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1.  CTNNA3 and SEMA3D: promising loci for asthma exacerbation identified through multiple GWAS 
BACKGROUND
Asthma exacerbations are a major cause of morbidity and medical cost.
OBJECTIVE
The objective of this study was to identify genetic predictors of exacerbations in subjects with asthma.
METHODS
We performed GWAS meta analysis of acute asthma exacerbation in two pediatric clinical trials: Childhood Asthma Management Program (CAMP, n=581) and Childhood Asthma Research and Education (CARE, n=205) network trials. Acute asthma exacerbations was defined as treatment with a five-day course of oral steroids. We obtained a replication cohort from BioVU (n=786), the Vanderbilt University electronic medical record-linked DNA biobank. We used CD4+ lymphocyte genome-wide mRNA expression profiling to identify associations of top SNPs with mRNA abundance of nearby genes.
RESULTS
A locus in CTNNA3 reached genome-wide significance (rs7915695, p=2.19*10-8, mean exacerbations 6.05 for minor alleles vs. 3.71 for homozygous major). Among four top SNPs replicated in BioVU, rs993312 in SEMA3D was significant (p=0.0083), and displayed stronger association among African Americans (p=0.0004 in BioVU, mean exacerbations 3.91 vs. 1.53; p=0.0089 in CAMP, mean exacerbations 6.0 vs. 3.25). CTNNA3 variants did not replicate in BioVU. A regulatory variant in the CTNNA3 locus was associated with CTNNA3 mRNA expression in CD4+ cells from asthmatics (p=0.00079). CTNNA3 appears to be active in immune response, and SEMA3D has a plausible role in airway remodeling. We also provide a replication of a previous association of P2RX7 with asthma exacerbation.
CONCLUSIONS
We identified two loci associated with exacerbations through GWAS. CTNNA3 met genome-wide significance thresholds and SEMA3D replicated in a clinical Biobank database.
doi:10.1016/j.jaci.2015.04.039
PMCID: PMC4676949  PMID: 26073756
Asthma; Exacerbation; GWAS; eQTL; CTNNA3; SEMA3D; BioBank; Childhood Asthma
2.  Whole genome prediction and heritability of childhood asthma phenotypes 
Abstract
Introduction
While whole genome prediction (WGP) methods have recently demonstrated successes in the prediction of complex genetic diseases, they have not yet been applied to asthma and related phenotypes. Longitudinal patterns of lung function differ between asthmatics, but these phenotypes have not been assessed for heritability or predictive ability. Herein, we assess the heritability and genetic predictability of asthma‐related phenotypes.
Methods
We applied several WGP methods to a well‐phenotyped cohort of 832 children with mild‐to‐moderate asthma from CAMP. We assessed narrow‐sense heritability and predictability for airway hyperresponsiveness, serum immunoglobulin E, blood eosinophil count, pre‐ and post‐bronchodilator forced expiratory volume in 1 sec (FEV1), bronchodilator response, steroid responsiveness, and longitudinal patterns of lung function (normal growth, reduced growth, early decline, and their combinations). Prediction accuracy was evaluated using a training/testing set split of the cohort.
Results
We found that longitudinal lung function phenotypes demonstrated significant narrow‐sense heritability (reduced growth, 95%; normal growth with early decline, 55%). These same phenotypes also showed significant polygenic prediction (areas under the curve [AUCs] 56% to 62%). Including additional demographic covariates in the models increased prediction 4–8%, with reduced growth increasing from 62% to 66% AUC. We found that prediction with a genomic relatedness matrix was improved by filtering available SNPs based on chromatin evidence, and this result extended across cohorts.
Conclusions
Longitudinal reduced lung function growth displayed extremely high heritability. All phenotypes with significant heritability showed significant polygenic prediction. Using SNP‐prioritization increased prediction across cohorts. WGP methods show promise in predicting asthma‐related heritable traits.
doi:10.1002/iid3.133
PMCID: PMC5134727  PMID: 27980782
Childhood asthma; heritability; longitudinal lung function patterns; polygenic prediction; whole‐genome prediction
4.  Stress and Bronchodilator Response in Children with Asthma 
Rationale: Stress is associated with asthma morbidity in Puerto Ricans (PRs), who have reduced bronchodilator response (BDR).
Objectives: To examine whether stress and/or a gene regulating anxiety (ADCYAP1R1) is associated with BDR in PR and non-PR children with asthma.
