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1.  Steroids, sex and the cerebellar cortex: implications for human disease 
Cerebellum (London, England)  2008;7(1):38-47.
Neurosteroids play an important role in the development of the cerebellum. In particular, estradiol and progesterone appear capable of inducing increases in dendritic spine density during development, and there is evidence that both are synthesized de novo in the cerebellum during critical developmental periods. In normal neonates and adults, there are few differences in the cerebellum between the sexes and most studies indicate that hormone and receptor levels also do not differ significantly during development. However, the sexes do differ significantly in risk of neuropsychological diseases associated with cerebellar pathology, and in animal models there are noticeable sex differences in the response to insult and genetic mutation. In both humans and animals, males tend to fare worse. Boys are more at risk for autism and Attention Deficit Hyperactivity Disorder than girls, and schizophrenia manifests at an earlier age in men. In rats males fare worse than females after perinatal exposure to polychlorinated biphenyls, and male mice heterozygous for the staggerer and reeler mutation show a more severe phenotype. Although very recent evidence suggests that differences in neurosteroid levels between the sexes in diseased animals may play a role in generating different disease phenotypes, the reason this hormonal difference occurs in diseased but not normal animals is currently unknown.
doi:10.1007/s12311-008-0003-6
PMCID: PMC2736099  PMID: 18418672
Neurosteroids; cerebellum; neuropsychological diseases; gender
2.  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
3.  Men: good health and high mortality. Sex differences in health and aging* 
This review examines sex differences in health and survival, with a focus on the Nordic countries. There is a remarkable discrepancy between the health and survival of the sexes: men are physically stronger and have fewer disabilities, but have substantially higher mortality at all ages compared with women: the so-called male-female health-survival paradox. A number of proposed explanations for this paradox are rooted in biological, social, and psychological interpretations. It is likely to be due to multiple causes that include fundamental biological differences between the sexes such as genetic factors, immune system responses, hormones, and disease patterns. Behavioral differences such as risk-taking and reluctance to seek and comply with medical treatment may also play a role. Another consideration is that part of the difference may be due to methodological challenges, such as selective non-participation and under-reporting of health problems, and delayed seeking of treatment by men. The Nordic countries provide a unique opportunity for such studies, as theyhave good-quality data in their national health registers, which cover the whole population, and a long tradition of high participation rates in surveys.
PMCID: PMC3629373  PMID: 18431075
Health; mortality; Nordic countries; review; sex differences
4.  The impact of sex, gender and pregnancy on 2009 H1N1 disease 
Children and young adults of reproductive age have emerged as groups that are highly vulnerable to the current 2009 H1N1 pandemic. The sex of an individual is a fundamental factor that can influence exposure, susceptibility and immune responses to influenza. Worldwide, the incidence, disease burden, morbidity and mortality rates following exposure to the 2009 H1N1 influenza virus differ between males and females and are often age-dependent. Pregnancy and differences in the presentation of various risk factors contribute to the worse outcome of infection in women. Vaccination and antiviral treatment efficacy also vary in a sex-dependent manner. Finally, sex-specific genetic and hormonal differences may contribute to the severity of influenza and the clearance of viral infection. The contribution of sex and gender to influenza can only be determined by a greater consideration of these factors in clinical and epidemiological studies and increased research into the biological basis underlying these differences.
doi:10.1186/2042-6410-1-5
PMCID: PMC3010100  PMID: 21208468
5.  Influence of sex differences on microRNA gene regulation in disease 
Sexual dimorphism is observed in most human diseases. The difference in the physiology and genetics between sexes can contribute tremendously to the disease prevalence, severity, and outcome. Both hormonal and genetic differences between males and females can lead to differences in gene expression patterns that can influence disease risk and course. MicroRNAs have emerged as potential regulatory molecules in all organisms. They can have a broad effect on every aspect of physiology, including embryogenesis, metabolism, and growth and development. Numerous microRNAs have been identified and elucidated to play a key role in cardiovascular diseases, as well as in neurological and autoimmune disorders. This is especially important as microRNA-based tools can be exploited as beneficial therapies for disease treatment and prevention. Sex steroid hormones as well as X-linked genes can have a considerable influence on the regulation of microRNAs. However, there are very few studies highlighting the role of microRNAs in sex biased diseases. This review attempts to summarize differentially regulated microRNAs in males versus females in different diseases and calls for more attention in this underexplored area that should set the basis for more effective therapeutic strategies for sexually dimorphic diseases.
