process in which blood is cleaned by passing it through a filtration machine) or by kidney transplantation.
Why Was This Study Done?
Like many other long-term conditions, the prevalence (the proportion of the population that has a specific disease) of chronic kidney disease and of end-stage renal disease, and treatment outcomes for these conditions, may differ between men and women. Some of these sex-specific differences may arise because of sex-specific differences in normal biological functions. Other sex-specific differences may be related to sex-specific differences in patient care or in patient awareness of chronic kidney disease. A comprehensive analysis of sex-specific differences among individuals with end-stage renal disease might identify both treatment inequalities and ways to improve sex-specific care. Here, in the Dialysis Outcomes and Practice Patterns Study (DOPPS), the researchers investigate sex-specific differences in the prevalence and practices of hemodialysis and in the characteristics of patients undergoing hemodialysis, and investigate the adult male-to-female mortality (death) rate among patients undergoing hemodialysis. The DOPPS is a prospective cohort study that is investigating the characteristics, treatment, and outcomes of adult patients undergoing hemodialysis in representative facilities in 19 countries (12 countries were available for analysis at the time of the current study).
What Did the Researchers Do and Find?
To investigate sex-specific differences in hemodialysis prevalence, the researchers compared data from the Human Mortality Database, which provides detailed population and mortality data for 37 countries, with data collected by the DOPPS. Forty-one percent of DOPPS patients were women, compared to 52% of the general population in 12 of the DOPPS countries. Next, the researchers used data collected from a randomly selected subgroup of patients to examine sex-specific differences in patient characteristics and mortality. The average estimated glomerular filtration rate at hemodialysis initiation was higher in men than women. Moreover, men were more frequently recipients of a kidney transplant than women. Notably, although in the general population in a given age group women were less likely to die than men, among hemodialysis patients, women were as likely to die as men. Finally, the researchers investigated which patient characteristics were associated with the largest sex-specific differences in mortality risk. The use of a hemodialysis catheter (a tube that is inserted into a patient's vein to transfer their blood into the hemodialysis machine) was associated with a lower mortality risk in men than in women.
What Do These Findings Mean?
These findings show that, among patients treated with hemodialysis for end-stage renal disease, women differ from men in many ways. Although some of these sex-specific differences may be related to biology, others may be related to patient care and to patient awareness of chronic kidney disease. Because this is an observational study, these findings cannot prove that the reported differences in hemodialysis prevalence, treatment, and mortality are actually caused by being a man or a woman. Importantly, however, these findings suggest that hemodialysis may abolish the survival advantage that women have over men in the general population and that fewer women than men are being treated for end-stage-renal disease, even though chronic kidney disease is more common in women than in men. Finally, the finding that the use of hemodialysis catheters for access to veins is associated with a higher mortality risk among women than among men suggests that, where possible, women should be offered a surgical process called arteriovenous fistula placement, which is recommended for access to veins during long-term hemodialysis but which may, in the past, have been underused in women.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001750.
More information about the DOPPS program is available
The US National Kidney and Urologic Diseases Information Clearinghouse provides information about all aspects of kidney disease; the US National Kidney Disease Education Program provides resources to help improve the understanding, detection, and management of kidney disease (in English and Spanish)
The UK National Health Service Choices website provides information for patients on chronic kidney disease and about hemodialysis, including some personal stories
The US National Kidney Foundation, a not-for-profit organization, provides information about chronic kidney disease and about hemodialysis (in English and Spanish)
The not-for-profit UK National Kidney Federation provides support and information for patients with kidney disease and for their carers, including information and personal stories about hemodialysis
World Kidney Day, a joint initiative between the International Society of Nephrology and the International Federation of Kidney Foundations, aims to raise awareness about kidneys and kidney disease
MedlinePlus has pages about chronic kidney disease and about hemodialysis
doi:10.1371/journal.pmed.1001750
PMCID: PMC4211675  PMID: 25350533
14.  Discovery of Sexual Dimorphisms in Metabolic and Genetic Biomarkers 
PLoS Genetics  2011;7(8):e1002215.
Metabolomic profiling and the integration of whole-genome genetic association data has proven to be a powerful tool to comprehensively explore gene regulatory networks and to investigate the effects of genetic variation at the molecular level. Serum metabolite concentrations allow a direct readout of biological processes, and association of specific metabolomic signatures with complex diseases such as Alzheimer's disease and cardiovascular and metabolic disorders has been shown. There are well-known correlations between sex and the incidence, prevalence, age of onset, symptoms, and severity of a disease, as well as the reaction to drugs. However, most of the studies published so far did not consider the role of sexual dimorphism and did not analyse their data stratified by gender. This study investigated sex-specific differences of serum metabolite concentrations and their underlying genetic determination. For discovery and replication we used more than 3,300 independent individuals from KORA F3 and F4 with metabolite measurements of 131 metabolites, including amino acids, phosphatidylcholines, sphingomyelins, acylcarnitines, and C6-sugars. A linear regression approach revealed significant concentration differences between males and females for 102 out of 131 metabolites (p-values<3.8×10−4; Bonferroni-corrected threshold). Sex-specific genome-wide association studies (GWAS) showed genome-wide significant differences in beta-estimates for SNPs in the CPS1 locus (carbamoyl-phosphate synthase 1, significance level: p<3.8×10−10; Bonferroni-corrected threshold) for glycine. We showed that the metabolite profiles of males and females are significantly different and, furthermore, that specific genetic variants in metabolism-related genes depict sexual dimorphism. Our study provides new important insights into sex-specific differences of cell regulatory processes and underscores that studies should consider sex-specific effects in design and interpretation.