Methods: This was a cross-sectional study of stress and BDR (percent change in FEV1 after BD) in 234 PRs ages 9–14 years with asthma. We assessed child stress using the Checklist of Children’s Distress Symptoms, and maternal stress using the Perceived Stress Scale. Replication analyses were conducted in two cohorts. Polymorphisms in ADCYAP1R1 were genotyped in our study and six replication studies. Multivariable models of stress and BDR were adjusted for age, sex, income, environmental tobacco smoke, and use of inhaled corticosteroids.
Measurements and Main Results: High child stress was associated with reduced BDR in three cohorts. PR children who were highly stressed (upper quartile, Checklist of Children’s Distress Symptoms) and whose mothers had high stress (upper quartile, Perceived Stress Scale) had a BDR that was 10.2% (95% confidence interval, 6.1–14.2%) lower than children who had neither high stress nor a highly stressed mother. A polymorphism in ADCYAP1R1 (rs34548976) was associated with reduced BDR. This single-nucleotide polymorphism is associated with reduced expression of the gene for the β2-adrenergic receptor (ADRB2) in CD4+ lymphocytes of subjects with asthma, and it affects brain connectivity of the amygdala and the insula (a biomarker of anxiety).
Conclusions: High child stress and an ADCYAP1R1 single-nucleotide polymorphism are associated with reduced BDR in children with asthma. This is likely caused by down-regulation of ADRB2 in highly stressed children.
doi:10.1164/rccm.201501-0037OC
PMCID: PMC4511425  PMID: 25918834
asthma; Puerto Ricans; bronchodilator response; stress
5.  A disease module in the interactome explains disease heterogeneity, drug response and captures novel pathways and genes in asthma 
Human Molecular Genetics  2015;24(11):3005-3020.
Recent advances in genetics have spurred rapid progress towards the systematic identification of genes involved in complex diseases. Still, the detailed understanding of the molecular and physiological mechanisms through which these genes affect disease phenotypes remains a major challenge. Here, we identify the asthma disease module, i.e. the local neighborhood of the interactome whose perturbation is associated with asthma, and validate it for functional and pathophysiological relevance, using both computational and experimental approaches. We find that the asthma disease module is enriched with modest GWAS P-values against the background of random variation, and with differentially expressed genes from normal and asthmatic fibroblast cells treated with an asthma-specific drug. The asthma module also contains immune response mechanisms that are shared with other immune-related disease modules. Further, using diverse omics (genomics, gene-expression, drug response) data, we identify the GAB1 signaling pathway as an important novel modulator in asthma. The wiring diagram of the uncovered asthma module suggests a relatively close link between GAB1 and glucocorticoids (GCs), which we experimentally validate, observing an increase in the level of GAB1 after GC treatment in BEAS-2B bronchial epithelial cells. The siRNA knockdown of GAB1 in the BEAS-2B cell line resulted in a decrease in the NFkB level, suggesting a novel regulatory path of the pro-inflammatory factor NFkB by GAB1 in asthma.
doi:10.1093/hmg/ddv001
PMCID: PMC4447811  PMID: 25586491
6.  Genome-wide Association Study and Admixture Mapping Reveal New Loci Associated with Total IgE Levels in Latinos 
Background
Immunoglobulin E (IgE) is a key mediator of allergic inflammation and is frequently elevated in allergic disorders.
Objective
To identify genetic variants associated with IgE levels in Latinos.
Methods
We performed a genome-wide association study (GWAS) and admixture mapping of total IgE levels in 3,334 Latinos from the Genes-environments & Admixture in Latino Americans (GALA II) study. Replication was evaluated in 454 Latinos, 1,564 European Americans, and 3,187 African Americans from independent studies.
Results
We confirmed associations of six genes identified by previous GWAS and identified a novel genome-wide significant association of a polymorphism in ZNF365 with total IgE (rs200076616, p=2.3x10−8). We next identified four admixture mapping peaks (6p21.32-p22.1, 13p22-31, 14q23.2, and 22q13.1) where local African, European, and/or Native American ancestry was significantly associated with IgE levels. The most significant peak was 6p21.32-p22.1, where Native American ancestry was associated with lower levels of IgE (p=4.95x10−8). All but 22q13.1 were replicated in an independent sample of Latinos, and two of the peaks were replicated in African Americans (6p21.32-p22.1 and 14q23.2). Fine mapping of 6p21.32-p22.1 identified six genome-wide significant single nucleotide polymorphisms in Latinos, two of which replicated in European Americans. Another SNP was peak-wide significant within 14q23.2 in African Americans (rs1741099, p=3.7x10−6), and replicated in non-African American samples (p=0.011).
