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1.  Predictors of poor response during asthma therapy differ with definition of outcome 
Pharmacogenomics  2009;10(8):1231-1242.
Aims
To evaluate phenotypic and genetic variables associated with a poor long-term response to inhaled corticosteroid therapy for asthma, based independently on lung function changes or asthma exacerbations.
Materials & methods
We tested 17 phenotypic variables and polymorphisms in FCER2 and CRHR1 in 311 children (aged 5–12 years) randomized to a 4-year course of inhaled corticosteroid during the Childhood Asthma Management Program (CAMP).
Results
Predictors of recurrent asthma exacerbations are distinct from predictors of poor lung function response. A history of prior asthma exacerbations, younger age and a higher IgE level (p < 0.05) are associated with recurrent exacerbations. By contrast, lower bronchodilator response to albuterol and the minor alleles of RS242941 in CRHR1 and T2206C in FCER2 (p < 0.05) are associated with poor lung function response. Poor lung function response does not increase the risk of exacerbations and vice versa (p = 0.72).
Conclusion
Genetic and phenotypic predictors of a poor long-term response to inhaled corticosteroids differ markedly depending on definition of outcome (based on exacerbations vs lung function). These findings are important in comparing outcomes of clinical trials and in designing future pharmacogenetic studies.
doi:10.2217/PGS.09.86
PMCID: PMC2746392  PMID: 19663668
asthma; corticosteroid; exacerbation; lung function; pharmacogenetics
2.  Pharmacogenetics of asthma 
Purpose of review
Patient response to the asthma drug classes, bronchodilators, inhaled corticosteroids and leukotriene modifiers, are characterized by a large degree of heterogeneity, which is attributable in part to genetic variation. Herein, we review and update the pharmacogenetics and pharmaogenomics of common asthma drugs.
Recent findings
Early studies suggest that bronchodilator reversibility and asthma worsening in patients on continuous short-acting and long-acting β-agonists are related to the Gly16Arg genotype for the ADRB2. More recent studies including genome-wide association studies implicate variants in other genes contribute to bronchodilator response heterogeneity and fail to replicate asthma worsening associated with continuous β-agonist use. Genetic determinants of the safety of long-acting β-agonist require further study. Variants in CRHR1, TBX21, and FCER2 contribute to variability in response for lung function, airways responsiveness, and exacerbations in patients taking inhaled corticosteroids. Variants in ALOX5, LTA4H, LTC4S, ABCC1, CYSLTR2, and SLCO2B1 contribute to variability in response to leukotriene modifiers.
Summary
Identification of novel variants that contribute to response heterogeneity supports future studies of single nucleotide polymorphism discovery and include gene expression and genome-wide association studies. Statistical models that predict the genomics of response to asthma drugs will complement single nucleotide polymorphism discovery in moving toward personalized medicine.
doi:10.1097/MCP.0b013e32831da8be
PMCID: PMC2754311  PMID: 19077707
asthma; genes; personalized medicine; polymorphisms; response heterogeneity
3.  Genome-wide Association Identifies the T Gene as a Novel Asthma Pharmacogenetic Locus 
Rationale: To date, most studies aimed at discovering genetic factors influencing treatment response in asthma have focused on biologic candidate genes. Genome-wide association studies (GWAS) can rapidly identify novel pharmacogenetic loci.
Objectives: To investigate if GWAS can identify novel pharmacogenetic loci in asthma.
Methods: Using phenotypic and GWAS genotype data available through the NHLBI-funded Single-nucleotide polymorphism Health association-Asthma Resource Project, we analyzed differences in FEV1 in response to inhaled corticosteroids in 418 white subjects with asthma. Of the 444,088 single nucleotide polymorphisms (SNPs) analyzed, the lowest 50 SNPs by P value were genotyped in an independent clinical trial population of 407 subjects with asthma.
Measurements and Main Results: The lowest P value for the GWAS analysis was 2.09 × 10−6. Of the 47 SNPs successfully genotyped in the replication population, three were associated under the same genetic model in the same direction, including two of the top four SNPs ranked by P value. Combined P values for these SNPs were 1.06 × 10−5 for rs3127412 and 6.13 × 10−6 for rs6456042. Although these two were not located within a gene, they were tightly correlated with three variants mapping to potentially functional regions within the T gene. After genotyping, each T gene variant was also associated with lung function response to inhaled corticosteroids in each of the trials associated with rs3127412 and rs6456042 in the initial GWAS analysis. On average, there was a twofold to threefold difference in FEV1 response for those subjects homozygous for the wild-type versus mutant alleles for each T gene SNP.
Conclusions: Genome-wide association has identified the T gene as a novel pharmacogenetic locus for inhaled corticosteroid response in asthma.
doi:10.1164/rccm.201111-2061OC
PMCID: PMC3381232  PMID: 22538805
polymorphism; genome; pharmacogenomics; glucocorticoid
4.  Predicting Inhaled Corticosteroid Response in Asthma with Two Associated SNPs 
The pharmacogenomics journal  2012;13(4):306-311.
Inhaled corticosteroids are the most commonly used controller medications prescribed for asthma. Two single-nucleotide polymorphisms (SNPs), rs1876828 in CRHR1 and rs37973 in GLCCI1, have previously been associated with corticosteroid efficacy. We studied data from four existing clinical trials of asthmatics who received inhaled corticosteroids and had lung function measured by forced expiratory volume in one second (FEV1) before and after the period of such treatment. We combined the two SNPs rs37973 and rs1876828 into a predictive test of FEV1 change using a Bayesian model, which identified patients with good or poor steroid response (highest or lowest quartile, respectively) with predictive performance of 65.7% (p = 0.039 vs. random) area under the receiver-operator characteristic curve in the training population and 65.9% (p = 0.025 vs. random) in the test population. These findings show that two genetic variants can be combined into a predictive test that achieves similar accuracy and superior replicability compared with single SNP predictors.
doi:10.1038/tpj.2012.15
PMCID: PMC3434304  PMID: 22641026
Pharmacogenetics; Asthma; Glucocorticoids; Predictive Modeling
5.  Common inversion polymorphism at 17q21.31 affects expression of multiple genes in tissue-specific manner 
BMC Genomics  2012;13:458.
Background
Chromosome 17q21.31 contains a common inversion polymorphism of approximately 900 kb in populations with European ancestry. Two divergent MAPT haplotypes, H1 and H2 are described with distinct linkage disequilibrium patterns across the region reflecting the inversion status at this locus. The MAPT H1 haplotype has been associated with progressive supranuclear palsy, corticobasal degeneration, Parkinson’s disease and Alzheimer’s disease, while the H2 is linked to recurrent deletion events associated with the 17q21.31 microdeletion syndrome, a disease characterized by developmental delay and learning disability.