doi:10.1186/2042-6410-5-3
PMCID: PMC3912347  PMID: 24484532
6.  Sex differences in kidney gene expression during the life cycle of F344 rats 
Background
The kidney functions in key physiological processes to filter blood and regulate blood pressure via key molecular transporters and ion channels. Sex-specific differences have been observed in renal disease incidence and progression, as well as acute kidney injury in response to certain drugs. Although advances have been made in characterizing the molecular components involved in various kidney functions, the molecular mechanisms responsible for sex differences are not well understood. We hypothesized that the basal expression levels of genes involved in various kidney functions throughout the life cycle will influence sex-specific susceptibilities to adverse renal events.
Methods
Whole genome microarray gene expression analysis was performed on kidney samples collected from untreated male and female Fischer 344 (F344) rats at eight age groups between 2 and 104 weeks of age.
Results
A combined filtering approach using statistical (ANOVA or pairwise t test, FDR 0.05) and fold-change criteria (>1.5 relative fold change) was used to identify 7,447 unique differentially expressed genes (DEGs). Principal component analysis (PCA) of the 7,447 DEGs revealed sex-related differences in mRNA expression at early (2 weeks), middle (8, 15, and 21 weeks), and late (104 weeks) ages in the rat life cycle. Functional analysis (Ingenuity Pathway Analysis) of these sex-different genes indicated over-representation of specific pathways and networks including renal tubule injury, drug metabolism, and immune cell and inflammatory responses. The mRNAs that code for the qualified urinary protein kidney biomarkers KIM-1, Clu, Tff3, and Lcn2 were also observed to show sex differences.
Conclusions
These data represent one of the most comprehensive in-life time course studies to be published, assessing sex differences in global gene expression in the F344 rat kidney. PCA and Venn analyses reveal specific periods of sexually dimorphic gene expression which are associated with functional categories (xenobiotic metabolism and immune cell and inflammatory responses) of key relevance to acute kidney injury and chronic kidney disease, which may underlie sex-specific susceptibility. Analysis of the basal gene expression patterns of renal genes throughout the life cycle of the rat will improve the use of current and future renal biomarkers and inform our assessments of kidney injury and disease.
doi:10.1186/2042-6410-4-14
PMCID: PMC3844475  PMID: 23902594
Kidney; Gene expression; Sex; Age; Biomarker
7.  Requirement of Male-Specific Dosage Compensation in Drosophila Females—Implications of Early X Chromosome Gene Expression 
PLoS Genetics  2010;6(7):e1001041.
Dosage compensation equates between the sexes the gene dose of sex chromosomes that carry substantially different gene content. In Drosophila, the single male X chromosome is hypertranscribed by approximately two-fold to effect this correction. The key genes are male lethal and appear not to be required in females, or affect their viability. Here, we show these male lethals do in fact have a role in females, and they participate in the very process which will eventually shut down their function—female determination. We find the male dosage compensation complex is required for upregulating transcription of the sex determination master switch, Sex-lethal, an X-linked gene which is specifically activated in females in response to their two X chromosomes. The levels of some X-linked genes are also affected, and some of these genes are used in the process of counting the number of X chromosomes early in development. Our data suggest that before the female state is set, the ground state is male and female X chromosome expression is elevated. Females thus utilize the male dosage compensation process to amplify the signal which determines their fate.