Conclusion
We confirmed genetic associations at six genes, and identified novel associations within ZNF365, HLA-DQA1, and 14q23.2. Our results highlight the importance of studying diverse, multi-ethnic populations to uncover novel loci associated with total IgE levels.
doi:10.1016/j.jaci.2014.10.033
PMCID: PMC4458233  PMID: 25488688
immunoglobulin E; genome-wide association study; admixture mapping; allergy; asthma; next-generation sequencing; Latinos; Hispanics; minority populations
8.  Noninvasive Analysis of the Sputum Transcriptome Discriminates Clinical Phenotypes of Asthma 
Rationale: The airway transcriptome includes genes that contribute to the pathophysiologic heterogeneity seen in individuals with asthma.
Objectives: We analyzed sputum gene expression for transcriptomic endotypes of asthma (TEA), gene signatures that discriminate phenotypes of disease.
Methods: Gene expression in the sputum and blood of patients with asthma was measured using Affymetrix microarrays. Unsupervised clustering analysis based on pathways from the Kyoto Encyclopedia of Genes and Genomes was used to identify TEA clusters. Logistic regression analysis of matched blood samples defined an expression profile in the circulation to determine the TEA cluster assignment in a cohort of children with asthma to replicate clinical phenotypes.
Measurements and Main Results: Three TEA clusters were identified. TEA cluster 1 had the most subjects with a history of intubation (P = 0.05), a lower prebronchodilator FEV1 (P = 0.006), a higher bronchodilator response (P = 0.03), and higher exhaled nitric oxide levels (P = 0.04) compared with the other TEA clusters. TEA cluster 2, the smallest cluster, had the most subjects that were hospitalized for asthma (P = 0.04). TEA cluster 3, the largest cluster, had normal lung function, low exhaled nitric oxide levels, and lower inhaled steroid requirements. Evaluation of TEA clusters in children confirmed that TEA clusters 1 and 2 are associated with a history of intubation (P = 5.58 × 10−6) and hospitalization (P = 0.01), respectively.
Conclusions: There are common patterns of gene expression in the sputum and blood of children and adults that are associated with near-fatal, severe, and milder asthma.
doi:10.1164/rccm.201408-1440OC
PMCID: PMC4451618  PMID: 25763605
molecular endotyping; genomic; RNA; severe asthma; pathway analysis
9.  Glucocorticoid Genes and the Developmental Origins of Asthma Susceptibility and Treatment Response 
Antenatal corticosteroids enhance lung maturation. However, the importance of glucocorticoid genes on early lung development, asthma susceptibility, and treatment response remains unknown. We investigated whether glucocorticoid genes are important during lung development and their role in asthma susceptibility and treatment response. We identified genes that were differentially expressed by corticosteroids in two of three genomic datasets: lymphoblastoid cell lines of participants in the Childhood Asthma Management Program, a glucocorticoid chromatin immunoprecipitation/RNA sequencing experiment, or a murine model; these genes made up the glucocorticoid gene set (GCGS). Using gene expression profiles from 38 human fetal lungs and C57BL/6J murine fetal lungs, we identified developmental genes that were in the top 5% of genes contributing to the top three principal components (PCs) most highly associated with post-conceptional age. Glucocorticoid genes that were enriched in this set of developmental genes were then included in the developmental glucocorticoid gene set (DGGS). We then investigated whether glucocorticoid genes are important during lung development, and their role in asthma susceptibility and treatment response. A total of 232 genes were included in the GCGS. Analysis of gene expression demonstrated that glucocorticoid genes were enriched in lung development (P = 7.02 × 10−26). The developmental GCGS was enriched for genes that were differentially expressed between subjects with asthma and control subjects (P = 4.26 × 10−3) and were enriched after treatment of subjects with asthma with inhaled corticosteroids (P < 2.72 × 10−4). Our results show that glucocorticoid genes are overrepresented among genes implicated in fetal lung development. These genes influence asthma susceptibility and treatment response, suggesting their involvement in the early ontogeny of asthma.
doi:10.1165/rcmb.2014-0109OC
PMCID: PMC4491138  PMID: 25192440
glucocorticoid genes; lung development; asthma; asthma treatment
10.  Joint GWAS Analysis: Comparing similar GWAS at different genomic resolutions identifies novel pathway associations with six complex diseases 
Genomics data  2014;2:202-211.