Results
In this study, we investigate the effect of the inversion on the expression of genes in the 17q21.31 region. We find the expression of several genes in and at the borders of the inversion to be affected; specific either to whole blood or different regions of the human brain. The H1 haplotype was found to be associated with an increased expression of LRRC37A4, PLEKH1M and MAPT. In contrast, a decreased expression of MGC57346, LRRC37A and CRHR1 was associated with H1.
Conclusions
Studies thus far have focused on the expression of MAPT in the inversion region. However, our results show that the inversion status affects expression of other genes in the 17q21.31 region as well. Given the link between the inversion status and different neurological diseases, these genes may also be involved in disease pathology, possibly in a tissue-specific manner.
doi:10.1186/1471-2164-13-458
PMCID: PMC3582489  PMID: 22950410
6.  CRHR1 genotypes, neural circuits and the diathesis for anxiety and depression 
Molecular psychiatry  2012;18(6):700-707.
The corticotrophin-releasing hormone (CRH) system integrates the stress response and is associated with stress-related psychopathology. Previous reports have identified interactions between childhood trauma and sequence variation in the CRH receptor 1 gene (CRHR1) that increase risk for affective disorders. However, the underlying mechanisms that connect variation in CRHR1 to psychopathology are unknown. To explore potential mechanisms, we used a validated rhesus macaque model to investigate association between genetic variation in CRHR1, anxious temperament (AT) and brain metabolic activity. In young rhesus monkeys, AT is analogous to the childhood risk phenotype that predicts the development of human anxiety and depressive disorders. Regional brain metabolism was assessed with 18F-labeled fluoro-2-deoxyglucose (FDG) positron emission tomography in 236 young, normally reared macaques that were also characterized for AT. We show that single nucleotide polymorphisms (SNPs) affecting exon 6 of CRHR1 influence both AT and metabolic activity in the anterior hippocampus and amygdala, components of the neural circuit underlying AT. We also find evidence for association between SNPs in CRHR1 and metabolism in the intraparietal sulcus and precuneus. These translational data suggest that genetic variation in CRHR1 affects the risk for affective disorders by influencing the function of the neural circuit underlying AT and that differences in gene expression or the protein sequence involving exon 6 may be important. These results suggest that variation in CRHR1 may influence brain function before any childhood adversity and may be a diathesis for the interaction between CRHR1 genotypes and childhood trauma reported to affect human psychopathology.
doi:10.1038/mp.2012.152
PMCID: PMC3663915  PMID: 23147386
amygdala; corticotrophin-releasing hormone; genetic association; hippocampus; non-human primate; rhesus macaque
7.  Association of corticotropin releasing hormone receptor 2 (CRHR2) genetic variants with acute bronchodilator response in asthma 
Pharmacogenetics and genomics  2008;18(5):373-382.
Objective
Corticotropin - releasing hormone receptor 2 (CRHR2) participates in smooth muscle relaxation response and may influence acute airway bronchodilator response to short – acting β2 agonist treatment of asthma. We aim to assess associations between genetic variants of CRHR2 and acute bronchodilator response in asthma.
Methods
We investigated 28 single nucleotide polymorphisms in CRHR2 for associations with acute bronchodilator response to albuterol in 607 Caucasian asthmatic subjects recruited as part of the Childhood Asthma Management Program (CAMP). Replication was conducted in two Caucasian adult asthma cohorts – a cohort of 427 subjects enrolled in a completed clinical trial conducted by Sepracor Inc. (MA, USA) and a cohort of 152 subjects enrolled in the Clinical Trial of Low-Dose Theopylline and Montelukast (LODO) conducted by the American Lung Association Asthma Clinical Research Centers.
Results
Five variants were significantly associated with acute bronchodilator response in at least one cohort (p-value ≤ 0.05). Variant rs7793837 was associated in CAMP and LODO (p-value = 0.05 and 0.03, respectively) and haplotype blocks residing at the 5’ end of CRHR2 were associated with response in all three cohorts.
Conclusion
We report for the first time, at the gene level, replicated associations between CRHR2 and acute bronchodilator response. While no single variant was significantly associated in all three cohorts, the findings that variants at the 5’ end of CRHR2 are associated in each of three cohorts strongly suggest that the causative variants reside in this region and its genetic effect, although present, is likely to be weak.
doi:10.1097/FPC.0b013e3282fa760a
PMCID: PMC3208318  PMID: 18408560
Asthma; genetics; corticotrophin releasing hormone receptor 2; CRHR2; bronchodilator response; polymorphism; β2 adrenergic receptor agonist
8.  Outcomes After Periodic Use of Inhaled Corticosteroids in Children 
Background
Many children with persistent asthma use inhaled corticosteroids on a periodic basis. Clinical trials in adults suggest that periodic use of inhaled corticosteroids may be effective for patients with mild persistent asthma. However, scant information exists on the clinical outcomes of children with asthma who are using inhaled corticosteroids on a periodic basis in real-world settings.
Objective
This prospective cohort study compared clinical outcomes during a 12-month follow-up period between children with persistent asthma whose parents believed that they were supposed to use inhaled steroids either (a) periodically or (b) daily year-round at the start of the period. The clinical outcomes studied were (1) asthma-related emergency department (ED) visits or hospitalizations, (2) uncontrolled asthma based on health care and medication use, and (3) outpatient visits for asthma.
Patients and methods
The study population included children with persistent asthma from two health plans whose parents reported that they were using inhaled corticosteroids during a baseline telephone interview. The interviews collected information on whether the children’s parents believed they were supposed to use inhaled corticosteroids on a periodic or daily basis, as well as baseline asthma symptom status, sociodemographic, and behavioral variables. We used computerized databases to identify clinical events for each child during the 12 months after their baseline interview. Uncontrolled asthma was defined as any asthma-related ED visit or hospitalization, two or more oral steroid prescription fills, or four or more beta-agonists canisters filled during the 12-month period. We compared these outcomes between the periodic versus daily users of inhaled corticosteroids using logistic regression analyses. We conducted both (1) a traditional logistic regression analysis in which we adjusted for selection bias by including covariates such as age, asthma physical status, sociodemographic and behavioral variables, and history of asthma-related health care use during the year before interview and (2) an analysis using propensity scores to more fully adjust for selection bias.
Results
Of a total of 476 children in the study, 55% of parents believed their children were supposed to be using inhaled corticosteroids on a periodic basis and 45% believed their children were supposed to be using them daily year-round based on the baseline parent interview. At baseline, periodic inhaled corticosteroid users had less severe asthma than daily users based on several measures including better asthma physical status scores on the Children’s Health Survey for Asthma (mean 87 ± 16.0 vs. 81 ± 17.4, p = < 0.0001). During the year before the baseline interview, periodic users compared with daily users were less likely to have an ED visit or hospitalization (10% vs. 23%, p = 0.0001) and less likely to have had five or more albuterol prescription fills (13% vs. 31%, p < 0.0001). During the follow-up year, those who believed inhaled steroids were for periodic use were less likely than those who believed inhaled steroids were for daily use to have an ED visit or hospitalization for asthma (OR 0.36, 95% CI: 0.18–0.73), even after adjusting for baseline asthma status and other covariates. Similarly, those who believed inhaled steroids were for periodic use were less likely to have uncontrolled asthma, OR 0.38 (95% CI: 0.24–0.62). Analyses using propensity score adjustment yielded similar results to the logistic regression analyses.