Author Summary
When substantially different, sex chromosomes present the challenge of not only gene dose inequity between the sexes, in the heterogametic sex where one chromosome (frequently the Y) carries few genes, but also an inequity relative to the autosomes which are diploid. Dosage compensation refers to the process which equates gene dose between the sexes. Recent results, however, indicate that the mammalian X chromosome avoids monosomy and has a level of expression that is two-fold relative to the autosomes. Hyperactive X chromosome expression in Caenorhabditis elegans has also been suggested, and dosage compensation in the hermaphrodite appears to lower expression of the X chromosomes to match autosome levels. We find that, before the female state is set in Drosophila, the X chromosomes may also express their genes at the two-fold male level and that this level of expression is used to female advantage to consolidate their sex determination. Together, the results suggest that elevated X chromosome expression may be the norm, and that the various dosage compensation processes different organisms utilize reflect a mechanism to counteract an initial hyperactive X chromosome state.
doi:10.1371/journal.pgen.1001041
PMCID: PMC2912388  PMID: 20686653
8.  Sex-biased chromatin and regulatory cross-talk between sex chromosomes, autosomes, and mitochondria 
Several autoimmune and neurological diseases exhibit a sex bias, but discerning the causes and mechanisms of these biases has been challenging. Sex differences begin to manifest themselves in early embryonic development, and gonadal differentiation further bifurcates the male and female phenotypes. Even at this early stage, however, there is evidence that males and females respond to environmental stimuli differently, and the divergent phenotypic responses may have consequences later in life. The effect of prenatal nutrient restriction illustrates this point, as adult women exposed to prenatal restrictions exhibited increased risk factors of cardiovascular disease, while men exposed to the same condition did not. Recent research has examined the roles of sex-specific genes, hormones, chromosomes, and the interactions among them in mediating sex-biased phenotypes. Such research has identified testosterone, for example, as a possible protective agent against autoimmune disorders and an XX chromosome complement as a susceptibility factor in murine models of lupus and multiple sclerosis. Sex-biased chromatin is an additional and likely important component. Research suggesting a role for X and Y chromosome heterochromatin in regulating epigenetic states of autosomes has highlighted unorthodox mechanisms of gene regulation. The crosstalk between the Y chromosomes and autosomes may be further mediated by the mitochondria. The organelles have solely maternal transmission and exert differential effects on males and females. Altogether, research supports the notion that the interaction between sex-biased elements might exert novel regulatory functions in the genome and contribute to sex-specific susceptibilities to autoimmune and neurological diseases.
doi:10.1186/2042-6410-5-2
PMCID: PMC3907150  PMID: 24422881
Gene expression regulation; Drosophila; Sexual dimorphisms; Sex chromosomes; Heterochromatin; Y chromosome; X chromosome; Sex difference
9.  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
10.  Estrogen regulation of protein expression and signaling pathways in the heart 
Sex differences in cardiovascular disease and cardiac physiology have been reported in humans as well as in animal models. Premenopausal women have reduced cardiovascular disease compared to men, but the incidence of cardiovascular disease in women increases following menopause. Sex differences in cardiomyocytes likely contribute to the differences in male–female physiology and response to disease. Sex differences in the heart have been noted in electrophysiology, contractility, signaling, metabolism, and cardioprotection. These differences appear to be due, at least in part, to differences in gene and protein expression as well as in posttranslational protein modifications. This review will focus primarily on estrogen-mediated male–female differences in protein expression and signaling pathways in the heart and cardiac cells. It should be emphasized that these basic differences are not intrinsically beneficial or detrimental per se; the difference can be good or bad depending on the context and circumstances.
doi:10.1186/2042-6410-5-6
PMCID: PMC3975301  PMID: 24612699
Cardiac; Estrogen; Ischemia-reperfusion; Metabolism
11.  Inheritance of Telomere Length in a Bird 
PLoS ONE  2011;6(2):e17199.
Telomere dynamics are intensively studied in human ageing research and epidemiology, with many correlations reported between telomere length and age-related diseases, cancer and death. While telomere length is influenced by environmental factors there is also good evidence for a strong heritable component. In human, the mode of telomere length inheritance appears to be paternal and telomere length differs between sexes, with females having longer telomeres than males. Genetic factors, e.g. sex chromosomal inactivation, and non-genetic factors, e.g. antioxidant properties of oestrogen, have been suggested as possible explanations for these sex-specific telomere inheritance and telomere length differences. To test the influence of sex chromosomes on telomere length, we investigated inheritance and sex-specificity of telomere length in a bird species, the kakapo (Strigops habroptilus), in which females are the heterogametic sex (ZW) and males are the homogametic (ZZ) sex. We found that, contrary to findings in humans, telomere length was maternally inherited and also longer in males. These results argue against an effect of sex hormones on telomere length and suggest that factors associated with heterogamy may play a role in telomere inheritance and sex-specific differences in telomere length.