Author Summary
The combination of genomic and metabolic studies during the last years has provided astonishing results. However, most of the studies published so far did not consider the role of sexual dimorphism and did not analyse their data stratified by sex. The investigation of 131 serum metabolite concentrations of >3,300 population-based samples (KORA F3/F4) revealed significant differences in the metabolite profile of males and females. Furthermore, a genome-wide picture of sex-specific genetic variations in human metabolism (>2,000 subjects from KORA F3/F4 cohorts) was investigated. Sex-specific genome-wide association studies (GWAS) showed differences in the effect of genetic variations on metabolites in men and women. SNPs in the CPS1 (carbamoyl-phosphate synthase 1) locus showed genome-wide significant differences in beta-estimates of sex-specific association analysis (significance level: 3.8×10−10) for glycine. As global metabolomic techniques are more and more refined to identify more compounds in single biological samples, the predictive power of this new technology will greatly increase. This suggests that metabolites, which may be used as predictive biomarkers to indicate the presence or severity of a disease, have to be used selectively depending on sex.
doi:10.1371/journal.pgen.1002215
PMCID: PMC3154959  PMID: 21852955
15.  Mutations in a Novel, Cryptic Exon of the Luteinizing Hormone/Chorionic Gonadotropin Receptor Gene Cause Male Pseudohermaphroditism 
PLoS Medicine  2008;5(4):e88.
Background
Male pseudohermaphroditism, or Leydig cell hypoplasia (LCH), is an autosomal recessive disorder in individuals with a 46,XY karyotype, characterized by a predominantly female phenotype, a blind-ending vagina, absence of breast development, primary amenorrhea, and the presence of testicular structures. It is caused by mutations in the luteinizing hormone/chorionic gonadotropin receptor gene (LHCGR), which impair either LH/CG binding or signal transduction. However, molecular analysis has revealed that the LHCGR is apparently normal in about 50% of patients with the full clinical phenotype of LCH. We therefore searched the LHCGR for novel genomic elements causative for LCH.
Methods and Findings
In the present study we have identified a novel, primate-specific bona fide exon (exon 6A) within the LHCGR gene. It displays composite characteristics of an internal/terminal exon and possesses stop codons triggering nonsense-mediated mRNA decay (NMD) in LHCGR. Transcripts including exon 6A are physiologically highly expressed in human testes and granulosa cells, and result in an intracellular, truncated LHCGR protein of 209 amino acids. We sequenced exon 6A in 16 patients with unexplained LCH and detected mutations in three patients. Functional studies revealed a dramatic increase in the expression of the mutated internal exon 6A transcripts, indicating aberrant NMD. These altered ratios of LHCGR transcripts result in the generation of predominantly nonfunctional LHCGR isoforms, thereby preventing proper expression and functioning.
Conclusions
The identification and characterization of this novel exon not only identifies a new regulatory element within the genomic organization of LHCGR, but also points toward a complex network of receptor regulation, including events at the transcriptional level. These findings add to the molecular diagnostic tools for LCH and extend our understanding of the endocrine regulation of sexual differentiation.
Joerg Gromoll and colleagues describe the identification and characterization of a novel exon that appears to be a new regulatory element within the luteinizing hormone/chorionic gonadotropin receptor gene of three individuals with Leydig cell hypoplasia.
Editors' Summary
Background.
A person's sex is determined by their complement of X and Y (sex) chromosomes. Someone who has two X chromosomes is genetically female and usually has ovaries and female external sex organs. Someone who has an X and a Y chromosome is genetically male and has testes and male external sex organs. Sometimes, though, the development of the reproductive organs proceeds abnormally, resulting in a person with an “intersex” condition whose chromosomes, gonads (ovaries or testes), and external sex organs do not correspond. Leydig cell hypoplasia (LCH; also called male pseudohermaphroditism or a disorder of sex development) is an XY female intersex condition. People with this inherited condition develop testes but also have a vagina (which is not connected to a womb), and they do not develop breasts or have periods. This mixture of sexual characteristics arises because the Leydig cells in the testes are underdeveloped. Leydig cells normally secrete testosterone, the hormone that promotes the development and maintenance of male sex characteristics. Before birth, chorionic gonadotropin (CG; a hormone made by the placenta) stimulates Leydig cell development and testosterone production; after birth, luteinizing hormone (LH), which is made by the pituitary gland, stimulates testosterone production. Both hormones bind to the LH/CG receptor, a protein on the surface of Leydig cells. In LCH, this receptor either does not bind CG and LH or fails to tell the Leydig cells to make testosterone.
Why Was This Study Done?
The gene that encodes the LH/CG receptor is called LHCGR. Several mutations (genetic changes) that inactivate the LC/CG receptor have been identified in people with LCH. However, the LHCGR gene is apparently normal in 50% of people with this intersex condition. In this study, the researchers examine the LHCGR gene in detail to try to find the underlying genetic defect in these individuals.
What Did the Researchers Do and Find?
