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).
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).
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.
asthma; corticosteroid; exacerbation; lung function; pharmacogenetics
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.
alcohol dependence; association; childhood sexual abuse; CRHR1; haplotype; interaction
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.
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.
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.
asthma; genes; personalized medicine; polymorphisms; response heterogeneity
There is a growing appreciation that chromosome inversions affect rates of adaptation, speciation, and the evolution of sex chromosomes. Comparative genomic studies have identified many new paracentric inversion polymorphisms. Population models suggest that inversions can spread by reducing recombination between alleles that independently increase fitness, without epistasis or coadaptation. Areas of linkage disequilibrium extend across large inversions but may be interspersed by areas with little disequilibrium. Genes located within inversions are associated with a variety of traits including those involved in climatic adaptation. Inversion polymorphisms may contribute to speciation by generating underdominance owing to inviable gametes, but an alternative view gaining support is that inversions facilitate speciation by reducing recombination, protecting genomic regions from introgression. Likewise, inversions may facilitate the evolution of sex chromosomes by reducing recombination between sex determining alleles and alleles with sex-specific effects. However, few genes within inversions responsible for fitness effects or speciation have been identified.
chromosomal rearrangement; coadaptation; epistasis; genetic variation; rapid evolution
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.
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.
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.
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.
Asthma; genetics; corticotrophin releasing hormone receptor 2; CRHR2; bronchodilator response; polymorphism; β2 adrenergic receptor agonist
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.
polymorphism; genome; pharmacogenomics; glucocorticoid
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.
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.
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.
An inversion polymorphism of approximately 900kb on chromosome 17q21, which includes the microtubule-associated protein tau (MAPT) gene defines two haplotype clades, H1 and H2. Several small case–control studies have observed a marginally significant excess of the H1/H1 diplotype among patients with Parkinson’s disease (PD), and one reported refining the association to a region spanning exons 1 to 4 of MAPT. We sought to replicate these findings.
We genotyped 1,762 PD patients and 2,010 control subjects for a single nucleotide polymorphism (SNP) that differentiates the H1 and H2 clades. We also analyzed four SNPs that define subhaplotypes within H1 previously reported to associate with PD or other neurodegenerative disorders.
After adjusting for age, sex, and site, we observed a robust association between the H1/H1 diplotype and PD risk (odds ratio for H1/H1 vs H1/H2 and H2/H2, 1.46; 95% confidence interval, 1.25–1.69; p = 8 × 10−7). The effect was evident in both familial and sporadic subgroups, men and women, and early- and late-onset disease. Within H1/H1 individuals, there was no significant difference between cases and control subjects in the overall frequency distribution of H1 subhaplotypes.
Our data provide strong evidence that the H1 clade, which contains MAPT and several other genes, is a risk factor for PD. However, attributing this finding to variants within a specific region of MAPT is premature. Thorough fine-mapping of the H1 clade in large numbers of individuals is now needed to identify the underlying functional variant(s) that alter susceptibility for PD.
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.
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.
Association study examining gene × environment interactions between genetic polymorphisms at the CRHR1 locus and measures of child abuse on adult depressive symptoms.
General medical clinics of a large, public, urban hospital and Emory University, Atlanta, Georgia.
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.
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).
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.
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.
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.
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).
The present study demonstrated that rs1741981 in HDAC1 was significantly associated with the response to corticosteroid treatment in asthmatics.
Asthma; Glucocorticoids; Histone deacetylase 1; Pharmacogenomics; Polymorphism
OBJECTIVE: To investigate the ratio of inhaled corticosteroid to bronchodilator as a measure of the quality of asthma prescribing by general practitioners. DESIGN: Ecological cross sectional study linking general practitioner asthma prescribing with hospital admission data and a measure of deprivation. SUBJECTS: 11 family health services authorities in the West Midlands region and 99 general practices in North Staffordshire. MAIN OUTCOME MEASURES: Hospital admission rates for asthma; the ratio of inhaled corticosteroid to bronchodilator; and Townsend deprivation scores. RESULTS: No overall significant correlation was found between admission rates for asthma and corticosteroid:bronchodilator ratios for family health services authorities (Spearman's rs = -0.109, P = 0.750) or general practices (rs = -0.084, P = 0.407). In deprived family health services authority areas and general practices an inverse non-significant correlation existed between admission rates for asthma and corticosteroid:bronchodilator ratios (rs = -0.300, P = 0.624; rs = -0.218, P = 0.136). In contrast, in more affluent areas and general practices a positive non-significant correlation existed between admission rates and corticosteroid:bronchodilator ratios (rs = 0.371, P = 0.468; rs = 0.038, P = 0.792). CONCLUSION: Although the corticosteroid:bronchodilator ratio may be a valid indicator of the quality of prescribing for individual patients with asthma, caution should be applied in interpreting aggregated ratios. Differences in the severity of asthma or the prevalence of chronic obstructive pulmonary disease may explain inconsistent associations between admission rates for asthma and corticosteroid:bronchodilator ratios in family health services authorities and general practices with different deprivation scores.