Conclusion
Children whose parents believed they were supposed to use inhaled corticosteroids on a periodic basis had less severe asthma at baseline than those whose parents believed they were supposed to be using them daily. Periodic users were less likely than daily users to have adverse asthma outcomes during 1-year follow-up. This suggests that clinicians may be applying appropriate selection criteria by choosing patients with less severe asthma for periodic inhaled corticosteroid regimens.
doi:10.1080/02770900802468517
PMCID: PMC4004094  PMID: 19544175
asthma; periodic inhaled corticosteroids; children
9.  Cross Species Association Examination of UCN3 and CRHR2 as Potential Pharmacological Targets for Antiobesity Drugs 
PLoS ONE  2006;1(1):e80.
Background
Obesity now constitutes a leading global public health problem. Studies have shown that insulin resistance affiliated with obesity is associated with intramyocellular lipid (IMCL) accumulation. Therefore, identification of genes associated with the phenotype would provide a clear target for pharmaceutical intervention and care for the condition. We hypothesized that urocortin 3 (UCN3) and corticotropin-releasing hormone receptor 2 (CRHR2) are associated with IMCL and subcutaneous fat depth (SFD), because the corticotropin-releasing hormone family of peptides are capable of strong anorectic and thermogenic effects.
Methodology/Principal Findings
We annotated both bovine UCN3 and CRHR2 genes and identified 12 genetic mutations in the former gene and 5 genetic markers in the promoter region of the latter gene. Genotyping of these 17 markers on Wagyu×Limousin F2 progeny revealed significant associations between promoter polymorphisms and SFD (P = 0.0203−0.0685) and between missense mutations of exon 2 and IMCL (P = 0.0055−0.0369) in the bovine UCN3 gene. The SFD associated promoter SNPs caused a gain/loss of 12 potential transcription regulatory binding sites, while the IMCL associated coding SNPs affected the secondary structure of UCN3 mRNA. However, none of five polymorphisms in CRHR2 gene clearly co-segregated with either trait in the population (P>0.6000).
Conclusions/Significance
Because UCN3 is located on human chromosome 10p15.1 where quantitative trait loci for obesity have been reported, our cross species study provides further evidence that it could be proposed as a potential target for developing antiobesity drugs. None of the markers in CRHR2 was associated with obesity-type traits in cattle, which is consistent with findings in human. Therefore, CRHR2 does not lend itself to the development of antiobesity drugs.
doi:10.1371/journal.pone.0000080
PMCID: PMC1762311  PMID: 17183713
10.  H2 haplotype at chromosome 17q21.31 protects against childhood sexual abuse-associated risk for alcohol consumption and dependence 
Addiction biology  2010;15(1):1-11.
Animal research supports a central role for corticotropin releasing factor (CRF) in actions of ethanol on brain function. An examination of alcohol consumption in adolescents reported a significant genotype × environment (G × E) interaction involving rs1876831, a CRHR1 polymorphism, and negative events. CRHR1 and at least 4 other genes are located at 17q21.31 in an extremely large block of high linkage disequilibrium resulting from a local chromosomal inversion; the minor allele of rs1876831 is contained within the H2 haplotype. Here we examine whether G × E interactions involving this haplotype and childhood sexual abuse (CSA) are associated with risk for alcohol consumption and dependence in Australian participants (N=1128 respondents from 476 families) of the Nicotine Addiction Genetics project. Telephone interviews provided data on DSM-IV alcohol dependence diagnosis and CSA and enabled calculation of lifetime alcohol consumption factor score (ACFS) from 4 indices of alcohol consumption. Individuals reporting a history of CSA had significantly higher ACFS and increased risk for alcohol dependence. A significant G × E interaction was found for ACFS involving the H2 haplotype and CSA (p<0.017). A similar G × E interaction was associated with protective effects against alcohol dependence risk (odds ratio 0.42; 95%CI 0.20 – 0.89). For each outcome, no significant CSA-associated risk was observed in H2 haplotype carriers. These findings support conducting further investigation of the H2 haplotype to determine the gene(s) responsible. Our results also suggest that severe early trauma may prove to be an important clinical covariate in the treatment of alcohol dependence.
doi:10.1111/j.1369-1600.2009.00181.x
PMCID: PMC3068622  PMID: 19878140
alcohol dependence; association; childhood sexual abuse; CRHR1; haplotype; interaction
11.  A polymorphism in the histone deacetylase 1 gene is associated with the response to corticosteroids in asthmatics 
Background/Aims
Recent investigations suggest that histone deacetylase 1 (HDAC1) and HDAC2 may be target molecules to predict therapeutic responses to corticosteroids. We evaluated the effects of variation in HDAC1 and HDAC2 on the response to corticosteroids in asthmatics.
Methods
Two single nucleotide polymorphisms (SNPs) were selected after resequencing HDAC1 and HDAC2. For the first analysis, we evaluated the association between those SNPs and asthma severity in 477 asthmatics. For the second analysis, we evaluated the effects of these SNPs on lung function improvements in response to corticosteroid treatment in 35 independent adult asthmatics and 70 childhood asthmatics.
Results
We found that one SNP in HDAC1 (rs1741981) was significantly related to asthma severity in a recessive model (corrected p = 0.036). Adult asthmatics who were homozygous for the minor allele of rs1741981 showed significantly lower % forced expiratory volume in 1 second (%FEV1) increases in response to systemic corticosteroids treatment compared with the heterozygotes or those homozygous for the major allele (12.7% ± 7.2% vs. 37.4% ± 33.7%, p = 0.018). Similarly, childhood asthmatics who were homozygous for the minor allele of rs1741981 showed significantly lower %FEV1 increases in response to inhaled corticosteroid treatment compared with the heterozygotes or those homozygous for the major allele (14.1% ± 5.9% vs. 19.4% ± 8.9%, p = 0.035).
Conclusions
The present study demonstrated that rs1741981 in HDAC1 was significantly associated with the response to corticosteroid treatment in asthmatics.
doi:10.3904/kjim.2013.28.6.708
PMCID: PMC3846997  PMID: 24307847
Asthma; Glucocorticoids; Histone deacetylase 1; Pharmacogenomics; Polymorphism
12.  Influence of Child Abuse on Adult Depression 
Archives of general psychiatry  2008;65(2):190-200.