The researchers used several molecular biology techniques to identify a new exon—exon 6A—within the human LHCGR gene. (Exons are DNA sequences that contain the information for making proteins; introns are DNA sequences that interrupt the coding sequence of a gene. Both introns and exons are transcribed into messenger RNA [mRNA] and the exons are then “spliced” together to make the mature mRNA, which is translated into protein.) The researchers identify several differently spliced LHCGR mRNA transcripts that contain exon 6A—a terminal exon 6A mRNA that contains exons 1–6 and exon 6A, and two internal exon 6A mRNAs that also contain exons 7–11. The researchers report that human testes express high levels of the terminal exon 6A transcript, which is translated into a short version of LHCGR protein that remains within the cell (full-length LHCGR moves to the cell surface). By contrast, testes contain low levels of the internal exon 6A mRNAs. This is because exon 6A contains two premature stop codons (DNA sequences that mark the end of a protein), which trigger “nonsense-mediated decay” (NMD), a cellular surveillance mechanism that regulates protein synthesis by degrading mRNAs that contain internal stop codons. When the researchers screened 16 people with LCH but without known mutations in the LHCGR gene, three had mutations in exon 6A. Laboratory experiments show that these mutations greatly increased the amounts of the internal exon 6A transcripts present in cells and interfered with the cells' normal response to chorionic gonadotropin.
What Do These Findings Mean?
These findings identify a new, functional exon in the LHCGR gene and show that mutations in this exon cause some cases of LCH. This is the first time that a human disease has been associated with mutations in an exon that is a target for NMD. In addition, these findings provide important insights into how the LHCGR is regulated. The researchers speculate that a complex network that involves the exon 6A-containing transcripts and NMD normally tightly regulates the production of functional LHCGR already at the transcriptional level. When mutations are present in exon 6A, they suggest, NMD is the predominant pathway for all the exon 6A-containing transcripts, thereby drastically decreasing the amount of functional LHCGR.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050088.
The MedlinePlus Encyclopedia has a page on intersex conditions (in English and Spanish)
Wikipedia has pages on intersexuality and on the LH/CG receptor (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The Intersex Society of North America provides information and support for the parents of children with intersex conditions
The Androgen Insensitivity Syndrome Support Group also provides some general information about intersex conditions, including information about LCH and other XY female conditions (in several languages)
Sequence-Structure-Function-Analysis (SSFA), run by a group of researchers in Germany (Leibniz-Institut für Molekulare Pharmakologie; Humboldt-Universitätzu Berlin), is a database dealing the sequence, structure, and function of glycoprotein hormone receptors
Glycoprotein-hormone Receptors Information System (GRIS), from Université Libre de Bruxelles and Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, is a database giving structural information on the LHCGR
doi:10.1371/journal.pmed.0050088
PMCID: PMC2323302  PMID: 18433292
16.  Pharmacogenomics in Early Phase Oncology Clinical Trials: Is There a Sweet Spot in Phase II? 
Clinical Cancer Research  2012;18(10):2809-2816.
Many clinical trials of oncology drugs now include at least a consideration of pharmacogenomics, the study of germline or acquired genetic factors governing a drug's response and toxicity. Besides the potential benefit to patients from the consideration of personalized pharmacogenomic information when making treatment decisions, there is a clear incentive for oncology drug developers to incorporate pharmacogenomic factors in the drug development process since pharmacogenomic biomarkers may allow predictive characterization of sub-populations within a disease that may particularly respond, or may allow preidentification of patients at highest risk for adverse events. There is, however, a lack of agreement in actual practice as to where in the oncology clinical drug development process pharmacogenomic studies should be incorporated. In this article, we examine the recent growth of pharmacogenomics in oncology clinical trials, especially in early phase studies, and examine several critical questions facing the incorporation of pharmacogenomics in early oncologic drug development. We show that phase II clinical trials in particular have a favorable track record for demonstrating positive pharmacogenomic signals, worthy of additional follow-up and validation, and that the phase II setting holds significant promise for potentially accelerating and informing future phase III trials. We conclude that phase II trials offer an ideal “sweet spot” for routine incorporation of pharmacogenomic questions in oncology drug development.
doi:10.1158/1078-0432.CCR-11-2445
PMCID: PMC3354016  PMID: 22427349
phase II; oncology; clinical trials; pharmacogenomics; biomarker development
17.  Patient profiling in diabetes and role of canagliflozin 
Background
Physicians attempt to achieve glycemic goals in patients with type 2 diabetes mellitus (T2DM) through various means, including glucose-lowering medications. There is interindividual variability in response to medications, which can be partially explained by the presence of genetic polymorphisms that affect drug metabolism. Pharmacogenomics studies the hereditary basis of interpatient variations in drug response and aims to identify subgroups of patients whose drug management could be tailored accordingly. The aim of this review is to explore patient profiling in the management of T2DM with a focus on the sodium glucose transporter inhibitor canagliflozin.
Methods
The PubMed database was searched using the terms “pharmacogenomics” and “diabetes” through May 31, 2014. Published articles and abstracts presented at national/international meetings were considered.
Results and conclusion
Genome-wide association studies have opened the door for patient profiling and research into genetic variants in multifactorial T2DM. Clinically, it may be possible to tailor the type of medication used based on the presence or absence of the various genetic variants. However, the polymorphisms studied may only explain some of the variability in response to T2DM drugs and needs further validation to ensure its authenticity. There are still unidentified factors which appear to play a role in the interindividual variability seen in clinical practice. The potential exists for pharmacogenomics to promote efficacious, safe, and cost-effective individualized diabetes management. Pharmacogenomics is still in its early stages, and the idea of defining patients genetically to predict individual responses to drugs and obtain safe and effective T2DM management is promising, in spite of existing barriers. Currently, clinical profiling of patients with T2DM and using an individualized approach with most drugs, including canagliflozin, based on comorbid conditions still remains the most accepted approach for the management of T2DM.
doi:10.2147/52761.S0
PMCID: PMC4270036  PMID: 25540592
personalized medicine; pharmacogenomics; genetic variants
18.  The Number of X Chromosomes Causes Sex Differences in Adiposity in Mice 
PLoS Genetics  2012;8(5):e1002709.