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.
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.
Significant associations (p < 0.05) were found between the P3 amplitude and alcohol dependence with multiple SNPs in the CRHR1 gene.
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.
P3; Disinhibition; Endophenotype; Stress; Corticotropin Releasing Factor (CRF)
Polymorphic inversions are a source of genetic variability with a direct impact on recombination frequencies. Given the difficulty of their experimental study, computational methods have been developed to infer their existence in a large number of individuals using genome-wide data of nucleotide variation. Methods based on haplotype tagging of known inversions attempt to classify individuals as having a normal or inverted allele. Other methods that measure differences between linkage disequilibrium attempt to identify regions with inversions but unable to classify subjects accurately, an essential requirement for association studies.
We present a novel method to both identify polymorphic inversions from genome-wide genotype data and classify individuals as containing a normal or inverted allele. Our method, a generalization of a published method for haplotype data , utilizes linkage between groups of SNPs to partition a set of individuals into normal and inverted subpopulations. We employ a sliding window scan to identify regions likely to have an inversion, and accumulation of evidence from neighboring SNPs is used to accurately determine the inversion status of each subject. Further, our approach detects inversions directly from genotype data, thus increasing its usability to current genome-wide association studies (GWAS).
We demonstrate the accuracy of our method to detect inversions and classify individuals on principled-simulated genotypes, produced by the evolution of an inversion event within a coalescent model . We applied our method to real genotype data from HapMap Phase III to characterize the inversion status of two known inversions within the regions 17q21 and 8p23 across 1184 individuals. Finally, we scan the full genomes of the European Origin (CEU) and Yoruba (YRI) HapMap samples. We find population-based evidence for 9 out of 15 well-established autosomic inversions, and for 52 regions previously predicted by independent experimental methods in ten (9+1) individuals [3,4]. We provide efficient implementations of both genotype and haplotype methods as a unified R package inveRsion.
Asthma genome-wide association studies (GWAS) have identified several asthma susceptibility genes with confidence; however the relative contribution of these genetic variants or single nucleotide polymorphisms (SNPs) to clinical endpoints (as opposed to disease diagnosis) remains largely unknown. Thus the aim of this study was to firstly bridge this gap in knowledge and secondly investigate whether these SNPs or those that are in linkage disequilibrium are likely to be functional candidates with respect to regulation of gene expression, using reported data from the ENCODE project.
Eleven of the key SNPs identified in eight loci from recent asthma GWAS were evaluated for association with asthma and clinical outcomes, including percent predicted FEV1, bronchial hyperresponsiveness (BHR) to methacholine, severity defined by British Thoracic Society steps and positive response to skin prick test, using the family based association test additive model in a well characterised UK cohort consisting of 370 families with at least two asthmatic children.
GSDMB SNP rs2305480 (Ser311Pro) was associated with asthma diagnosis (p = 8.9×10-4), BHR (p = 8.2×10-4) and severity (p = 1.5×10-4) with supporting evidence from a second GSDMB SNP rs11078927 (intronic). SNPs evaluated in IL33, IL18R1, IL1RL1, SMAD3, IL2RB, PDE4D, CRB1 and RAD50 did not show association with any phenotype tested when corrected for multiple testing. Analysis using ENCODE data provides further insight into the functional relevance of these SNPs.
Our results provide further support for the role of GSDMB SNPs in determining multiple asthma related phenotypes in childhood asthma including associations with lung function and disease severity.
Asthma; ENCODE; eQTL; GWAS; Clinical endpoints
Responses of patients with persistent asthma to ambient air pollution may be different from those of general populations. For example, asthma medications may modify the effects of ambient air pollutants on peak expiratory flow (PEF). Few studies examined the association between air pollution and PEF in patients with persistent asthma on well-defined medication regimens using asthma clinical trial data. Airway obstruction effects of ambient air pollutants, using 14,919 person-days of daily self-measured peak expiratory flow (PEF), were assessed from 154 patients with persistent asthma during the 16 wk of active treatment in the Salmeterol Off Corticosteroids Study trial. The three therapies were an inhaled corticosteroid, an inhaled long-acting β-agonist, and placebo. The participants were nonsmokers aged 12 through 63 yr, recruited from 6 university-based ambulatory care centers from February 1997 to January 1999. Air pollution data were derived from the U.S. Environmental Protection Agency Aerometric Information Retrieval System. An increase of 10 ppb of ambient daily mean concentrations of NO2 was associated with a decrease in PEF of 1.53 L/min (95% confidence interval [CI] −2.93 to −0.14) in models adjusted for age, gender, race/ethnicity, asthma clinical center, season, week, daily average temperature, and daily average relative humidity. The strongest association between NO2 and PEF was observed among the patients treated with salmeterol. Negative associations were also found between PEF and SO2 and between PEF and PM10, respectively. The results show that the two medication regimens protected against the effects of PM10. However, salmeterol increased the sensitivity to NO2 and triamcinalone enhanced the sensitivity to SO2.