doi:10.1371/journal.pone.0017199
PMCID: PMC3043093  PMID: 21364951
12.  Hormonal Influences on Lung Function and Response to Environmental Agents 
Numerous studies in humans and experimental animals have identified considerable sex differences in respiratory physiology and in the response of the lung to environmental agents. These differences appear to be mediated, at least in part, by sex hormones and their nuclear receptors. Moreover, animal models are increasingly used to study pathogenic mechanisms and test potential therapies for a variety of human lung diseases, many of which appear to be influenced by sex and sex hormones. In this article, data are summarized from studies of lung function and disease in which sex differences have been observed. Specific attention is paid to animal models of acute lung injury, nonallergic and allergic lung inflammation, and lung fibrosis. It is anticipated that continued investigation of the role of sex and sex hormones in animal models will provide valuable insight into the pathogenesis and potential treatments for a variety of acute and chronic human lung diseases.
doi:10.1513/pats.200904-020RM
PMCID: PMC3266051  PMID: 19934354
sex; sex hormones; respiratory mechanics; inflammation; airway
13.  Male Sex Hormones Exacerbate Lung Function Impairment after Bleomycin-Induced Pulmonary Fibrosis 
The roles of sex hormones as modulators of lung function and disease have received significant attention as differential sex responses to various lung insults have been recently reported. The present study used a bleomycin-induced pulmonary fibrosis model in C57BL/6 mice to examine potential sex differences in physiological and pathological outcomes. Endpoints measured included invasive lung function assessment, immunological response, lung collagen deposition, and a quantitative histological analysis of pulmonary fibrosis. Male mice had significantly higher basal static lung compliance than female mice (P < 0.05) and a more pronounced decline in static compliance after bleomycin administration when expressed as overall change or percentage of baseline change (P < 0.05). In contrast, there were no significant differences between the sexes in immune cell infiltration into the lung or in total lung collagen content after bleomycin. Total lung histopathology scores measured using the Ashcroft method did not differ between the sexes, while a quantitative histopathology scoring system designed to determine where within the lung the fibrosis occurred indicated a tendency toward more fibrosis immediately adjacent to airways in bleomycin-treated male versus female mice. Furthermore, castrated male mice exhibited a female-like response to bleomycin while female mice given exogenous androgen exhibited a male-like response. These data indicate that androgens play an exacerbating role in decreased lung function after bleomycin administration, and traditional measures of fibrosis may miss critical differences in lung function between the sexes. Sex differences should be carefully considered when designing and interpreting experimental models of pulmonary fibrosis in mice.
doi:10.1165/rcmb.2007-0340OC
PMCID: PMC2438447  PMID: 18276795
fibrosis; bleomycin; sex; respiratory mechanics
14.  Pharmacogenomics: Application to the Management of Cardiovascular Disease 
The past decade has seen substantial advances in cardiovascular pharmacogenomics. Genetic determinants of response to clopidogrel and warfarin have been defined, resulting in changes to the product labels for these drugs that suggest the use of genetic information as a guide for therapy. Genetic tests are available, as are guidelines for incorporation of genetic information into patient-care decisions. These guidelines and the literature supporting them are reviewed herein. Significant advances have also been made in the pharmacogenomics of statin-induced myopathy and the response to β-blockers in heart failure, although the clinical applications of these findings are less clear. Other areas hold promise, including the pharmacogenomics of antihypertensive drugs, aspirin, and drug-induced long-QT syndrome (diLQTS). The potential value of pharmacogenomics in the discovery and development of new drugs is also described. In summary, pharmacogenomics has current applications in the management of cardiovascular disease, with clinically relevant data continuing to mount.