Sexual dimorphism in body weight, fat distribution, and metabolic disease has been attributed largely to differential effects of male and female gonadal hormones. Here, we report that the number of X chromosomes within cells also contributes to these sex differences. We employed a unique mouse model, known as the “four core genotypes,” to distinguish between effects of gonadal sex (testes or ovaries) and sex chromosomes (XX or XY). With this model, we produced gonadal male and female mice carrying XX or XY sex chromosome complements. Mice were gonadectomized to remove the acute effects of gonadal hormones and to uncover effects of sex chromosome complement on obesity. Mice with XX sex chromosomes (relative to XY), regardless of their type of gonad, had up to 2-fold increased adiposity and greater food intake during daylight hours, when mice are normally inactive. Mice with two X chromosomes also had accelerated weight gain on a high fat diet and developed fatty liver and elevated lipid and insulin levels. Further genetic studies with mice carrying XO and XXY chromosome complements revealed that the differences between XX and XY mice are attributable to dosage of the X chromosome, rather than effects of the Y chromosome. A subset of genes that escape X chromosome inactivation exhibited higher expression levels in adipose tissue and liver of XX compared to XY mice, and may contribute to the sex differences in obesity. Overall, our study is the first to identify sex chromosome complement, a factor distinguishing all male and female cells, as a cause of sex differences in obesity and metabolism.
Author Summary
Differences exist between men and women in the development of obesity and related metabolic diseases such as type 2 diabetes and cardiovascular disease. Previous studies have focused on the sex-biasing role of hormones produced by male and female gonads, but these cannot account fully for the sex differences in metabolism. We discovered that removal of the gonads uncovers an important genetic determinant of sex differences in obesity—the presence of XX or XY sex chromosomes. We used a novel mouse model to tease apart the effects of male and female gonads from the effects of XX or XY chromosomes. Mice with XX sex chromosomes (relative to XY), regardless of their type of gonad, had increased body fat and ate more food during the sleep period. Mice with two X chromosomes also had accelerated weight gain, fatty liver, and hyperinsulinemia on a high fat diet. The higher expression levels of a subset of genes on the X chromosome that escape inactivation may influence adiposity and metabolic disease. The effect of X chromosome genes is present throughout life, but may become particularly significant with increases in longevity and extension of the period spent with reduced gonadal hormone levels.
doi:10.1371/journal.pgen.1002709
PMCID: PMC3349739  PMID: 22589744
19.  Placental contribution to the origins of sexual dimorphism in health and diseases: sex chromosomes and epigenetics 
Sex differences occur in most non-communicable diseases, including metabolic diseases, hypertension, cardiovascular disease, psychiatric and neurological disorders and cancer. In many cases, the susceptibility to these diseases begins early in development. The observed differences between the sexes may result from genetic and hormonal differences and from differences in responses to and interactions with environmental factors, including infection, diet, drugs and stress. The placenta plays a key role in fetal growth and development and, as such, affects the fetal programming underlying subsequent adult health and accounts, in part for the developmental origin of health and disease (DOHaD). There is accumulating evidence to demonstrate the sex-specific relationships between diverse environmental influences on placental functions and the risk of disease later in life. As one of the few tissues easily collectable in humans, this organ may therefore be seen as an ideal system for studying how male and female placenta sense nutritional and other stresses, such as endocrine disruptors. Sex-specific regulatory pathways controlling sexually dimorphic characteristics in the various organs and the consequences of lifelong differences in sex hormone expression largely account for such responses. However, sex-specific changes in epigenetic marks are generated early after fertilization, thus before adrenal and gonad differentiation in the absence of sex hormones and in response to environmental conditions. Given the abundance of X-linked genes involved in placentogenesis, and the early unequal gene expression by the sex chromosomes between males and females, the role of X- and Y-chromosome-linked genes, and especially those involved in the peculiar placenta-specific epigenetics processes, giving rise to the unusual placenta epigenetic landscapes deserve particular attention. However, even with recent developments in this field, we still know little about the mechanisms underlying the early sex-specific epigenetic marks resulting in sex-biased gene expression of pathways and networks. As a critical messenger between the maternal environment and the fetus, the placenta may play a key role not only in buffering environmental effects transmitted by the mother but also in expressing and modulating effects due to preconceptional exposure of both the mother and the father to stressful conditions.
doi:10.1186/2042-6410-4-5
PMCID: PMC3618244  PMID: 23514128
Epigenetics; Histone modifications; DNA methylation; Nutrition; DOHaD; Environment; Fetal programming; Sexual dimorphism
20.  The role of X-chromosome inactivation in female predisposition to autoimmunity 
Arthritis Research  2000;2(5):399-406.