Context
Genetic inheritance and developmental life stress both contribute to major depressive disorder in adults. Child abuse and trauma alter the endogenous stress response, principally corticotropin-releasing hormone and its downstream effectors, suggesting that a gene × environment interaction at this locus may be important in depression.
Objective
To examine whether the effects of child abuse on adult depressive symptoms are moderated by genetic polymorphisms within the corticotropin-releasing hormone type 1 receptor (CRHR1) gene.
Design
Association study examining gene × environment interactions between genetic polymorphisms at the CRHR1 locus and measures of child abuse on adult depressive symptoms.
Setting
General medical clinics of a large, public, urban hospital and Emory University, Atlanta, Georgia.
Participants
The primary participant population was 97.4% African American, of low socioeconomic status, and with high rates of lifetime trauma (n=422). A supportive independent sample (n=199) was distinct both ethnically (87.7% Caucasian) and socioeconomically (less impoverished).
Main Outcome Measures
Beck Depression Inventory scores and history of major depressive disorder by the Structured Clinical Interview for DSM-IV Axis I Disorders.
Results
Fifteen single-nucleotide polymorphisms spanning 57 kilobases of the CRHR1 gene were examined. We found significant gene × environment interactions with multiple individual single-nucleotide polymorphisms (eg, rs110402, P=.008) as well as with a common haplotype spanning intron 1 (P <.001). Specific CRHR1 polymorphisms appeared to moderate the effect of child abuse on the risk for adult depressive symptoms. These protective effects were supported with similar findings in a second independent sample (n=199).
Conclusions
These data support the corticotropin-releasing hormone hypothesis of depression and suggest that a gene × environment interaction is important for the expression of depressive symptoms in adults with CRHR1 risk or protective alleles who have a history of child abuse.
doi:10.1001/archgenpsychiatry.2007.26
PMCID: PMC2443704  PMID: 18250257
13.  Single-Nucleotide Polymorphisms in Corticotropin Releasing Hormone Receptor 1 Gene (CRHR1) Are Associated With Quantitative Trait of Event-Related Potential and Alcohol Dependence 
Background
Endophenotypes reflect more proximal effects of genes than diagnostic categories, hence providing a more powerful strategy in searching for genes involved in complex psychiatric disorders. There is strong evidence suggesting the P3 amplitude of the event-related potential (ERP) as an endophenotype for the risk of alcoholism and other disinhibitory disorders. Recent studies demonstrated a crucial role of corticotropin releasing hormone receptor 1 (CRHR1) in the environmental stress response and ethanol self-administration in animal models. The aim of the present study was to test the potential associations between single-nucleotide polymorphisms (SNPs) in the CRHR1 gene and the quantitative trait, P3 amplitude during the processing of visual target signals in an oddball paradigm, as well as alcohol dependence diagnosis.
Methods
We analyzed a sample from the Collaborative Study on the Genetics of Alcoholism (COGA) comprising 1049 Caucasian subjects from 209 families (including 472 alcohol-dependent individuals). Quantitative transmission disequilibrium test (QTDT) and family-based association test (FBAT) were used to test the association, and false discovery rate (FDR) was applied to correct for multiple comparisons.
Results
Significant associations (p < 0.05) were found between the P3 amplitude and alcohol dependence with multiple SNPs in the CRHR1 gene.
Conclusions
Our results suggest that CRHR1 may be involved in modulating the P3 component of the ERP during information processing and in vulnerability to alcoholism. These findings underscore the utility of electrophysiology and the endophenotype approach in the genetic study of psychiatric disorders.
doi:10.1111/j.1530-0277.2010.01173.x
PMCID: PMC3248053  PMID: 20374216
P3; Disinhibition; Endophenotype; Stress; Corticotropin Releasing Factor (CRF)
14.  Depression and Anxiety Symptoms Among Women Who Carry the FMR1 Premutation: Impact of Raising a Child With Fragile X Syndrome Is Moderated by CRHR1 Polymorphisms 
The fragile X mental retardation gene, FMR1, contains a polymorphic CGG repeat in the 5′-untranslated region of exon 1. Once unstable, this repeat is capable of expansion across generations. Women who carry a premutation allele (55–199 repeats) are at risk of passing on a full mutation allele (>200 repeats) to their offspring. A full mutation leads to the most common form of inherited intellectual disability, fragile X syndrome (FXS). Mounting evidence suggests that premutation carriers may be vulnerable to symptoms of anxiety and depression. The goal of this study was to test the hypothesis that among women who carry a premutation, the stress of raising a child with FXS would be moderated by genetic factors influencing endogenous cortisol responses, which could in turn modulate anxiety and depression symptoms. To this end, we genotyped single nucleotide polymorphisms (SNPs) at the corticotrophin releasing hormone receptor 1 locus (CRHR1) in 460 women. Participants completed self-report questionnaires assessing symptoms of depression [Centers for Epidemiological Studies Depression Scale (CESD)], anxiety [State-Trait Anxiety Inventory (STAI) and Social Phobia and Anxiety Inventory (SPAI)], and mood [Positive and Negative Affect Schedule (PANAS)]. Results indicate a statistically significant interaction between CRHR1 genotype and the status of raising a child with FXS to predict social anxiety symptoms reported on the SPAI (rs7209436, P = 0.0001). Our data suggest that genetic variants in CRHR1 that associate with differential cortisol activation may also modulate levels of anxiety related to the stress of raising a child with FXS among women who carry an FMR1 premutation.
doi:10.1002/ajmg.b.32061
PMCID: PMC3696495  PMID: 22573456
FMR1 premutation; fragile X syndrome; hypothalamic-pituitary-adrenal axis; cortisol; gene–environment interaction
15.  Interaction of Childhood Maltreatment with the Corticotropin-Releasing Hormone Receptor Gene: Effects on HPA Axis Reactivity 
Biological psychiatry  2009;66(7):681-685.
Background
Variation in the corticotropin-releasing hormone receptor (CRHR1) gene has been shown to interact with early-life stress to predict adult depression. This study was conducted to determine whether CRHR1 polymorphisms interact with childhood maltreatment to predict HPA axis reactivity, which has been linked to both depression and early-life stress.
Methods
One-hundred twenty-nine White non-Hispanic adults completed the Childhood Trauma Questionaire, the dexamethasone/corticotropin-releasing hormone test, and provided blood samples for genotyping of two CRHR1 polymorphisms.
Results
Both rs110402 and rs242924 (which were in tight linkage disequilibrium, D’=0.98) showed a significant interaction with maltreatment in the prediction of cortisol response to the Dex/CRH test (p<.05). For subjects with maltreatment, the GG genotype of each SNP was associated with elevated cortisol responses to the test.