doi:10.1038/clpt.2011.179
PMCID: PMC3190669  PMID: 21918509
15.  Sex chromosomes and male ornaments: a comparative evaluation in ray-finned fishes 
Theory predicts that the mechanism of genetic sex determination can substantially influence the evolution of sexually selected traits. For example, female heterogamety (ZZ/ZW) can favour the evolution of extreme male traits under Fisher's runaway model of sexual selection. We empirically test whether the genetic system of sex determination has played a role in the evolution of exaggerated male ornaments in actinopterygiian fishes, a clade in which both female-heterogametic and male-heterogametic systems of sex determination have evolved multiple times. Using comparative methods both uncorrected and corrected for phylogenetic non-independence, we detected no significant correlation between sex-chromosome systems and sexually selected traits in males. Results suggest that sex-determination mechanism is at best a relatively minor factor affecting the outcomes of sexual selection in ray-finned fishes.
doi:10.1098/rspb.2005.3334
PMCID: PMC1560031  PMID: 16555792
female preference; genetic sex determination; secondary sexual characters
16.  Balancing sex chromosome expression and satisfying the sexes 
Fly  2012;6(1):26-29.
Equalizing sex chromosome expression between the sexes when they have largely differing gene content appears to be necessary, and across species, is accomplished in a variety of ways. Even in birds, where the process is less than complete,1 a mechanism to reduce the difference in gene dose between the sexes exists. In early development, while the dosage difference is unregulated and still in flux, it is frequently exploited by sex determination mechanisms. The Drosophila female sex determination process is one clear example, determining the sexes based on X chromosome dose. Recent data show that in Drosophila, the female sex not only reads this gene balance difference, but at the same time usurps the moment. Taking advantage of the transient default state of male dosage compensation, the sex determination master-switch Sex-lethal which resides on the X, has its expression levels enhanced before it works to correct the gene imbalance.2 Intriguingly, key developmental genes which could create developmental havoc if their levels were unbalanced show more exquisite regulation,3 suggesting nature distinguishes them and ensures their expression is kept in the desirable range.
doi:10.4161/fly.18822
PMCID: PMC3365834  PMID: 22388008
dosage compensation; Drosophila; male-specific lethals; sex determination; Sex-lethal; X chromosome
17.  Male/Female Differences in Neuroprotection and Neuromodulation of Brain Dopamine 
The existence of a sex difference in Parkinson’s disease (PD) is observed as related to several variables, including susceptibility of the disease, age at onset, and symptoms. These differences between men and women represent a significant characteristic of PD, which suggest that estrogens may exert beneficial effects against the development and the progression of the disease. This paper reviews the neuroprotective and neuromodulator effects of 17β-estradiol and progesterone as compared to androgens in the nigrostriatal dopaminergic (NSDA) system of both female and male rodents. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice model of PD and methamphetamine toxicity faithfully reproduce the sex differences of PD in that endogenous estrogen levels appear to influence the vulnerability to toxins targeting the NSDA system. Exogenous 17β-estradiol and/or progesterone treatments show neuroprotective properties against NSDA toxins while androgens fail to induce any beneficial effect. Sex steroid treatments show male and female differences in their neuroprotective action against methamphetamine toxicity. NSDA structure and function, as well as the distribution of estrogen receptors, show sex differences and may influence the susceptibility to the toxins and the response to sex steroids. Genomic and non-genomic actions of 17β-estradiol converge to promote survival factors and the presence of both estrogen receptors α and β are critical to 17β-estradiol neuroprotective action against MPTP toxicity.
doi:10.3389/fendo.2011.00035
PMCID: PMC3356083  PMID: 22654803
17β-estradiol; androgens; dopamine; neuroprotection; neuromodulation; sex difference; MPTP; methamphetamine
18.  Pharmacogenetics and Pharmacogenomics of Anticancer Agents 
Large interindividual variation is observed in both the response and toxicity associated with anticancer therapy. The etiology of this variation is multifactorial, but is due in part to host genetic variations. Pharmacogenetic and pharmacogenomic studies have successfully identified genetic variants that contribute to this variation in susceptibility to chemotherapy. This review provides an overview of the progress made in the field of pharmacogenetics and pharmacogenomics using a five-stage architecture, which includes 1) determining the role of genetics in drug response; 2) screening and identifying genetic markers; 3) validating genetic markers; 4) clinical utility assessment; and 5) pharmacoeconomic impact. Examples are provided to illustrate the identification, validation, utility, and challenges of these pharmacogenetic and pharmacogenomic markers, with the focus on the current application of this knowledge in cancer therapy. With the advance of technology, it becomes feasible to evaluate the human genome in a relatively inexpensive and efficient manner; however, extensive pharmacogenetic research and education are urgently needed to improve the translation of pharmacogenetic concepts from bench to bedside.