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.
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.
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.
An important etiological hypothesis about depression is stress has neurotoxic effects that damage the hippocampal cells. Corticotropin-releasing hormone (CRH) regulates brain-derived neurotrophic factor (BDNF) expression through influencing cAMP and Ca2+ signaling pathways during the course. The aim of this study is to examine the single and combined effects of CRH receptor 1 (CRHR1) and BDNF genes in recurrent major depressive disorder (MDD).
The sample consists of 181 patients with recurrent MDD and 186 healthy controls. Whether genetic variations interaction between CRHR1 and BDNF genes might be associated with increased susceptibility to recurrent MDD was studied by using a gene-based association analysis of single-nucleotide polymorphisms (SNPs). CRHR1 gene (rs1876828, rs242939 and rs242941) and BDNF gene (rs6265) were identified in the samples of patients diagnosed with recurrent MDD and matched controls. Allelic association between CRHR1 rs242939 and recurrent MDD was found in our sample (allelic: p = 0.018, genotypic: p = 0.022) with an Odds Ratio 0.454 (95% CI 0.266–0.775). A global test of these four haplotypes showed a significant difference between recurrent MDD group and control group (chi-2 = 13.117, df = 3, P = 0.016. Furthermore, BDNF and CRHR1 interactions were found in the significant 2-locus, gene–gene interaction models (p = 0.05) using a generalized multifactor dimensionality reduction (GMDR) method.
Our results suggest that an interaction between CRHR1 and BDNF genes constitutes susceptibility to recurrent MDD.
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.
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.
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).
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.
Neuroticism; CRHR1; maltreatment; genetics; personality; HPA axis
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.
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.
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.
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.
Cortisol; Dex/CRH test; HPA axis; genetics; CRHR1 gene; gene-environment interaction
Rationale: Inhaled β-agonists are one of the most widely used classes of drugs for the treatment of asthma. However, a substantial proportion of patients with asthma do not have a favorable response to these drugs, and identifying genetic determinants of drug response may aid in tailoring treatment for individual patients.
Objectives: To screen variants in candidate genes in the steroid and β-adrenergic pathways for association with response to inhaled β-agonists.
Methods: We genotyped 844 single nucleotide polymorphisms (SNPs) in 111 candidate genes in 209 children and their parents participating in the Childhood Asthma Management Program. We screened the association of these SNPs with acute response to inhaled β-agonists (bronchodilator response [BDR]) using a novel algorithm implemented in a family-based association test that ranked SNPs in order of statistical power. Genes that had SNPs with median power in the highest quartile were then taken for replication analyses in three other asthma cohorts.
Measurements and Main Results: We identified 17 genes from the screening algorithm and genotyped 99 SNPs from these genes in a second population of patients with asthma. We then genotyped 63 SNPs from four genes with significant associations with BDR, for replication in a third and fourth population of patients with asthma. Evidence for association from the four asthma cohorts was combined, and SNPs from ARG1 were significantly associated with BDR. SNP rs2781659 survived Bonferroni correction for multiple testing (combined P value = 0.00048, adjusted P value = 0.047).
Conclusions: These findings identify ARG1 as a novel gene for acute BDR in both children and adults with asthma.
pharmacogenetics; asthma; bronchodilator agents
The response to treatment for asthma is characterized by wide interindividual variability, with a significant number of patients who have no response. We hypothesized that a genomewide association study would reveal novel pharmacogenetic determinants of the response to inhaled glucocorticoids.
We analyzed a small number of statistically powerful variants selected on the basis of a family-based screening algorithm from among 534,290 single-nucleotide polymorphisms (SNPs) to determine changes in lung function in response to inhaled glucocorticoids. A significant, replicated association was found, and we characterized its functional effects.