Conclusions
Variation in the CRHR1 moderates the effect of childhood maltreatment on cortisol responses to the Dex/CRH test. Excessive HPA axis activation could represent a mechanism of interactions of risk genes with stress in the development of mood and anxiety disorders.
doi:10.1016/j.biopsych.2009.05.012
PMCID: PMC2881567  PMID: 19596121
Cortisol; Dex/CRH test; HPA axis; genetics; CRHR1 gene; gene-environment interaction
16.  Asthma in adults 
Clinical Evidence  2010;2010:1501.
Introduction
About 10% of adults have suffered an attack of asthma, and up to 5% of these have severe disease that responds poorly to treatment. Patients with severe disease have an increased risk of death, but patients with mild-to-moderate disease are also at risk of exacerbations. Most guidelines about the management of asthma follow stepwise protocols. This review does not endorse or follow any particular protocol, but presents the evidence about specific interventions.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for chronic asthma? What are the effects of treatments for acute asthma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 99 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions. For acute asthma: beta2 agonists (plus ipratropium bromide, pressured metered-dose inhalers, short-acting continuous nebulised, short-acting intermittent nebulised, and short-acting intravenous); corticosteroids (inhaled); corticosteroids (single oral, combined inhaled, and short courses); education about acute asthma; generalist care; helium-oxygen mixture (heliox); magnesium sulphate (intravenous and adding isotonic nebulised magnesium to inhaled beta2 agonists); mechanical ventilation; oxygen supplementation (controlled 28% oxygen and controlled 100% oxygen); and specialist care. For chronic asthma: beta2 agonists (adding long-acting inhaled beta2 agonists when asthma is poorly controlled by inhaled corticosteroids, or short-acting inhaled beta2 agonists as needed for symptom relief); inhaled corticosteroids (low dose and increasing dose); leukotriene antagonists (with or without inhaled corticosteroids); and theophylline (when poorly controlled by inhaled corticosteroids).
Key Points
About 10% of adults have suffered an attack of asthma, and up to 5% of these have severe disease that responds poorly to treatment. These people have an increased risk of death.
Most guidelines about the management of asthma follow stepwise protocols. This review does not endorse or follow any particular protocol, but presents the evidence about specific interventions.
Taking short-acting beta2 agonists as needed is as likely to relieve symptoms and improve lung function as a regular dosing schedule in adults with chronic asthma.
Adding long-acting beta2 agonists to inhaled corticosteroids decreases the number of exacerbations and improves symptoms, lung function, and quality of life in people with mild-to-moderate persistent asthma that is poorly controlled with corticosteroids.
CAUTION: Long-acting beta2 agonists have been associated with increased asthma-related mortality, and should always be used with inhaled corticosteroids.
Low-dose inhaled corticosteroids improve symptoms and lung function in persistent asthma compared with placebo or regular inhaled beta2 agonists. Leukotriene antagonists are more effective than placebo at reducing symptoms, but we don't know if adding leukotriene antagonists to inhaled corticosteroids is of benefit in people with chronic asthma.CAUTION: Leukotriene antagonists have been associated with a possible increased risk of neuropsychiatric events.Adding theophylline to inhaled corticosteroids may improve lung function in people with mild or moderate chronic asthma that is poorly controlled with inhaled corticosteroids, but we don't know if they are of benefit compared with long-acting beta2 agonists or leukotriene antagonists.
In people with an acute attack of asthma, supplementation of beta2 agonists with 28% oxygen, systemic corticosteroids (short courses), additional beta2 agonists (various routes of administration), or ipratropium bromide improve symptoms. Inhaled corticosteroids seem to improve lung function in people with acute asthma. However, we don't know whether inhaled corticosteroids are as effective as systemic corticosteroids at improving symptom severity, lung function, and hospital admissions. Inhaled plus oral corticosteroids and oral corticosteroids alone may have similar effects in preventing relapse and improving lung function.Beta2 agonists delivered from a metered-dose inhaler using a spacer are as effective at improving lung function as those given by a nebuliser or given intravenously. Giving beta2 agonists intravenously is more invasive than giving beta2 agonists by nebuliser.In people with severe acute asthma, continuous nebulised short-acting beta2 agonists may also improve lung function more than intermittent nebulised short-acting beta2 agonists.We don't know if intravenous magnesium sulphate, nebulised magnesium alone, or adding nebulised magnesium to inhaled beta2 agonists improves lung function in people with acute asthma.We don't know whether helium-oxygen mixture (heliox) is more effective at improving lung function compared with usual care. Mechanical ventilation may be life saving in severe acute asthma, but it is associated with high levels of morbidity. Specialist care of acute asthma may lead to improved outcomes compared with generalist care.We don't know whether education to help self-manage asthma improves symptom severity, lung function, or quality of life, but it may reduce hospital admissions.
PMCID: PMC2907598  PMID: 21718577
17.  Combination formoterol and budesonide as maintenance and reliever therapy versus inhaled steroid maintenance for chronic asthma in adults and children 
Background
Traditionally inhaled treatment for asthma has been considered as preventer and reliever therapy. The combination of formoterol and budesonide in a single inhaler introduces the possibility of using a single inhaler for both prevention and relief of symptoms (single inhaler therapy).
Objectives
The aim of this review is to compare formoterol and corticosteroid in single inhaler for maintenance and relief of symptoms with inhaled corticosteroids for maintenance and a separate reliever inhaler.
Search methods
We last searched the Cochrane Airways Group trials register in September 2008.
Selection criteria
Randomised controlled trials in adults and children with chronic asthma.
Data collection and analysis
Two review authors independently assessed studies for inclusion and extracted the characteristics and results of each study. Authors or manufacturers were asked to supply unpublished data in relation to primary outcomes.
Main results
Five studies on 5,378 adults compared single inhaler therapy with current best practice, and did not show a significant reduction in participants with exacerbations causing hospitalisation (Peto OR 0.59; 95% CI 0.24 to 1.45) or treated with oral steroids (OR 0.83; 95% CI 0.66 to 1.03). Three of these studies on 4281 adults did not show a significant reduction in time to first severe exacerbation needing medical intervention (HR 0.96; 95% CI 0.85 to 1.07). These trials demonstrated a reduction in the mean total daily dose of inhaled corticosteroids with single inhaler therapy (mean reduction ranged from 107 to 267 micrograms/day, but the trial results were not combined due to heterogeneity). The full results from four further studies on 4,600 adults comparing single inhaler therapy with current best practice are awaited.
Three studies including 4,209 adults compared single inhaler therapy with higher dose budesonide maintenance and terbutaline for symptom relief. No significant reduction was found with single inhaler therapy in the risk of patients suffering an asthma exacerbation leading to hospitalisation (Peto OR 0.56; 95% CI 0.28 to 1.09), but fewer patients on single inhaler therapy needed a course of oral corticosteroids (OR 0.54; 95% CI 0.45 to 0.64). These results translate into an eleven month number needed to treat of 14 (95% CI 12 to 18), to prevent one patient being treated with oral corticosteroids for an exacerbation. The run-in for these studies involved withdrawal of long-acting beta2-agonists, and patients were recruited who were symptomatic during run-in.