We propose that the phenomenon of X-chromosome inactivation in females may constitute a risk factor for loss of T-cell tolerance; specifically that skewed X-chromosome inactivation in the thymus may lead to inadequate thymic deletion. Using a DNA methylation assay, we have examined the X-chromosome inactivation patterns in peripheral blood from normal females (n = 30), female patients with a variety of autoimmune diseases (n = 167). No differences between patients and controls were observed. However, locally skewed X-chromsome inactivation may exist in the thymus, and therefore the underlying hypothesis remains to be disproved.
Introduction:
A reduction in the sex ratio (male : female) is characteristic of most autoimmune disorders. The increased prevalence in females ranges from a modest 2:1 for multiple sclerosis [1], to approximately 10:1 for systemic lupus erythematosus [2]. This tendency toward autoimmunity in females is often ascribed to hormonal differences, because in a number of experimental disease models estrogens exacerbated disease, and androgens can inhibit disease activity [3,4]. However, human studies have failed to demonstrate a clear-cut influence of hormonal environment on disease susceptibility to lupus or other autoimmune disorders. In addition, many childhood forms of autoimmunity, such as juvenile rheumatoid arthritis, exhibit female predominance [5]. Interestingly, juvenile (type 1) diabetes is an exception to this general trend, with a sex ratio close to 1 in most studies [6]. Therefore, it is reasonable to consider alternative explanations for the increased prevalence of autoimmune diseases in human females.
A unifying feature of autoimmune disorders appears to be the loss of immunologic tolerance to self-antigens, and in many of these diseases there is evidence that T-cell tolerance has been broken. The most profound form of T-cell tolerance involves deletion of potentially self-reactive T cells during thymic selection. Thus, lack of exposure to a self-antigen in the thymus may lead to the presence of autoreactive T cells and may increase the risk of autoimmunity. An elegant example of this has recently been reported [7].
The existence of X-chromosome inactivation in females offers a potential mechanism whereby X-linked self-antigens may escape presentation in the thymus or in other peripheral sites that are involved in tolerance induction. Early in female development, one of the two X chromosomes in each cell undergoes an ordered process of inactivation, with subsequent silencing of most genes on the inactive X chromosome [8]. This phenomenon occurs at a very early embryonic stage [9], and thus all females are mosaic and may occasionally exhibit extreme skewing towards one or the other parental X chromosome. In theory, this may result in a situation in which polymorphic self-antigens on one X chromosome may fail to be expressed at sufficiently high levels in a tolerizing compartment, such as the thymus, and yet may be expressed at a considerable frequency in the peripheral soma. Thus, females may be predisposed to a situation in which they can occasionally express X-linked autoantigens in the periphery to which they have been inefficiently tolerized. Stewart [10] has recently speculated that such a mechanism may play a role in the predisposition to systemic lupus.
This hypothesis predicts that females with autoimmunity may be particularly prone to this mechanism of `inadequate tolerization' by virtue of extremely skewed X-chromosome inactivation. We therefore performed a comprehensive analysis of X-chromosome inactivation patterns in populations of females with multiple sclerosis, systemic lupus erythematosus, juvenile rheumatoid arthritis, and type 1 (insulin-dependent) diabetes mellitus, and in female control individuals. The results do not provide support for a major role for skewed X-chromosome inactivation in female predisposition to autoimmunity; however, neither is the underlying hypothesis disproved by the present data.
Materials and method:
DNA was obtained from female patients from the following sources: 45 persons with juvenile diabetes seen at the Virginia Mason Research Center in Seattle, Washington; 58 multiple sclerosis patients seen at the New York Hospital Multiple Sclerosis Center; 46 patients with systemic lupus erythematosus seen at the Hospital for Special Surgery (New York); 18 patients with juvenile rheumatoid arthritis seen at the Children's Hospital Medical Center in Cleveland. In addition, 30 healthy age-matched females were studied as normal controls.
Employing a modification of previously described methods [11], we utilized a fluorescent Hpa II/PCR assay of the androgen receptor (AR) locus to assess X-chromosome inactivation patterns. The AR gene contains a polymorphic CAG repeat, which is flanked by Hpa II sites. These Hpa II sites are methylated on the inactive X chromosome, and are unmethylated on the active X chromosome. By performing PCR amplification across this region after cutting with the methylation-sensitive enzyme Hpa II, the relative amounts of the methylated AR alleles can be quantitatively determined with a high degree of accuracy; variance on repeated assays is approximately 4% [12].
Skewing of X-chromosome inactivation is expressed as percentage deviation from equal (50:50) inactivation of the upper and lower AR alleles. Therefore, the maximal possible deviation is 50%, in which case all of the X chromosomes bearing one of the AR alleles are inactivated.
Results:
We examined X-chromosome inactivation patterns in several different populations. The results are summarized in Fig. 1. A wide range of X-inactivation skewing was observed in all five groups. Approximately 5% (nine out of 197) of individuals exhibited extreme skewing (greater than 40% deviation from a 50:50 distribution). However, there was no difference between the groups, either in the overall mean skewing, or in the fraction of individuals with extreme skewing (>40%).
Although the present study was not initiated in order to examine allelic variation in the AR gene per se, the data provide an opportunity to address this question. Excessively long CAG repeats in the AR are a rare cause of spinal-bulbar muscular atrophy [13], and AR repeat length appears to have an influence on the biology of certain tumors [14,15]. In this context, it has been shown that transcription of AR correlates inversely with repeat length [16]. We therefore compared AR repeat length in control individuals and patients with autoimmunity. No differences were observed for mean repeat length, or for maximum and minimum repeat length, among the five groups.
