A genome-wide association study of plasma total IgE concentrations in the Framingham Heart Study.
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ABSTRACT: Background
Atopy and plasma IgE concentration are genetically complex traits, and the specific genetic risk factors that lead to IgE dysregulation and clinical atopy are an area of active investigation.Objective
We sought to ascertain the genetic risk factors that lead to IgE dysregulation.Methods
A genome-wide association study (GWAS) was performed in 6819 participants from the Framingham Heart Study (FHS). Seventy of the top single nucleotide polymorphisms (SNPs) were selected based on P values and linkage disequilibrium among neighboring SNPs and evaluated in a meta-analysis with 5 independent populations from the Cooperative Health Research in the Region of Augsburg cohort, the British 1958 Birth Cohort, and the Childhood Asthma Management Program cohort.Results
Thirteen SNPs located in the region of 3 genes, FCER1A, signal transducer and activator of transcription 6 (STAT6), and IL13, were found to have genome-wide significance in the FHS cohort GWAS. The most significant SNPs from the 3 regions were rs2251746 (FCER1A, P = 2.11 × 10(-12)), rs1059513 (STAT6, P = 2.87 × 10(-8)), and rs1295686 (IL13, P = 3.55 × 10(-8)). Four additional gene regions, HLA-G, HLA-DQA2, HLA-A, and Duffy blood group, chemokine receptor (DARC), reached genome-wide statistical significance in a meta-analysis combining the FHS and replication cohorts, although the DARC association did not appear independent of SNPs in the nearby FCER1A gene.Conclusion
This GWAS of the FHS cohort has identified genetic loci in HLA genes that might have a role in the pathogenesis of IgE dysregulation and atopy. It also confirmed the association of the known susceptibility loci FCER1A, STAT6, and IL13 for the dysregulation of total IgE.
SUBMITTER: Granada M
PROVIDER: S-EPMC3293994 | biostudies-literature | 2012 Mar
REPOSITORIES: biostudies-literature
Publications
A genome-wide association study of plasma total IgE concentrations in the Framingham Heart Study.
Granada Mark M Wilk Jemma B JB Tuzova Marina M Strachan David P DP Weidinger Stephan S Albrecht Eva E Gieger Christian C Heinrich Joachim J Himes Blanca E BE Hunninghake Gary M GM Celedón Juan C JC Weiss Scott T ST Cruikshank William W WW Farrer Lindsay A LA Center David M DM O'Connor George T GT
The Journal of allergy and clinical immunology 20111109 3
<h4>Background</h4>Atopy and plasma IgE concentration are genetically complex traits, and the specific genetic risk factors that lead to IgE dysregulation and clinical atopy are an area of active investigation.<h4>Objective</h4>We sought to ascertain the genetic risk factors that lead to IgE dysregulation.<h4>Methods</h4>A genome-wide association study (GWAS) was performed in 6819 participants from the Framingham Heart Study (FHS). Seventy of the top single nucleotide polymorphisms (SNPs) were s ...[more]
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Project description:Pulmonary function measures obtained by spirometry are used to diagnose chronic obstructive pulmonary disease (COPD) and are highly heritable. We conducted genome-wide association (GWA) analyses (Affymetrix 100K SNP GeneChip) for measures of lung function in the Framingham Heart Study.Ten spirometry phenotypes including percent of predicted measures, mean spirometry measures over two examinations, and rates of change based on forced expiratory volume in one second (FEV1), forced vital capacity (FVC), forced expiratory flow from the 25th to 75th percentile (FEF25-75), the FEV1/FVC ratio, and the FEF25-75/FVC ratio were examined. Percent predicted phenotypes were created using each participant's latest exam with spirometry. Predicted lung function was estimated using models defined in the set of healthy never-smokers, and standardized residuals of percent predicted measures were created adjusting for smoking status, pack-years, and body mass index (BMI). All modeling was performed stratified by sex and cohort. Mean spirometry phenotypes were created using data from two examinations and adjusting for age, BMI, height, smoking and pack-years. Change in pulmonary function over time was studied using two to four examinations with spirometry to calculate slopes, which were then adjusted for age, height, smoking and pack-years.Analyses were restricted to 70,987 autosomal SNPs with minor allele frequency > or = 10%, genotype call rate > or = 80%, and Hardy-Weinberg equilibrium p-value > or = 0.001. A SNP in the interleukin 6 receptor (IL6R) on chromosome 1 was among the best results for percent predicted FEF25-75. A non-synonymous coding SNP in glutathione S-transferase omega 2 (GSTO2) on chromosome 10 had top-ranked results studying the mean FEV1 and FVC measurements from two examinations. SNPs nearby the SOD3 and vitamin D binding protein genes, candidate genes for COPD, exhibited association to percent predicted phenotypes.GSTO2 and IL6R are credible candidate genes for association to pulmonary function identified by GWA. These and other observed associations warrant replication studies. This resource of GWA results for pulmonary function measures is publicly available at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite.
| S-EPMC1995616 | biostudies-literature
Project description:BackgroundTotal serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE.ObjectiveWe aimed to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum by leveraging data from the National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine program; the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA); and the Atopic Dermatitis Research Network (N = 21,901).MethodsWe performed genome-wide association within strata of study, disease, and ancestry groups, and we combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data.ResultsWe identified 6 loci at genome-wide significance (P < 5 × 10-9), including 4 loci previously reported as genome-wide significant for tIgE, as well as new regions in chr11q13.5 and chr15q22.2, which were also identified in prior genome-wide association studies of atopic dermatitis and asthma. In the HLA allele association study, HLA-A∗02:01 was associated with decreased tIgE level (Pdiscovery = 2 × 10-4; Preplication = 5 × 10-4; Pdiscovery+replication = 4 × 10-7), and HLA-DQB1∗03:02 was strongly associated with decreased tIgE level in Hispanic/Latino ancestry populations (PHispanic/Latino discovery+replication = 8 × 10-8).ConclusionWe performed the largest genome-wide association study and HLA association study of tIgE focused on ancestrally diverse populations and found several known tIgE and allergic disease loci that are relevant in non-European ancestry populations.