One study included children (N = 224), in which single inhaler therapy was compared to higher dose budesonide. There was a significant reduction in participants who needed an increase in their inhaled steroids with single inhaler therapy, but there were only two hospitalisations for asthma and no separate data on courses of oral corticosteroids. Less inhaled and oral corticosteroids were used in the single inhaler therapy group and the annual height gain was also 1 cm greater in the single inhaler therapy group, [95% CI 0.3 to 1.7 cm].
There was no significant difference found in fatal or non-fatal serious adverse events for any of the comparisons.
Authors’ conclusions
Single inhaler therapy can reduce the risk of asthma exacerbations needing oral corticosteroids in comparison with fixed dose maintenance inhaled corticosteroids. Guidelines and common best practice suggest the addition of regular long-acting beta2-agonist to inhaled corticosteroids for uncontrolled asthma, and single inhaler therapy has not been demonstrated to significantly reduce exacerbations in comparison with current best practice, although results of five large trials are awaiting full publication. Single inhaler therapy is not currently licensed for children under 18 years of age in the United Kingdom.
doi:10.1002/14651858.CD007313.pub2
PMCID: PMC4053857  PMID: 19370682
Administration; Inhalation; AdrenalCortexHormones [*administration & dosage]; Anti-Asthmatic Agents [*administration & dosage]; Asthma [*drug therapy]; Bronchodilator Agents [administration & dosage]; Budesonide [*administration & dosage]; Chronic Disease; Drug Therapy; Combination; Ethanolamines [*administration & dosage]; Terbutaline [administration & dosage]; Adult; Child; Humans
18.  Polymorphisms in CRHR1 and the serotonin transporter loci: gene x gene x environment interactions on depressive symptoms 
Background
Gene x environment (GxE) interactions mediating depressive symptoms have been separately identified in the stress-sensitive serotonergic (5-HTTLPR) and corticotropin-releasing hormone (CRHR1) systems. Our objective was to examine whether the effects of child abuse are moderated by gene x gene (GxG) interactions between CRHR1 and 5-HTTLPR polymorphisms.
Methods
We used an association study examining GxGxE interactions of CRHR1 and 5-HTTLPR polymorphisms and measures of child abuse on adult depressive symptomatology. The participant population (N=1392) was African-American, of low socioeconomic status (60% with <$1000/month family income), and with high rates of childhood and lifetime trauma. Depressive symptoms were measured with Beck Depression Inventory (BDI) and history of Major Depression by Structure Clinical Interview based on DSM-IV (SCID).
Results
We first replicated an interaction of child abuse and 5-HTTLPR on lifetime SCID diagnosis of major depression in a subsample (N= 236) of the study population – the largest African American 5-HTTLPR cohort reported to date. We then extended our previously reported interaction with both a CRHR1 SNP (rs110402) and TCA haplotype interacting with child abuse to predict current symptoms (N=1059; p = 0.0089). We found that the 5-HTTLPR S allele interacted with CRHR1 haplotypes and child abuse to predict current depressive symptoms (N = 856, p = 0.016).
Conclusions
These data suggest that GxE interactions predictive of depressive symptoms may be differentially sensitive to levels of childhood trauma, and the effects of child abuse are moderated by genetic variation at both the CRHR1 and 5-HTTLPR loci and by their GxG interaction.
doi:10.1002/ajmg.b.31052
PMCID: PMC2924813  PMID: 20029939
Child Abuse; Childhood Maltreatmet; Trauma; Depression; PTSD; Genetic; risk factor
19.  Polymorphisms in CRHR1 and the Serotonin Transporter Loci: Gene × Gene × Environment Interactions on Depressive Symptoms 
American Journal of Medical Genetics  2009;153B(3):812-824.
Gene × environment (G × E) interactions mediating depressive symptoms have been separately identified in the stress-sensitive serotonergic (5-HTTLPR) and corticotropin-releasing hormone (CRHR1) systems. Our objective was to examine whether the effects of child abuse are moderated by gene × gene (G × G) interactions between CRHR1 and 5-HTTLPR polymorphisms. We used an association study examining G × G × E interactions of CRHR1 and 5-HTTLPR polymorphisms and measures of child abuse on adult depressive symptomatology. The participant population (N = 1,392) was African-American, of low socioeconomic status (60% with <$1,000/month family income), and with high rates of childhood and lifetime trauma. Depressive symptoms were measured with Beck Depression Inventory (BDI) and history of Major Depression by Structure Clinical Interview based on DSM-IV (SCID). We first replicated an interaction of child abuse and 5-HTTLPR on lifetime SCID diagnosis of major depression in a subsample (N = 236) of the study population—the largest African-American 5-HTTLPR cohort reported to date. We then extended our previously reported interaction with both a CRHR1 SNP (rs110402) and TCA haplotype interacting with child abuse to predict current symptoms (N = 1,059; P = 0.0089). We found that the 5-HTTLPR S allele interacted with CRHR1 haplotypes and child abuse to predict current depressive symptoms (N = 856, P = 0.016). These data suggest that G × E interactions predictive of depressive symptoms may be differentially sensitive to levels of childhood trauma, and the effects of child abuse are moderated by genetic variation at both the CRHR1 and 5-HTTLPR loci and by their G × G interaction. © 2009 Wiley-Liss, Inc.
doi:10.1002/ajmg.b.31052
PMCID: PMC2924813  PMID: 20029939
child abuse; childhood maltreatment; trauma; depression; PTSD; genetic; risk factor
20.  Moderation of the association between childhood maltreatment and Neuroticism by the corticotropin-releasing hormone receptor 1 gene 
Background
Neuroticism is a personality trait reflecting the tendency to experience negative affect. It is a major risk for psychopathology, especially depression and anxiety disorders. Childhood maltreatment is another major risk factor for psychopathology and may influence personality. Maltreatment may interact with genotype to predict developmental outcomes. Variation in three polymorphisms of the CRHR1 gene has been found to moderate the association of childhood maltreatment with depression, and we hypothesized that it would also be linked to Neuroticism.
Methods
Variation in three CRHR1 SNPs (rs110402, rs242924, rs7209436) was assessed in 339 maltreated and 275 demographically similar nonmaltreated children, who participated in a day camp research program. Maltreated children were further categorized based on the number of types of maltreatment they had experienced and the most severe form of maltreatment experienced. Genotype and maltreatment status were used to predict the Big Five personality traits, as assessed by camp counselors following a week of interaction with children.
Results
CRHR1 genotype significantly moderated the association of maltreatment with Neuroticism but none of the other traits. Having two copies of the TAT haplotype of CRHR1 was associated with higher levels of Neuroticism among maltreated children relative to nonmaltreated children, with the exception of sexually abused children and children who had experienced 3 or 4 types of abuse. Effects sizes of these interactions ranged from η2 = .01 (p = .02) to η2 = .03 (p = .006).