Discussion:
The reason for the female predominance in most autoimmune diseases remains obscure. The present study was initiated in order to address the hypothesis that a nonhormonal mechanism related to X inactivation might be involved. The hypothesis rests on the idea that skewing of X inactivation might lead to a deficiency of tolerance induction in the thymus, particularly with respect to polymorphic X-linked autoantigens. The hypothesis predicts that skewed X inactivation would be more prevalent in females with autoimmune diseases than in female control individuals. This was not observed.
Nevertheless, these negative data do not rule out a role for X inactivation in female predisposition to loss of tolerance. A general model for how this mechanism might operate is shown in Fig. 2. Thymocytes undergo selection in the thymic parenchyma and, in the case of negative selection, the selecting elements appear to be derived from the bone marrow and consist mainly of thymic dendritic cells. If the thymic dendritic cell population exhibits random X inactivation, it is highly likely that differentiating thymocytes will contact dendritic cells that express self-antigens on both X chromosomes. This situation is outlined schematically on the left side of Fig. 2. However, if there is extremely skewed X inactivation in the thymic dendritic cell population, a particular thymocyte might not come into contact with dendritic cells that express one of the two X chormosomes. This would lead to a situation where T cells may undergo thymic maturation without having been negatively selected for antigens that are expressed on the predominantly inactive X chromosome. This situation is shown on the right side of Fig. 2.
In order for this mechanism to be physiologically relevant, some assumptions must be made. First, defective tolerance from skewed X inactivation should only be directed at X-linked antigens that are polymorphic, and for which the individual is heterozygous. Thus, this mechanism would not be expected to lead to lack of tolerance commonly, unless there are at least several highly polymorphic X-linked autoantigens in the population that are involved in thymic deletion events. Second, if this actually leads to autoimmunity, it also predicts that the initial break in tolerance that leads to disease should involve an X-linked autoantigen that is expressed in a peripheral nontolerizing site or circumstance.
A recent report [7] has elegantly demonstrated the importance of thymic deletion events in predisposition to autoimmune disease. The proteolipid protein (PLP) autoantigen is expressed in alternatively spliced forms, which exhibit tissue specific expression. A nonspliced variant is expressed in peripheral neural tissue. However, in the thymus a splice variant results in the lack of thymic expression of an immunodominant peptide. This results in loss of tolerace of T cells to this peptide, presumably on the basis of lack of thymic deletion of thymocytes that are reactive with this antigen. Interestingly, PLP is encoded on the X chromsome. However, there is no evidence that genetic polymorphisms control the level splicing of PLP within the thymus. Nevertheless, these data illustrate the potential importance of deficiencies in thymic deletion for autoimmune T-cell reactivity.
The present results suggest that if skewed X inactivation is relevant to thymic tolerance induction, then the effect does not depend on global skewing of X-chromosome inactivation, at least in the hematopoietic compartment. In this study we examined X-inactivation patterns in peripheral blood mononuclear cells, and the results should reflect the state of X inactivation in all mesenchymal tissues, including dendritic cells. X inactivation occurs at a very early time point in development, and thus the results in one tissue should reflect the general situation in the rest of the body. However, there may be exceptions to this. We have occasionally observed differences in X-inactivation patterns between buccal mucosa (an ectodermally derived tissue) and peripheral blood in the same individiual (unpublished observations). This could be a chance event, or it may result from selection for certain X-linked alleles during embryonic development, as has been described in carriers of X-linked immunodeficiencies [17].
Another consideration is that certain tissue microenvironments may be derived from very small numbers of founder cells, and thus may exhibit skewed utilization of one or the other X chromosome, even if the tissue as a whole is not skewed. This situation could vary over time. Thus, there may be time points at which certain thymic microenvironments are populated by dendritic cells that, for stochastic reasons, all utilize the same X chromosome. This would create a `window of opportunity' in which a given thymocyte, in a given selecting location, could escape negative selection by antigens on the inactive X chromosome. The likelihood of this happening would obviously depend on the number of dendritic cells that are usually contacted by a thymocyte during thymic selection. There is limited information on this point, although Stewart [10] has theorized that this number may be as low as 15. If this is the case, then escape from thymic deletion may still occur in females who are heterozygous for a relevant X-linked antigen, even if the hematopoietic cells in general do not exhibit extreme skewing.
In conclusion, we suggest that X-chromosome inactivation needs to be considered as a potential factor in the predominance of females in most autoimmune diseases. Our inability to show an increase in X-chromosome skewing in females with autoimmunity does not eliminate this as an etiologic contributor to loss of immunologic tolerance. Future experiments must be directed at a detailed analysis of tissue patterns of X inactivation, as well as at a search for potential X-linked autoantigens.
PMCID: PMC17816  PMID: 11056674
autoimmunity; gender; immune tolerance; X chromosome
21.  Genomic and Functional Studies of Drosophila Sex Hierarchy Regulated Gene Expression in Adult Head and Nervous System Tissues 
PLoS Genetics  2007;3(11):e216.
The Drosophila sex determination hierarchy controls all aspects of somatic sexual differentiation, including sex-specific differences in adult morphology and behavior. To gain insight into the molecular-genetic specification of reproductive behaviors and physiology, we identified genes expressed in the adult head and central nervous system that are regulated downstream of sex-specific transcription factors encoded by doublesex (dsx) and fruitless (fru). We used a microarray approach and identified 54 genes regulated downstream of dsx. Furthermore, based on these expression studies we identified new modes of DSX-regulated gene expression. We also identified 90 and 26 genes regulated in the adult head and central nervous system tissues, respectively, downstream of the sex-specific transcription factors encoded by fru. In addition, we present molecular-genetic analyses of two genes identified in our studies, calphotin (cpn) and defective proboscis extension response (dpr), and begin to describe their functional roles in male behaviors. We show that dpr and dpr-expressing cells are required for the proper timing of male courtship behaviors.