doi:10.3322/caac.20002
PMCID: PMC3109906  PMID: 19147868
19.  Emerging role of microRNAs in drug response 
Current pharmacogenomic studies have begun to integrate genetics, gene expression and pharmacologic phenotypes. MicroRNAs (miRNAs), small RNAs (21–25 nucleotides) found in almost all metazoan genomes, have been discovered to be a novel class of gene regulators that generally down-regulate gene expression at the post-transcriptional level. Experimental evidence for the roles of miRNAs in regulating pharmacology-related genes and drug response is now accumulating. Given the universal roles of miRNAs in various diseases such as human cancer, their potential effects on therapeutic treatments (e.g., chemotherapy) for these diseases could be expected. The on-going efforts of pharmacogenomics to incorporate miRNAs could provide more insights into the complex phenotype of drug response, though more studies may be necessary to evaluate their effects in patients since most of the current findings are indirect or in vitro.
PMCID: PMC3233195  PMID: 21154161
microRNA; gene expression; gene regulation; drug response; pharmacogene; pharmacogenomics
20.  Systems biology asks new questions about sex differences 
Females and males differ in physiology and in the incidence and progression of diseases. The sex-biased proximate factors causing sex differences in phenotype include direct effects of gonadal hormones and of genes represented unequally in the genome because of their X- or Y-linkage. Novel systems approaches have begun to assess the magnitude and character of sex differences in organization of gene networks on a genome-wide scale. These studies identify functionally related modules of genes that are co-expressed differently in males and females, and sites in the genome that regulate gene networks in a sex-specific manner. The measurement of the aggregate behavior of genes uncovers novel sex differences that can be related more effectively to susceptibility to disease.
doi:10.1016/j.tem.2009.06.007
PMCID: PMC2787703  PMID: 19783453
21.  Analysis of autosomal genes reveals gene–sex interactions and higher total genetic risk in men with systemic lupus erythematosus 
Annals of the Rheumatic Diseases  2011;71(5):694-699.
Objectives
Systemic lupus erythematosus (SLE) is a sexually dimorphic autoimmune disease which is more common in women, but affected men often experience a more severe disease. The genetic basis of sexual dimorphism in SLE is not clearly defined. A study was undertaken to examine sex-specific genetic effects among SLE susceptibility loci.
Methods
A total of 18 autosomal genetic susceptibility loci for SLE were genotyped in a large set of patients with SLE and controls of European descent, consisting of 5932 female and 1495 male samples. Sex-specific genetic association analyses were performed. The sex–gene interaction was further validated using parametric and nonparametric methods. Aggregate differences in sex-specific genetic risk were examined by calculating a cumulative genetic risk score for SLE in each individual and comparing the average genetic risk between male and female patients.
Results
A significantly higher cumulative genetic risk for SLE was observed in men than in women. (P = 4.52×10−8) A significant sex–gene interaction was seen primarily in the human leucocyte antigen (HLA) region but also in IRF5, whereby men with SLE possess a significantly higher frequency of risk alleles than women. The genetic effect observed in KIAA1542 is specific to women with SLE and does not seem to have a role in men.
Conclusions
The data indicate that men require a higher cumulative genetic load than women to develop SLE. These observations suggest that sex bias in autoimmunity could be influenced by autosomal genetic susceptibility loci.
doi:10.1136/annrheumdis-2011-200385
PMCID: PMC3324666  PMID: 22110124
22.  Role of Sex Steroid Hormones in Bacterial-Host Interactions 
BioMed Research International  2012;2013:928290.