Conclusions
Variation in CRHR1 moderates the association of maltreatment with Neuroticism. The effects of specific types of maltreatment on Neuroticism are differentially moderated by CRHR1 genotype, as are the effects of experiencing more or fewer types of maltreatment.
doi:10.1111/j.1469-7610.2011.02404.x
PMCID: PMC3134545  PMID: 21438878
Neuroticism; CRHR1; maltreatment; genetics; personality; HPA axis
21.  Genetics of Asthma Susceptibility and Severity 
Clinics in chest medicine  2012;33(3):431-443.
The interaction of genes and environmental exposures influences the development of asthma and determines asthma severity. This review focuses on recent developments in genetic studies of asthma onset and progression. Genome-wide association studies (GWAS) are currently the most effective approach to study genetics of complex diseases. There have been two large meta-analyses of asthma susceptibility, GABRIEL and EVE, which identified the same four chromosomal regions, many of which had also been identified in previous GWAS: loci in the ORMDL3 region of 17q21, IL1RL/IL18R genes on chromosome 2q, the TSLP gene region on 5q22, and IL33 on chromosome 9p24. These regions were associated with asthma in individuals of different ethnic backgrounds. EVE also identified a novel asthma susceptibility locus, PYHIN1, in individuals of African descent. Genome-wide screens for asthma susceptibility in Asian adults and children both identified genetic variants in the major histocompatiblity complex gene region (HLA region) on chromosome 6p21 as highly associated with asthma risk. This locus was one of the first candidate genes identified for asthma and has been a significant predictor of asthma risk in several GWAS.
There is also a need to understand asthma disease heterogeneity as different phenotypes may reflect several pathogenic pathways. Genes that are associated with phenotypes including lung function, biomarker levels and asthma therapeutic responses provide insight into mechanisms of asthma severity progression. For example, the HHIP gene is a significant predictor of pulmonary function changes in asthma and in the normal population. A joint model of risk variants in lung function genes were highly associated with lower FEV1 and increased asthma severity criteria. In addition, a genome-wide screen to discover pharmacogenetic associations related to response to inhaled glucocorticoids identified two correlated SNPs in the GLCCI1 gene that confer a significant lung function response to this asthma therapy.
Future genetic studies for asthma susceptibility and severity will incorporate exome or whole-genome sequencing to identify common and rare genetic variants. Using these variants identified in comprehensively phenotyped asthmatics will lead to the development of personalized therapy in individuals with asthma.
doi:10.1016/j.ccm.2012.05.005
PMCID: PMC3431509  PMID: 22929093
Asthma; genetics; susceptibility; severity; personalized medicine; therapy; lung function
22.  Nucleotide, Cytogenetic and Expression Impact of the Human Chromosome 8p23.1 Inversion Polymorphism 
PLoS ONE  2009;4(12):e8269.
Background
The human chromosome 8p23.1 region contains a 3.8–4.5 Mb segment which can be found in different orientations (defined as genomic inversion) among individuals. The identification of single nucleotide polymorphisms (SNPs) tightly linked to the genomic orientation of a given region should be useful to indirectly evaluate the genotypes of large genomic orientations in the individuals.
Results
We have identified 16 SNPs, which are in linkage disequilibrium (LD) with the 8p23.1 inversion as detected by fluorescent in situ hybridization (FISH). The variability of the 8p23.1 orientation in 150 HapMap samples was predicted using this set of SNPs and was verified by FISH in a subset of samples. Four genes (NEIL2, MSRA, CTSB and BLK) were found differentially expressed (p<0.0005) according to the orientation of the 8p23.1 region. Finally, we have found variable levels of mosaicism for the orientation of the 8p23.1 as determined by FISH.
Conclusion
By means of dense SNP genotyping of the region, haplotype-based computational analyses and FISH experiments we could infer and verify the orientation status of alleles in the 8p23.1 region by detecting two short haplotype stretches at both ends of the inverted region, which are likely the relic of the chromosome in which the original inversion occurred. Moreover, an impact of 8p23.1 inversion on gene expression levels cannot be ruled out, since four genes from this region have statistically significant different expression levels depending on the inversion status. FISH results in lymphoblastoid cell lines suggest the presence of mosaicism regarding the 8p23.1 inversion.
doi:10.1371/journal.pone.0008269
PMCID: PMC2790694  PMID: 20011547
23.  Population Genomics of Inversion Polymorphisms in Drosophila melanogaster 
PLoS Genetics  2012;8(12):e1003056.
Chromosomal inversions have been an enduring interest of population geneticists since their discovery in Drosophila melanogaster. Numerous lines of evidence suggest powerful selective pressures govern the distributions of polymorphic inversions, and these observations have spurred the development of many explanatory models. However, due to a paucity of nucleotide data, little progress has been made towards investigating selective hypotheses or towards inferring the genealogical histories of inversions, which can inform models of inversion evolution and suggest selective mechanisms. Here, we utilize population genomic data to address persisting gaps in our knowledge of D. melanogaster's inversions. We develop a method, termed Reference-Assisted Reassembly, to assemble unbiased, highly accurate sequences near inversion breakpoints, which we use to estimate the age and the geographic origins of polymorphic inversions. We find that inversions are young, and most are African in origin, which is consistent with the demography of the species. The data suggest that inversions interact with polymorphism not only in breakpoint regions but also chromosome-wide. Inversions remain differentiated at low levels from standard haplotypes even in regions that are distant from breakpoints. Although genetic exchange appears fairly extensive, we identify numerous regions that are qualitatively consistent with selective hypotheses. Finally, we show that In(1)Be, which we estimate to be ∼60 years old (95% CI 5.9 to 372.8 years), has likely achieved high frequency via sex-ratio segregation distortion in males. With deeper sampling, it will be possible to build on our inferences of inversion histories to rigorously test selective models—particularly those that postulate that inversions achieve a selective advantage through the maintenance of co-adapted allele complexes.
Author Summary
Chromosomal inversions are known to respond to powerful natural selection in many species. Despite this evidence, little progress has been made towards understanding the nature of selection that affects inversions. Here, we utilize two recently released population-resequencing projects from D. melanogaster to address many of the unknown features of polymorphic inversions. We find evidence that inversions in this species are generally very young, with ages on the order of hundreds to tens of thousands of years, and that the majority of inversions originated in ancestral African populations. Inversions are also the source of the majority of genetic structure within populations and affect polymorphism chromosome-wide. We are able to confirm experimentally that one X-chromosome inversion achieves an advantage by selfishly increasing its transmission through males. Future work will build on our basic inferences to identify potential selective mechanisms and candidate genes in the other inversions studied.
doi:10.1371/journal.pgen.1003056
PMCID: PMC3527211  PMID: 23284285
24.  Regular treatment with salmeterol for chronic asthma: serious adverse events 
Background
Epidemiological evidence has suggested a link between beta2-agonists and increases in asthma mortality. There has been much debate about possible causal links for this association, and whether regular (daily) long-acting beta2-agonists are safe.