We show here that combining two existing genome wide association studies (GWAS) yields additional biologically relevant information, beyond that obtained by either GWAS separately. We propose Joint GWAS Analysis, a method that compares a pair of GWAS for similarity among the top SNP associations, top genes identified, gene functional clusters, and top biological pathways. We show that Joint GWAS Analysis identifies additional enriched biological pathways that would be missed by traditional Single-GWAS analysis. Furthermore, we examine the similarities of six complex genetic disorders at the SNP-level, gene-level, gene-cluster-level, and pathway-level. We make concrete hypotheses regarding novel pathway associations for several complex disorders considered, based on the results of Joint GWAS Analysis. Together, these results demonstrate that common complex disorders share substantially more genomic architecture than has been previously realized and that the meta-analysis of GWAS needs not be limited to GWAS of the same phenotype to be informative.
doi:10.1016/j.gdata.2014.04.004
PMCID: PMC4378545  PMID: 25838990
Systems genetics; GWAS; Meta-analysis; Pathway enrichment; Pleiotropy
11.  A genome-wide survey of CD4+ lymphocyte regulatory genetic variants identifies novel asthma genes 
Background
Genome-wide association studies have yet to identify the majority of genetic variants involved in asthma. We hypothesized that expression quantitative trait locus (eQTL) mapping can identify novel asthma genes by enabling prioritization of putative functional variants for association testing.
Objective
We evaluated 6,706 cis-acting expression-associated variants (eSNP) identified through a genome-wide eQTL survey of CD4+ lymphocytes for association with asthma.
Methods
eSNP were tested for association with asthma in 359 asthma cases and 846 controls from the Childhood Asthma Management Program, with verification using family-based testing. Significant associations were tested for replication in 579 parent-child trios with asthma from Costa Rica. Further functional validation was performed by Formaldehyde Assisted Isolation of Regulatory Elements (FAIRE)-qPCR and Chromatin-Immunoprecipitation (ChIP)-PCR in lung derived epithelial cell lines (Beas-2B and A549) and Jurkat cells, a leukemia cell line derived from T lymphocytes.
Results
Cis-acting eSNP demonstrated associations with asthma in both cohorts. We confirmed the previously-reported association of ORMDL3/GSDMB variants with asthma (combined p=2.9 × 108). Reproducible associations were also observed for eSNP in three additional genes: FADS2 (p=0.002), NAGA (p=0.0002), and F13A1 (p=0.0001). We subsequently demonstrated that FADS2 mRNA is increased in CD4+ lymphocytes in asthmatics, and that the associated eSNPs reside within DNA segments with histone modifications that denote open chromatin status and confer enhancer activity.
Conclusions
Our results demonstrate the utility of eQTL mapping in the identification of novel asthma genes, and provide evidence for the importance of FADS2, NAGA, and F13A1 in the pathogenesis of asthma.
doi:10.1016/j.jaci.2014.04.011
PMCID: PMC4253878  PMID: 24934276
Asthma; CD4+; lymphocytes; regulatory variants; Expression Quantitative Trait Locus (eQTL); Haplotype; Integrative Genomics
12.  Genome-wide interaction studies reveal sex-specific asthma risk alleles 
Human Molecular Genetics  2014;23(19):5251-5259.
Asthma is a complex disease with sex-specific differences in prevalence. Candidate gene studies have suggested that genotype-by-sex interaction effects on asthma risk exist, but this has not yet been explored at a genome-wide level. We aimed to identify sex-specific asthma risk alleles by performing a genome-wide scan for genotype-by-sex interactions in the ethnically diverse participants in the EVE Asthma Genetics Consortium. We performed male- and female-specific genome-wide association studies in 2653 male asthma cases, 2566 female asthma cases and 3830 non-asthma controls from European American, African American, African Caribbean and Latino populations. Association tests were conducted in each study sample, and the results were combined in ancestry-specific and cross-ancestry meta-analyses. Six sex-specific asthma risk loci had P-values < 1 × 10−6, of which two were male specific and four were female specific; all were ancestry specific. The most significant sex-specific association in European Americans was at the interferon regulatory factor 1 (IRF1) locus on 5q31.1. We also identify a Latino female-specific association in RAP1GAP2. Both of these loci included single-nucleotide polymorphisms that are known expression quantitative trait loci and have been associated with asthma in independent studies. The IRF1 locus is a strong candidate region for male-specific asthma susceptibility due to the association and validation we demonstrate here, the known role of IRF1 in asthma-relevant immune pathways and prior reports of sex-specific differences in interferon responses.
doi:10.1093/hmg/ddu222
PMCID: PMC4159149  PMID: 24824216
13.  Ethnic-Specific Associations of Rare and Low Frequency DNA Sequence Variants with Asthma 
Nature communications  2015;6:5965.
Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (<1%) and low frequency (1–5%) variants using the Illumina HumanExome BeadChip array in 4,794 asthma cases, 4,707 non-asthmatic controls, and 590 case-parent trios representing European Americans, African Americans/African Caribbeans, and Latinos. Our study reveals one low frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P=4.31×10−6; OR=1.25; MAF=1.21%) and two genes harboring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12-21 asthma locus in the Latino and combined samples (P=7.81×10−8 and 4.09×10−8, respectively) and MTHFR in the African ancestry sample (P=1.72×10−6). Our results suggest that associations with rare and low frequency variants are ethnic specific and not likely to explain a significant proportion of the “missing heritability” of asthma.
doi:10.1038/ncomms6965
PMCID: PMC4309441  PMID: 25591454
14.  Association of defensin β-1 gene polymorphisms with asthma 
Background
Defensins are antimicrobial peptides that may take part in airway inflammation and hyperresponsiveness.
Objective
We characterized the genetic diversity in the defensin β-1 (DEFB1) locus and tested for an association between common genetic variants and asthma diagnosis.
Methods
To identify single nucleotide polymorphisms (SNPs), we resequenced this gene in 23 self-defined European Americans and 24 African Americans. To test whether DEFB1 genetic variants are associated with asthma, we genotyped 4 haplotype-tag SNPs in 517 asthmatic and 519 control samples from the Nurses’ Health Study (NHS) and performed a case-control association analysis. To replicate these findings, we evaluated the DEFB1 polymorphisms in a second cohort from the Childhood Asthma Management Program.
Results
Within the NHS, single SNP testing suggested an association between asthma diagnosis and a 5′ genomic SNP (g.–1816 T>C; P = .025) and intronic SNP (IVS+692 G>A; P = .054). A significant association between haplotype (Adenine, Cytosine, Thymine, Adenine [ACTA]) and asthma (P = .024) was also identified. Associations between asthma diagnosis and both DEFB1 polymorphisms were observed in Childhood Asthma Management Program, a second cohort: g.–1816 T>C and IVS+692 G>A demonstrated significant transmission distortion (P = .05 and .007, respectively). Transmission distortion was not observed in male subjects. The rare alleles (–1816C and +692A) were undertransmitted to offspring with asthma, suggesting a protective effect, contrary to the findings in the NHS cohort. Similar effects were evident at the haplotype level: ACTA was undertransmitted (P = .04) and was more prominent in female subjects (P = .007).
Conclusion
Variation in DEFB1 contributes to asthma diagnosis, with apparent gender-specific effects.
doi:10.1016/j.jaci.2004.11.013
PMCID: PMC4475026  PMID: 15696078
Asthma; asthma genetics; defensin; association studies
15.  Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma 
Nature Communications  2015;6:5965.
Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (<1%) and low-frequency (1–5%) variants using the Illumina HumanExome BeadChip array in 4,794 asthma cases, 4,707 non-asthmatic controls and 590 case–parent trios representing European Americans, African Americans/African Caribbeans and Latinos. Our study reveals one low-frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P=4.31 × 10−6; OR=1.25; MAF=1.21%) and two genes harbouring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12–21 asthma locus in the Latino and combined samples (P=7.81 × 10−8 and 4.09 × 10−8, respectively) and MTHFR in the African ancestry sample (P=1.72 × 10−6). Our results suggest that associations with rare and low-frequency variants are ethnic specific and not likely to explain a significant proportion of the ‘missing heritability’ of asthma.
Common variants account for only a small amount of the heritable risk for developing asthma. Using a meta-analysis approach, Igartua et al. identify one low-frequency missense mutation and two genes with functional variants that are associated with asthma, but only in specific ethnic groups.
doi:10.1038/ncomms6965
PMCID: PMC4309441  PMID: 25591454
16.  Joint GWAS Analysis: Comparing similar GWAS at different genomic resolutions identifies novel pathway associations with six complex diseases 
Genomics Data  2014;2:202-211.
We show here that combining two existing genome wide association studies (GWAS) yields additional biologically relevant information, beyond that obtained by either GWAS separately. We propose Joint GWAS Analysis, a method that compares a pair of GWAS for similarity among the top SNP associations, top genes identified, gene functional clusters, and top biological pathways. We show that Joint GWAS Analysis identifies additional enriched biological pathways that would be missed by traditional Single-GWAS analysis. Furthermore, we examine the similarities of six complex genetic disorders at the SNP-level, gene-level, gene-cluster-level, and pathway-level. We make concrete hypotheses regarding novel pathway associations for several complex disorders considered, based on the results of Joint GWAS Analysis. Together, these results demonstrate that common complex disorders share substantially more genomic architecture than has been previously realized and that the meta-analysis of GWAS needs not be limited to GWAS of the same phenotype to be informative.
doi:10.1016/j.gdata.2014.04.004
PMCID: PMC4378545  PMID: 25838990
Systems genetics; GWAS; Meta-analysis; Pathway enrichment; Pleiotropy
17.  Classification of childhood asthma phenotypes and long-term clinical responses to inhaled anti-inflammatory medications 
Background
Although recent studies have identified the presence of phenotypic clusters in asthmatic patients, the clinical significance and temporal stability of these clusters have not been explored.