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Project description:BACKGROUND:Systemic biomarkers provide insights into disease pathogenesis, diagnosis, and risk stratification. Many systemic biomarker concentrations are heritable phenotypes. Genome-wide association studies (GWAS) provide mechanisms to investigate the genetic contributions to biomarker variability unconstrained by current knowledge of physiological relations. METHODS:We examined the association of Affymetrix 100K GeneChip single nucleotide polymorphisms (SNPs) to 22 systemic biomarker concentrations in 4 biological domains: inflammation/oxidative stress; natriuretic peptides; liver function; and vitamins. Related members of the Framingham Offspring cohort (n = 1012; mean age 59 +/- 10 years, 51% women) had both phenotype and genotype data (minimum-maximum per phenotype n = 507-1008). We used Generalized Estimating Equations (GEE), Family Based Association Tests (FBAT) and variance components linkage to relate SNPs to multivariable-adjusted biomarker residuals. Autosomal SNPs (n = 70,987) meeting the following criteria were studied: minor allele frequency > or = 10%, call rate > or = 80% and Hardy-Weinberg equilibrium p > or = 0.001. RESULTS:With GEE, 58 SNPs had p < 10(-6): the top SNPs were rs2494250 (p = 1.00*10(-14)) and rs4128725 (p = 3.68*10(-12)) for monocyte chemoattractant protein-1 (MCP1), and rs2794520 (p = 2.83*10(-8)) and rs2808629 (p = 3.19*10(-8)) for C-reactive protein (CRP) averaged from 3 examinations (over about 20 years). With FBAT, 11 SNPs had p < 10(-6): the top SNPs were the same for MCP1 (rs4128725, p = 3.28*10(-8), and rs2494250, p = 3.55*10(-8)), and also included B-type natriuretic peptide (rs437021, p = 1.01*10(-6)) and Vitamin K percent undercarboxylated osteocalcin (rs2052028, p = 1.07*10(-6)). The peak LOD (logarithm of the odds) scores were for MCP1 (4.38, chromosome 1) and CRP (3.28, chromosome 1; previously described) concentrations; of note the 1.5 support interval included the MCP1 and CRP SNPs reported above (GEE model). Previous candidate SNP associations with circulating CRP concentrations were replicated at p < 0.05; the SNPs rs2794520 and rs2808629 are in linkage disequilibrium with previously reported SNPs. GEE, FBAT and linkage results are posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite. CONCLUSION:The Framingham GWAS represents a resource to describe potentially novel genetic influences on systemic biomarker variability. The newly described associations will need to be replicated in other studies.
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Project description:Blood lipid levels including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are highly heritable. Genome-wide association is a promising approach to map genetic loci related to these heritable phenotypes.In 1087 Framingham Heart Study Offspring cohort participants (mean age 47 years, 52% women), we conducted genome-wide analyses (Affymetrix 100K GeneChip) for fasting blood lipid traits. Total cholesterol, HDL-C, and TG were measured by standard enzymatic methods and LDL-C was calculated using the Friedewald formula. The long-term averages of up to seven measurements of LDL-C, HDL-C, and TG over a approximately 30 year span were the primary phenotypes. We used generalized estimating equations (GEE), family-based association tests (FBAT) and variance components linkage to investigate the relationships between SNPs (on autosomes, with minor allele frequency > or =10%, genotypic call rate > or =80%, and Hardy-Weinberg equilibrium p > or = 0.001) and multivariable-adjusted residuals. We pursued a three-stage replication strategy of the GEE association results with 287 SNPs (P < 0.001 in Stage I) tested in Stage II (n approximately 1450 individuals) and 40 SNPs (P < 0.001 in joint analysis of Stages I and II) tested in Stage III (n approximately 6650 individuals).Long-term averages of LDL-C, HDL-C, and TG were highly heritable (h2 = 0.66, 0.69, 0.58, respectively; each P < 0.0001). Of 70,987 tests for each of the phenotypes, two SNPs had p < 10(-5) in GEE results for LDL-C, four for HDL-C, and one for TG. For each multivariable-adjusted phenotype, the number of SNPs with association p < 10(-4) ranged from 13 to 18 and with p < 10(-3), from 94 to 149. Some results confirmed previously reported associations with candidate genes including variation in the lipoprotein lipase gene (LPL) and HDL-C and TG (rs7007797; P = 0.0005 for HDL-C and 0.002 for TG). The full set of GEE, FBAT and linkage results are posted at the database of Genotype and Phenotype (dbGaP). After three stages of replication, there was no convincing statistical evidence for association (i.e., combined P < 10(-5) across all three stages) between any of the tested SNPs and lipid phenotypes.Using a 100K genome-wide scan, we have generated a set of putative associations for common sequence variants and lipid phenotypes. Validation of selected hypotheses in additional samples did not identify any new loci underlying variability in blood lipids. Lack of replication may be due to inadequate statistical power to detect modest quantitative trait locus effects (i.e., <1% of trait variance explained) or reduced genomic coverage of the 100K array. GWAS in FHS using a denser genome-wide genotyping platform and a better-powered replication strategy may identify novel loci underlying blood lipids.
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