We identified a significant pharmacogenetic association at SNP rs37972, replicated in four independent populations totaling 935 persons (P = 0.0007), which maps to the glucocorticoid-induced transcript 1 gene (GLCCI1) and is in complete linkage disequilibrium (i.e., perfectly correlated) with rs37973. Both rs37972 and rs37973 are associated with decrements in GLCCI1 expression. In isolated cell systems, the rs37973 variant is associated with significantly decreased luciferase reporter activity. Pooled data from treatment trials indicate reduced lung function in response to inhaled glucocorticoids in subjects with the variant allele (P = 0.0007 for pooled data). Overall, the mean (± SE) increase in forced expiratory volume in 1 second in the treated subjects who were homozygous for the mutant rs37973 allele was only about one third of that seen in similarly treated subjects who were homozygous for the wild-type allele (3.2 ± 1.6% vs. 9.4 ± 1.1%), and their risk of a poor response was significantly higher (odds ratio, 2.36; 95% confidence interval, 1.27 to 4.41), with genotype accounting for about 6.6% of overall inhaled glucocorticoid response variability.
A functional GLCCI1 variant is associated with substantial decrements in the response to inhaled glucocorticoids in patients with asthma. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00000575.)
The human genome is a highly dynamic structure that shows a wide range of genetic polymorphic variation. Unlike other types of structural variation, little is known about inversion variants within normal individuals because such events are typically balanced and are difficult to detect and analyze by standard molecular approaches. Using sequence-based, cytogenetic and genotyping approaches, we characterized six large inversion polymorphisms that map to regions associated with genomic disorders with complex segmental duplications mapping at the breakpoints. We developed a metaphase FISH-based assay to genotype inversions and analyzed the chromosomes of 27 individuals from three HapMap populations. In this subset, we find that these inversions are less frequent or absent in Asians when compared with European and Yoruban populations. Analyzing multiple individuals from outgroup species of great apes, we show that most of these large inversion polymorphisms are specific to the human lineage with two exceptions, 17q21.31 and 8p23 inversions, which are found to be similarly polymorphic in other great ape species and where the inverted allele represents the ancestral state. Investigating linkage disequilibrium relationships with genotyped SNPs, we provide evidence that most of these inversions appear to have arisen on at least two different haplotype backgrounds. In these cases, discovery and genotyping methods based on SNPs may be confounded and molecular cytogenetics remains the only method to genotype these inversions.
The British Thoracic Association has conducted a confidential inquiry into death from asthma of adults aged 15 to 64 years resident in the West Midland and Mersey regions in 1979. Information concerning the patients, their asthma, and death was obtained by questionnaire, interview with the general medical practitioner and a relative, and from patient records. A panel of three physicians, helped by a pathologist, identified 90 patients as dying of asthma and assessed management and treatment in the last year, last month of life, and the fatal attack. They were generally chronic asthmatics, but unstable, most having suffered severe attacks previously. Corticosteroids and bronchodilator drugs were in general underprescribed or not given in sufficiently large doses. Inhaled corticosteroids and cromoglycate had frequently not been tried. The patient's co-operation with the management of the asthma was satisfactory for only 42 of the 90 patients. For 71 of the patients the fatal attack lasted under 24 hours; of the 77 who died at home or at work, 50 did not receive any medical attention in the fatal attack. Failure to recognise the severity of the asthma by patients, relatives, and doctor often caused delay in starting appropriate treatment. The interaction of several of these adverse factors often contributed to the patient's death. The panel considered that there were potentially preventable factors contributory to the death of 77 (86%) of the 90 patients. Within the limits of retrospective judgment the panel considered that the routine management of the asthma was often unsatisfactory as patients known to suffer severe acute attacks were often not adequately supervised or instructed in the management and treatment of their asthma. From this retrospective inquiry we concluded that closer overall supervision, including careful attention to patient education, earlier and more intensive treatment, and pre-arranged immediate admission to hospital for asthma emergencies is desirable.
Major classes of medication in asthma management include bronchodilating β2-agonists, anti-inflammatory inhaled corticosteroids, leukotriene modifiers and theophyllines. However, all asthmatics do not respond to the same extent to a given medication. Available data suggest that a substantial range of individual variability, as much as 70%, may be due to genetic characteristics of each patient. Pharmacogenomics offers the potential to optimize medications for individual asthmatics by using genetic information to improve efficacy or avoid adverse effects. The best-studied case of the potential contribution of pharmacogenomics to treatment response in asthma comes from studies on human β2 adrenergic receptors. In addition, genetic variation in β2-adrenergic receptor (Arg16Gly) may predict response to anticholinergics for the treatment of asthma. In case of inhaled corticosteroids, a recent investigation using a traditional SNP-based approach identified a gene for corticotropin releasing hormone receptor 1 as a potential marker of response. Another major pathway that has been investigated is the pathway underlying response to cysteinyl leukotriene receptor antagonist. It is likely that in the near future, pharmacogenomic approaches based on individual genetic information will be introduced into an asthma treatment guideline and this guideline will allow us to identify those who have the best chance to respond to a specific medication.
Asthma; pharmacogenomics; treatment response
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.
amygdala; corticotrophin-releasing hormone; genetic association; hippocampus; non-human primate; rhesus macaque