Objective
Our aim was to examine the clinical relevance and temporal stability of phenotypic clusters in children with asthma.
Methods
We applied spectral clustering to clinical data from 1041 children with asthma participating in the Childhood Asthma Management Program. Posttreatment randomization follow-up data collected over 48 months were used to determine the effect of these clusters on pulmonary function and treatment response to inhaled anti-inflammatory medication.
Results
We found 5 reproducible patient clusters that could be differentiated on the basis of 3 groups of features: atopic burden, degree of airway obstruction, and history of exacerbation. Cluster grouping predicted long-term asthma control, as measured by the need for oral prednisone (P < .0001) or additional controller medications (P = .001), as well as longitudinal differences in pulmonary function (P < .0001). We also found that the 2 clusters with the highest rates of exacerbation had different responses to inhaled corticosteroids when compared with the other clusters. One cluster demonstrated a positive response to both budesonide (P = .02) and nedocromil (P = .01) compared with placebo, whereas the other cluster demonstrated minimal responses to both budesonide (P = .12) and nedocromil (P = .56) compared with placebo.
Conclusion
Phenotypic clustering can be used to identify longitudinally consistent and clinically relevant patient subgroups, with implications for targeted therapeutic strategies and clinical trials design.
PMCID: PMC4047642  PMID: 24892144
Childhood asthma; asthma phenotypes; inhaled corticosteroids; cluster analysis; asthma classification; longitudinal study
18.  A Meta-analysis of Genome-wide Association Studies for Serum Total IgE in Diverse Study Populations 
Background
Immunoglobulin E (IgE) is both a marker and mediator of allergic inflammation. Despite reported differences in serum total IgE levels by race-ethnicity, African American and Latino individuals have not been well represented in genetic studies of total IgE.
Objective
To identify the genetic predictors of serum total IgE levels.
Methods
We used genome wide association (GWA) data from 4,292 individuals (2,469 African Americans, 1,564 European Americans, and 259 Latinos) in the EVE Asthma Genetics Consortium. Tests for association were performed within each cohort by race-ethnic group (i.e., African American, Latino, and European American) and asthma status. The resulting p-values were meta-analyzed accounting for sample size and direction of effect. Top single nucleotide polymorphism (SNP) associations from the meta-analysis were reassessed in six additional cohorts comprising 5,767 individuals.
Results
We identified 10 unique regions where the combined association statistic was associated with total serum IgE levels (P-value <5.0×10−6) and the minor allele frequency was ≥5% in two or more population groups. Variant rs9469220, corresponding to HLA-DQB1, was the most significantly associated SNP with serum total IgE levels when assessed in both the replication cohorts and the discovery and replication sets combined (P-value = 0.007 and 2.45×10−7, respectively). In addition, findings from earlier GWA studies were also validated in the current meta-analysis.
Conclusion
This meta-analysis independently identified a variant near HLA-DQB1 as a predictor of total serum IgE in multiple race-ethnic groups. This study also extends and confirms the findings of earlier GWA analyses in African American and Latino individuals.
doi:10.1016/j.jaci.2012.10.002
PMCID: PMC3596497  PMID: 23146381
meta-analysis; genome wide association study; total immunoglobulin E; race-ethnicity; continental population groups
19.  Further Replication Studies of the EVE Consortium Meta-Analysis Identifies Two Asthma Risk Loci in European Americans 
Background
Genome-wide association studies of asthma have implicated many genetic risk factors, with well-replicated associations at approximately 10 loci that account for only a small proportion of the genetic risk.
Objectives
We aimed to identify additional asthma risk loci by performing an extensive replication study of the results from the EVE Consortium meta-analysis.
Methods
We selected 3186 SNPs for replication based on the p-values from the EVE Consortium meta-analysis. These SNPs were genotyped in ethnically diverse replication samples from nine different studies, totaling to 7202 cases, 6426 controls, and 507 case-parent trios. Association analyses were conducted within each participating study and the resulting test statistics were combined in a meta-analysis.