Author Summary
The fruit fly Drosophila is an excellent model system to use to understand the molecular-genetic basis of male courtship behavior, as the potential for this behavior is specified by a well-understood genetic regulatory hierarchy, called the sex determination hierarchy. The sex hierarchy consists of a pre-mRNA splicing cascade that culminates in the production of sex-specific transcription factors, encoded by doublesex (dsx) and fruitless (fru). dsx specifies all the anatomical differences between the sexes, and fru is required for all aspects of male courtship behavior. In this study, we measure gene expression differences between males and females, and between sex hierarchy mutants and wild-type animals, to identify genes that underlie the differences between males and females. We have performed these studies on adult head and nervous system tissues, as these tissues are important for establishing the potential for behaviors. We have identified several genes regulated downstream of dsx and fru and more extensively characterized two genes that are more highly expressed in males. One gene regulated downstream of dsx is expressed in the retina and is known to have a function in visual transduction. The other gene, regulated downstream of fru, plays a role in the timing of male courtship behavior.
doi:10.1371/journal.pgen.0030216
PMCID: PMC2082469  PMID: 18039034
22.  Analysis of Complex Patterns of Human Exposure and Immunity to Schistosomiasis mansoni: The Influence of Age, Sex, Ethnicity and IgE 
Background
Numerous factors may influence Schistosoma infection intensity and prevalence within endemic communities, including exposure-related factors such as local environment and behaviour, and factors relating to susceptibility to infection such as immunology and genetics. While animal studies performed in the laboratory can be tightly controlled, human populations are highly heterogeneous, varying according to demographic characteristics, genetic background and exposure to infection. The heterogeneous nature of human water contact behaviour in particular makes it difficult to distinguish between a lack of cercarial exposure and reduced susceptibility to infection as the cause for low levels of infection in the field.
Methods and Principal Findings
In this study we investigate risk factors for Schistosoma mansoni infection in a rural Ugandan fishing community receiving treatment as part of a multi-disciplinary longitudinal reinfection study. More specifically, we examine the influence that age, sex and ethnic background have on susceptibility to reinfection after anti-helminth drug treatment, but use individual estimates of cercarial exposure and multivariable methods in an attempt to remove noise created by environmental and behavioural heterogeneities. We then investigate whether schistosome-specific IgE immune responses could account for any remaining variations in susceptibility to reinfection. Our findings suggest that observed ethnic- and sex-related variations in S. mansoni reinfection were due to variations in cercarial exposure, as opposed to biological differences in susceptibility to infection. Age-related differences in reinfection were not explained by exposure, however, and appeared linked to the balance of IgE and IgG4 to the tegumental antigen SmTAL1 (formerly Sm22.6), which itself was significantly related to resistance to reinfection.
Conclusions
This study highlights the benefit of taking a multidisciplinary approach in complex field settings; it allows the ecology of a population to be understood and thus more robust conclusions to be made.
Author Summary
Human schistosomiasis is a chronic parasitic disease affecting around 200 million people worldwide. Infection occurs when cercariae penetrate the skin during water contact. Although there is effective treatment for schistosomiasis, individuals remain susceptible to reinfection after treatment; some individuals, however, appear more susceptible to reinfection than others. The highly heterogeneous nature of human water contact behaviour makes it difficult to identify whether low levels of reinfection are caused by immunity or a simple lack of cercarial exposure; this complicates the characterisation of risk factors for infection and immune correlates of protection. Here, we take a multidisciplinary approach using individual estimates of cercarial exposure and multivariable analysis to allow for environmental and behavioural heterogeneities. We examine the influence of demographic factors and antibody responses on susceptibility to reinfection. While observed ethnic- and sex-related variations in Schistosoma mansoni reinfection could be explained by differences in exposure, age-related differences appeared linked to the balance of specific IgE and IgG4 antibodies, themselves related to resistance to reinfection. Our study highlights the benefits of a multidisciplinary approach in complex field settings: it improves our understanding of a population's ecology and therefore the biology of disease.
doi:10.1371/journal.pntd.0000820
PMCID: PMC2939029  PMID: 20856909
23.  Sex and Death: The Effects of Innate Immune Factors on the Sexual Reproduction of Malaria Parasites 
PLoS Pathogens  2011;7(3):e1001309.