Objectives
The aim of this review is to assess the risk of fatal and non-fatal serious adverse events in trials that randomised patients with chronic asthma to regular salmeterol versus placebo or regular short-acting beta2-agonists.
Search methods
We identified trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trial registers for unpublished trial data and FDA submissions in relation to salmeterol. The date of the most recent search was August 2011.
Selection criteria
We included controlled parallel design clinical trials on patients of any age and severity of asthma if they randomised patients to treatment with regular salmeterol and were of at least 12 weeks’ duration. Concomitant use of inhaled corticosteroids was allowed, as long as this was not part of the randomised treatment regimen.
Data collection and analysis
Two authors independently selected trials for inclusion in the review. One author extracted outcome data and the second checked them. We sought unpublished data on mortality and serious adverse events.
Main results
The review includes 26 trials comparing salmeterol to placebo and eight trials comparing with salbutamol. These included 62,815 participants with asthma (including 2,599 children). In six trials (2,766 patients), no serious adverse event data could be obtained.
All-cause mortality was higher with regular salmeterol than placebo but the increase was not significant (Peto odds ratio (OR) 1.33 (95% CI 0.85 to 2.08)). Non-fatal serious adverse events were significantly increased when regular salmeterol was compared with placebo (OR 1.15 95% CI 1.02 to 1.29). One extra serious adverse event occurred over 28 weeks for every 188 people treated with regular salmeterol (95% CI 95 to 2606). There is insufficient evidence to assess whether the risk in children is higher or lower than in adults. We found no significant increase in fatal or non-fatal serious adverse events when regular salmeterol was compared with regular salbutamol.
We combined individual patient data from the two largest studies (SNS: n=25,180 and SMART: n=26,355), as all the asthma-related deaths in adults occurred in these studies. In patients who were not taking inhaled corticosteroids, compared to regular salbutamol or placebo, there was a significant increase in risk of asthma-related death with regular salmeterol (Peto OR 6.15 95% CI 1.73 to 21.84). The confidence interval for patients who were taking inhaled corticosteroids is wide and cannot rule in or out an increase in asthma mortality in the presence of an inhaled corticosteroid (Peto OR 2.03 95% CI 0.82 to 5.00).
Authors’ conclusions
In comparison with placebo, we have found an increased risk of serious adverse events with regular salmeterol. There is also a clear increase in risk of asthma-related mortality in patients not using inhaled corticosteroids in the two large surveillance studies. Although the increase in asthma-related mortality was smaller in patients taking inhaled corticosteroids at baseline, the confidence interval is wide, so we cannot conclude that the inhaled corticosteroids abolish the risks of regular salmeterol. The adverse effects of regular salmeterol in children remain uncertain due to the small number of children studied.
doi:10.1002/14651858.CD006363.pub2
PMCID: PMC4015854  PMID: 18646149
Adrenergic beta-Agonists [therapeutic use]; Albuterol [administration & dosage; adverse effects; *analogs & derivatives; therapeutic use]; Anti-Asthmatic Agents [administration & dosage; *adverse effects]; Asthma [drug therapy; *mortality]; Bronchodilator Agents [administration & dosage; *adverse effects]; Cause of Death; Placebos [therapeutic use]; Randomized Controlled Trials as Topic; Adult; Child; Humans
25.  A Widespread Chromosomal Inversion Polymorphism Contributes to a Major Life-History Transition, Local Adaptation, and Reproductive Isolation 
PLoS Biology  2010;8(9):e1000500.
A set of experiments demonstrates the involvement of a chromosomal inversion in the adaptive transition between annual and perennial ecotypes of the yellow monkeyflower, Mimulus guttatus
The role of chromosomal inversions in adaptation and speciation is controversial. Historically, inversions were thought to contribute to these processes either by directly causing hybrid sterility or by facilitating the maintenance of co-adapted gene complexes. Because inversions suppress recombination when heterozygous, a recently proposed local adaptation mechanism predicts that they will spread if they capture alleles at multiple loci involved in divergent adaptation to contrasting environments. Many empirical studies have found inversion polymorphisms linked to putatively adaptive phenotypes or distributed along environmental clines. However, direct involvement of an inversion in local adaptation and consequent ecological reproductive isolation has not to our knowledge been demonstrated in nature. In this study, we discovered that a chromosomal inversion polymorphism is geographically widespread, and we test the extent to which it contributes to adaptation and reproductive isolation under natural field conditions. Replicated crosses between the prezygotically reproductively isolated annual and perennial ecotypes of the yellow monkeyflower, Mimulus guttatus, revealed that alternative chromosomal inversion arrangements are associated with life-history divergence over thousands of kilometers across North America. The inversion polymorphism affected adaptive flowering time divergence and other morphological traits in all replicated crosses between four pairs of annual and perennial populations. To determine if the inversion contributes to adaptation and reproductive isolation in natural populations, we conducted a novel reciprocal transplant experiment involving outbred lines, where alternative arrangements of the inversion were reciprocally introgressed into the genetic backgrounds of each ecotype. Our results demonstrate for the first time in nature the contribution of an inversion to adaptation, an annual/perennial life-history shift, and multiple reproductive isolating barriers. These results are consistent with the local adaptation mechanism being responsible for the distribution of the two inversion arrangements across the geographic range of M. guttatus and that locally adaptive inversion effects contribute directly to reproductive isolation. Such a mechanism may be partially responsible for the observation that closely related species often differ by multiple chromosomal rearrangements.
Author Summary
Genome rearrangements that change the order of genes along a chromosome are known as inversions and have long been hypothesized to be involved in the origin of species. Yet the way inversions contribute to adaptation and speciation remains mysterious. In this study, we identified a geographically widespread adaptive inversion polymorphism in the yellow monkeyflower, Mimulus guttatus. One arrangement of the inverted region is found in an annual ecotype of this species that lives in Mediterranean habitats characterized by reduced soil water availability in the summer. The other arrangement appears in a perennial ecotype that lives in habitats with high year-round soil moisture. The inversion was observed to influence morphological and flowering time differences between these ecotypes across most of western North America. To test whether the inversion polymorphism contributes to adaptation and reproductive isolation, we conducted a field experiment by breeding plants to reciprocally swap the alternative chromosomal arrangements between the annual and perennial genetic backgrounds. We demonstrated that this inversion polymorphism contributes to local adaptation, the annual/perennial life-history transition, and three reproductive isolating barriers. These results are consistent with the theory that adaptation to local environments can drive the spread of chromosomal inversions and promote speciation.
doi:10.1371/journal.pbio.1000500
PMCID: PMC2946948  PMID: 20927411

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