Results
Two novel associations were replicated in European Americans: rs1061477 in the KLK3 gene on chromosome 19 (combined OR = 1.18; 95% CI 1.10 – 1.25) and rs9570077 (combined OR =1.20 95% CI 1.12–1.29) on chromosome 13q21. We could not replicate any additional associations in the African American or Latino individuals.
Conclusions
This extended replication study identified two additional asthma risk loci in populations of European descent. The absence of additional loci for African Americans and Latino individuals highlights the difficulty in replicating associations in admixed populations.
doi:10.1016/j.jaci.2012.07.054
PMCID: PMC3666859  PMID: 23040885
Asthma; genetic risk factors; meta-analysis; KLK3
20.  Very important pharmacogene summary for VDR 
Pharmacogenetics and genomics  2012;22(10):758-763.
doi:10.1097/FPC.0b013e328354455c
PMCID: PMC3678550  PMID: 22588316
drug response; genetic variants; pharmacogenomics; vitamin D receptor
21.  IL10 Gene Polymorphisms Are Associated With Asthma Phenotypes in Children 
Genetic epidemiology  2004;26(2):155-165.
IL10 is an anti-inflammatory cytokine that has been found to have lower production in macrophages and mononuclear cells from asthmatics. Since reduced IL10 levels may influence the severity of asthma phenotypes, we examined IL10 single-nucleotide polymorphisms (SNPs) for association with asthma severity and allergy phenotypes as quantitative traits. Utilizing DNA samples from 518 Caucasian asthmatic children from the Childhood Asthma Management Program (CAMP) and their parents, we genotyped six IL10 SNPs: 3 in the promoter, 2 in introns, and one in the 3′ UTR. Using family-based association tests, each SNP was tested for association with asthma and allergy phenotypes individually. Population-based association analysis was performed with each SNP locus, the promoter haplotypes and the 6-loci haplotypes. The 3′ UTR SNP was significantly associated with FEV1 as a percent of predicted (FEV1PP) (P=0.0002) in both the family and population analyses. The promoter haplotype GCC was positively associated with IgE levels and FEV1PP (P=0.007 and 0.012, respectively). The promoter haplotype ATA was negatively associated with lnPC20 and FEV1PP (P=0.008 and 0.043, respectively). Polymorphisms in IL10 are associated with asthma phenotypes in this cohort. Further studies of variation in the IL10 gene may help elucidate the mechanism of asthma development in children.
doi:10.1002/gepi.10298
PMCID: PMC3705717  PMID: 14748015
interleukin 10 (IL10); single nucleotide polymorphism (SNP); genetic association; family-based association test (FBAT); haplotype; promoter; 3′; untranslated region (3′UTR)
22.  Genomewide association study of the age of onset of childhood asthma 
BACKGROUND
Childhood asthma is a complex disease with known heritability and phenotypic diversity. Although an earlier onset has been associated with more severe disease, there has been no genome-wide association study of the age of onset of asthma in children.
OBJECTIVE
To identify genetic variants associated with earlier onset of childhood asthma.
METHODS
We conducted the first genome-wide association study (GWAS) of the age of onset of childhood asthma among participants in the Childhood Asthma Management Program (CAMP), and used three independent cohorts from North America, Costa Rica, and Sweden for replication.
RESULTS
Two SNPs were associated with earlier onset of asthma in the combined analysis of CAMP and the replication cohorts: : rs9815663 (Fisher’s P value=2.31 × 10−8) and rs7927044 (P=6.54 × 10−9). Of these two SNPs, rs9815663 was also significantly associated with earlier asthma onset in an analysis including only the replication cohorts. Ten SNPs in linkage disequilibrium with rs9815663 were also associated with earlier asthma onset (2.24 × 10−7 < P < 8.22 ×10−6). Having ≥1 risk allele of the two SNPs of interest (rs9815663 and rs7927044) was associated with lower lung function and higher asthma medication use during 4 years of follow-up in CAMP.
CONCLUSIONS
We have identified two SNPs associated with earlier onset of childhood asthma in four independent cohorts.
doi:10.1016/j.jaci.2012.03.020
PMCID: PMC3387331  PMID: 22560479
Asthma; pediatrics; age of onset; asthma genetics; C1orf100; genome-wide association study; pediatric asthma
23.  A Genome-Wide Association Study on African-Ancestry Populations For Asthma 
Background
Asthma is a complex disease characterized by striking ethnic disparities not explained entirely by environmental, social, cultural, or economic factors. Of the limited genetic studies performed on populations of African descent, notable differences in susceptibility allele frequencies have been observed.
Objectives
To test the hypothesis that some genes may contribute to the profound disparities in asthma.