Malaria parasites must undergo a round of sexual reproduction in the blood meal of a mosquito vector to be transmitted between hosts. Developing a transmission-blocking intervention to prevent parasites from mating is a major goal of biomedicine, but its effectiveness could be compromised if parasites can compensate by simply adjusting their sex allocation strategies. Recently, the application of evolutionary theory for sex allocation has been supported by experiments demonstrating that malaria parasites adjust their sex ratios in response to infection genetic diversity, precisely as predicted. Theory also predicts that parasites should adjust sex allocation in response to host immunity. Whilst data are supportive, the assumptions underlying this prediction – that host immune responses have differential effects on the mating ability of males and females – have not yet been tested. Here, we combine experimental work with theoretical models in order to investigate whether the development and fertility of male and female parasites is affected by innate immune factors and develop new theory to predict how parasites' sex allocation strategies should evolve in response to the observed effects. Specifically, we demonstrate that reactive nitrogen species impair gametogenesis of males only, but reduce the fertility of both male and female gametes. In contrast, tumour necrosis factor-α does not influence gametogenesis in either sex but impairs zygote development. Therefore, our experiments demonstrate that immune factors have complex effects on each sex, ranging from reducing the ability of gametocytes to develop into gametes, to affecting the viability of offspring. We incorporate these results into theory to predict how the evolutionary trajectories of parasite sex ratio strategies are shaped by sex differences in gamete production, fertility and offspring development. We show that medical interventions targeting offspring development are more likely to be ‘evolution-proof’ than interventions directed at killing males or females. Given the drive to develop medical interventions that interfere with parasite mating, our data and theoretical models have important implications.
Author Summary
Malaria and related parasites cause some of the most serious infectious diseases of humans, domestic animals and wildlife. To be transmitted, these parasites produce male and female sexual stages that differentiate into gametes and mate when taken up in a mosquito blood meal. Despite the need to develop a transmission-blocking intervention, remarkably little is understood about the evolution of parasite mating strategies. However, recent research demonstrates that producing the right ratio of male to female stages is central to mating success. Evolutionary theory predicts that sex ratios are adjusted in line with a variety of factors that affect mating success, including host immunity. We test this theory by investigating whether ubiquitous immune factors differentially affect the production and fertility of males and females. Our experiments demonstrate that immune factors have complex, sex-specific effects, from reducing gamete production to affecting offspring viability. We use these results to generate theory predicting how such effects shape the evolutionary trajectories of parasite sex ratio strategies. Given the drive to develop medical interventions that prevent transmission by blocking parasite mating, our results have important implications. Specifically, we suggest that medical interventions targeting offspring development are more likely to be ‘evolution-proof’ than interventions with sex-specific effects.
doi:10.1371/journal.ppat.1001309
PMCID: PMC3048364  PMID: 21408620
24.  Cancer Pharmacogenomics and Pharmacoepidemiology: Setting a Research Agenda to Accelerate Translation 
Recent advances in genomic research have demonstrated a substantial role for genomic factors in predicting response to cancer therapies. Researchers in the fields of cancer pharmacogenomics and pharmacoepidemiology seek to understand why individuals respond differently to drug therapy, in terms of both adverse effects and treatment efficacy. To identify research priorities as well as the resources and infrastructure needed to advance these fields, the National Cancer Institute (NCI) sponsored a workshop titled “Cancer Pharmacogenomics: Setting a Research Agenda to Accelerate Translation” on July 21, 2009, in Bethesda, MD. In this commentary, we summarize and discuss five science-based recommendations and four infrastructure-based recommendations that were identified as a result of discussions held during this workshop. Key recommendations include 1) supporting the routine collection of germline and tumor biospecimens in NCI-sponsored clinical trials and in some observational and population-based studies; 2) incorporating pharmacogenomic markers into clinical trials; 3) addressing the ethical, legal, social, and biospecimen- and data-sharing implications of pharmacogenomic and pharmacoepidemiologic research; and 4) establishing partnerships across NCI, with other federal agencies, and with industry. Together, these recommendations will facilitate the discovery and validation of clinical, sociodemographic, lifestyle, and genomic markers related to cancer treatment response and adverse events, and they will improve both the speed and efficiency by which new pharmacogenomic and pharmacoepidemiologic information is translated into clinical practice.
doi:10.1093/jnci/djq390
PMCID: PMC2982809  PMID: 20944079
25.  The Weaker Sex? The Propensity for Male-Biased Piglet Mortality 
PLoS ONE  2012;7(1):e30318.
For the most part solutions to farm animal welfare issues, such as piglet mortality, are likely to lie within the scientific disciplines of environmental design and genetic selection, however understanding the ecological basis of some of the complex dynamics observed between parent and offspring could make a valuable contribution. One interesting, and often discussed, aspect of mortality is the propensity for it to be sex-biased. This study investigated whether known physiological and behavioural indicators of piglet survival differed between the sexes and whether life history strategies (often reported in wild or feral populations) relating to parental investment were being displayed in a domestic population of pigs. Sex ratio (proportion of males (males/males+females)) at birth was 0.54 and sex allocation (maternal investment measured as piglet birth weight/litter weight) was statistically significantly male-biased at 0.55 (t35 = 2.51 P = 0.017), suggesting that sows invested more in sons than daughters during gestation. Despite this investment in birth weight, a known survival indicator, total pre-weaning male mortality was statistically significantly higher than female mortality (12% vs. 7% respectively z = 2.06 P = 0.040). Males tended to suffer from crushing by the sow more than females and statistically significantly more males died from disease-related causes. Although males were born on average heavier, with higher body mass index and ponderal index, these differences were not sustained. In addition male piglets showed impaired thermoregulation compared to females. These results suggest male-biased mortality exists despite greater initial maternal investment, and therefore reflects the greater susceptibility of this sex to causal mortality factors. Life history strategies are being displayed by a domestic population of pigs with sows in this study displaying a form of parental optimism by allocating greater resources at birth to males and providing an over-supply of this more vulnerable sex in expectation of sex-biased mortality.
doi:10.1371/journal.pone.0030318
PMCID: PMC3260262  PMID: 22272334

Results 1-25 (1574057)