Sex steroid hormones play important physiological roles in reproductive and nonreproductive tissues, including immune cells. These hormones exert their functions by binding to either specific intracellular receptors that act as ligand-dependent transcription factors or membrane receptors that stimulate several signal transduction pathways. The elevated susceptibility of males to bacterial infections can be related to the usually lower immune responses presented in males as compared to females. This dimorphic sex difference is mainly due to the differential modulation of the immune system by sex steroid hormones through the control of proinflammatory and anti-inflammatory cytokines expression, as well as Toll-like receptors (TLRs) expression and antibody production. Besides, sex hormones can also affect the metabolism, growth, or virulence of pathogenic bacteria. In turn, pathogenic, microbiota, and environmental bacteria are able to metabolize and degrade steroid hormones and their related compounds. All these data suggest that sex steroid hormones play a key role in the modulation of bacterial-host interactions.
doi:10.1155/2013/928290
PMCID: PMC3591248  PMID: 23509808
23.  Pharmacogenomics in cardiovascular disorders: Steps in approaching personalized medicine in cardiovascular medicine 
Some of the most commonly prescribed medications are those for cardiovascular maladies. The beneficial effects of these medications have been well documented. However, there can be substantial variation in response to these medications among patients, which may be due to genetic variation. For this reason pharmacogenomic studies are emerging across all aspects of cardiovascular medicine. The goal of pharmacogenomics is to tailor treatment to an individual’s genetic makeup in order to improve the benefit-to-risk ratio. This review examines the potential pharmacogenomic parameters which may lead to a future of personalized medicine. For example, it has been found that patients with CYP2C9 and VKORC1 gene variations have a different response to warfarin. Other studies looking at β-blockers, ACE inhibitors, ARBs, diuretics and statins have shown some results linking genetic variations to pharmacologic response. However these studies have not impacted clinical use yet, unlike warfarin findings, as the small retrospective studies need to be followed up by larger prospective studies for definitive results.
PMCID: PMC3513202  PMID: 23226035
cardiovascular; pharmacogenomics; genetics; cardiovascular medicine; personalized medicine; polymorphism
24.  A Sex Difference in Synaptic Efficacy at the Laryngeal Neuromuscular Junction of Xenopus laevis 
Under physiological conditions, the response of Xenopus laevis laryngeal muscle fibers to nerve stimulation is sexually differentiated; subthreshold potentials are common in males and rare in females. This sex difference in muscle fiber response is correlated with sex differences in vocal behavior. Quantal analyses at male and female laryngeal synapses were performed to determine if there is a sex difference in synaptic strength. Quantal content at laryngeal synapses is significantly higher in females than in males. Values for quantal content in males can be increased by raising extracellular calcium concentration. There is no sex difference in miniature endplate potential amplitude suggesting that ACh receptor number or properties are not different in the sexes. Sex differences in synaptic strength thus appear presynaptic in origin; transmitter release is less in males. Ultrastructural analyses of the laryngeal motor terminal indicate that there is no sex difference in the length of active zones or in the number of channels per length of active zone. Thus, ultrastructural characteristics of the laryngeal motor terminal do not account for the pronounced sex difference in quantal content.
PMCID: PMC3493209  PMID: 7891126
active zones; frog; miniature endplate potentials; quantal content; synaptic strength; vocal behavior
25.  Sex differences in primary hypertension 
Men have higher blood pressure than women through much of life regardless of race and ethnicity. This is a robust and highly conserved sex difference that it is also observed across species including dogs, rats, mice and chickens and it is found in induced, genetic and transgenic animal models of hypertension. Not only do the differences between the ovarian and testicular hormonal milieu contribute to this sexual dimorphism in blood pressure, the sex chromosomes also play a role in and of themselves. This review primarily focuses on epidemiological studies of blood pressure in men and women and experimental models of hypertension in both sexes. Gaps in current knowledge regarding what underlie male-female differences in blood pressure control are discussed. Elucidating the mechanisms underlying sex differences in hypertension may lead to the development of anti-hypertensives tailored to one's sex and ultimately to improved therapeutic strategies for treating this disease and preventing its devastating consequences.
doi:10.1186/2042-6410-3-7
PMCID: PMC3331829  PMID: 22417477

Results 1-25 (1195727)