Methods
We performed a genome-wide association study in two independent populations of African ancestry (935 African American asthma cases and controls from the Baltimore-Washington, D.C. area, and 929 African Caribbean asthmatics and their family members from Barbados) to identify single-nucleotide polymorphisms (SNPs) associated with asthma.
Results
Meta-analysis combining these two African-ancestry populations yielded three SNPs with a combined P-value <10-5 in genes of potential biological relevance to asthma and allergic disease: rs10515807, mapping to alpha-1B-adrenergic receptor (ADRA1B) gene on chromosome 5q33 (3.57×10-6); rs6052761, mapping to prion-related protein (PRNP) on chromosome 20pter-p12 (2.27×10-6); and rs1435879, mapping to dipeptidyl peptidase 10 (DPP10) on chromosome 2q12.3-q14.2. The generalizability of these findings was tested in family and case-control panels of UK and German origin, respectively, but none of the associations observed in the African groups were replicated in these European studies.
Conclusions
Evidence for association was also examined in four additional case-control studies of African Americans; however, none of the SNPs implicated in the discovery population were replicated. This study illustrates the complexity of identifying true associations for a complex and heterogeneous disease such as asthma in admixed populations, especially populations of African descent.
doi:10.1016/j.jaci.2009.08.031
PMCID: PMC3606015  PMID: 19910028
Asthma; GWAS; ADRA1B; PRNP; DPP10; African ancestry; ethnicity; polymorphism; genetic association
24.  Identification of a chronic obstructive pulmonary disease genetic determinant that regulates HHIP 
Human Molecular Genetics  2011;21(6):1325-1335.
Multiple intergenic single-nucleotide polymorphisms (SNPs) near hedgehog interacting protein (HHIP) on chromosome 4q31 have been strongly associated with pulmonary function levels and moderate-to-severe chronic obstructive pulmonary disease (COPD). However, whether the effects of variants in this region are related to HHIP or another gene has not been proven. We confirmed genetic association of SNPs in the 4q31 COPD genome-wide association study (GWAS) region in a Polish cohort containing severe COPD cases and healthy smoking controls (P = 0.001 to 0.002). We found that HHIP expression at both mRNA and protein levels is reduced in COPD lung tissues. We identified a genomic region located ∼85 kb upstream of HHIP which contains a subset of associated SNPs, interacts with the HHIP promoter through a chromatin loop and functions as an HHIP enhancer. The COPD risk haplotype of two SNPs within this enhancer region (rs6537296A and rs1542725C) was associated with statistically significant reductions in HHIP promoter activity. Moreover, rs1542725 demonstrates differential binding to the transcription factor Sp3; the COPD-associated allele exhibits increased Sp3 binding, which is consistent with Sp3's usual function as a transcriptional repressor. Thus, increased Sp3 binding at a functional SNP within the chromosome 4q31 COPD GWAS locus leads to reduced HHIP expression and increased susceptibility to COPD through distal transcriptional regulation. Together, our findings reveal one mechanism through which SNPs upstream of the HHIP gene modulate the expression of HHIP and functionally implicate reduced HHIP gene expression in the pathogenesis of COPD.
doi:10.1093/hmg/ddr569
PMCID: PMC3284120  PMID: 22140090
25.  Integration of Mouse and Human Genome-Wide Association Data Identifies KCNIP4 as an Asthma Gene 
PLoS ONE  2013;8(2):e56179.
Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS) data. We used Efficient Mixed Model Association (EMMA) analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values <0.001 were selected for further study in human GWAS. The results of the previously reported EVE consortium asthma GWAS meta-analysis consisting of 12,958 diverse North American subjects from 9 study centers were used to select a subset of homologous genes with evidence of association with asthma in humans. Following validation attempts in three human asthma GWAS (i.e., Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG) and two human AHR GWAS (i.e., SHARP, DAG), the Kv channel interacting protein 4 (KCNIP4) gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e-04), while the strongest associations for Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG were 1.5e-03, 1.0e-03, 3.1e-03 at rs7664617, rs4697177, rs4696975, respectively. At a SNP level, the strongest association across all asthma GWAS was at rs4697177 (P-value 1.1e-04). The smallest P-values for association with AHR were 2.3e-03 at rs11947661 in SHARP and 2.1e-03 at rs402802 in DAG. Functional studies are required to validate the potential involvement of KCNIP4 in modulating asthma susceptibility and/or AHR. Our results suggest that a useful approach to identify genes associated with human asthma is to leverage mouse AHR association data.
doi:10.1371/journal.pone.0056179
PMCID: PMC3572953  PMID: 23457522

Results 1-25 (44)