Multiethnic genome-wide and HLA association study of total serum IgE level.

BACKGROUND: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE. OBJECTIVE: We 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). METHODS: We 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. RESULTS: We 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). CONCLUSION: We 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.

Fine-mapping of the 6q25 locus identifies a novel SNP associated with breast cancer risk in African-American women.

The rs2046210 single nucleotide polymorphism (SNP) in the 6q25.1 region was identified in a breast cancer genome-wide association study of Chinese women. The SNP has been replicated in European ancestry populations, but replication efforts have failed in African ancestry populations. We evaluated a total of 13 tagging SNPs in the linkage disequilibrium block around rs2046210 in a case-control study of breast cancer nested within the Black Women's Health Study, which included 1191 cases and 1941 controls. Replication of initial significant findings was carried out in 665 cases and 821 controls of African ancestry from the Women's Circle of Health Study (WCHS). No significant association was found for rs2046210 in univariate analysis. A new SNP, rs2046211, was significantly associated with reduced risk of breast cancer and was replicated in data from WCHS. In joint analyses that included both SNPs, the rs2046210-A allele was associated with increased risk of breast cancer [odds ratio (OR) = 1.14; 95% confidence interval (CI) = 1.02-1.28], and the rs2046211-G allele was associated with reduced risk (OR = 0.80; 95% CI = 0.67-0.95). Haplotype analysis confirmed these results and showed that the rs2046210-A allele is present in high-risk (rs2046211-C/rs2046210-A) and low-risk (rs2046211-G/rs2046210-A) haplotypes. Our results confirm the importance of 6q25.1 as a breast cancer susceptibility region. We replicated the rs2046210 association, after accounting for the haplotype background that included rs2046211 in African-American women, and we report the presence of a novel signal that is tagged by rs2046211.

The Pharmacogenetics of Statin Therapy on Clinical Events: No Evidence that Genetic Variation Affects Statin Response on Myocardial Infarction.

Background: The pharmacogenetic effect on cardiovascular disease reduction in response to statin treatment has only been assessed in small studies. In a pharmacogenetic genome wide association study (GWAS) analysis within the Genomic Investigation of Statin Therapy (GIST) consortium, we investigated whether genetic variation was associated with the response of statins on cardiovascular disease risk reduction. Methods: The investigated endpoint was incident myocardial infarction (MI) defined as coronary heart disease death and definite and suspect non-fatal MI. For imputed single nucleotide polymorphisms (SNPs), regression analysis was performed on expected allelic dosage and meta-analysed with a fixed-effects model, inverse variance weighted meta-analysis. All SNPs with p-values <5.0 × 10-4 in stage 1 GWAS meta-analysis were selected for further investigation in stage-2. As a secondary analysis, we extracted SNPs from the Stage-1 GWAS meta-analysis results based on predefined hypotheses to possibly modifying the effect of statin therapy on MI. Results: In stage-1 meta-analysis (eight studies, n = 10,769, 4,212 cases), we observed no genome-wide significant results (p < 5.0 × 10-8). A total of 144 genetic variants were followed-up in the second stage (three studies, n = 1,525, 180 cases). In the combined meta-analysis, no genome-wide significant hits were identified. Moreover, none of the look-ups of SNPs known to be associated with either CHD or with statin response to cholesterol levels reached Bonferroni level of significance within our stage-1 meta-analysis. Conclusion: This GWAS analysis did not provide evidence that genetic variation affects statin response on cardiovascular risk reduction. It does not appear likely that genetic testing for predicting effects of statins on clinical events will become a useful tool in clinical practice.

Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group.

BACKGROUND: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described. METHODS: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL. RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls. CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.

Unique lipoprotein phenotype and genotype associated with exceptional longevity.

CONTEXT: Individuals with exceptional longevity have a lower incidence and/or significant delay in the onset of age-related disease, and their family members may inherit biological factors that modulate aging processes and disease susceptibility. OBJECTIVE: To identify specific biological and genetic factors that are associated with or reliably define a human longevity phenotype. DESIGN, SETTING, AND PARTICIPANTS: In a case-control design, 213 Ashkenazi Jewish probands with exceptional longevity (mean [SD] age, 98.2 [5.3] years) and their offspring (n = 216; mean [SD] age, 68.3 [6.7] years) were recruited from 1998 to 2002, while an age-matched control group of Ashkenazi Jews (n = 258) and participants from the Framingham Offspring Study (n = 589) were accepted as control groups. MAIN OUTCOME MEASURES: Detailed questionnaires, physical examination, and blood samples were taken, including assessment of lipids and lipoprotein subclass levels and particle sizes by proton nuclear magnetic resonance. Samples were also genotyped for the codon 405 isoleucine to valine (I405V) variation in the cholesteryl ester transfer protein (CETP) gene, which is involved in regulation of lipoprotein and its particle sizes. RESULTS: High-density lipoprotein (HDL) and low-density lipoprotein (LDL) particle sizes were significantly higher in probands compared with both control groups (P =.001 for both), independent of plasma levels of HDL and LDL cholesterol and apolipoprotein A1 and B. This phenotype was also typical of the proband's offspring but not of the age-matched controls. The HDL and LDL particle sizes were significantly larger in offspring and controls without hypertension or cardiovascular disease, (P =.001 and P =.008, respectively). Furthermore, lipoprotein particle sizes, but not plasma LDL levels, were significantly higher in offspring and controls without the metabolic syndrome (P<.001). Probands and offspring had a 2.9- and 3.6-fold (in men) and 2.7- and 1.5-fold (in women) increased frequency, respectively, of homozygosity for the 405 valine allele of CETP (VV genotype), respectively, compared with controls (P<.001 for both). Those probands with the VV genotype had increased lipoprotein sizes and lower serum CETP concentrations. CONCLUSIONS: Individuals with exceptional longevity and their offspring have significantly larger HDL and LDL particle sizes. This phenotype is associated with a lower prevalence of hypertension, cardiovascular disease, the metabolic syndrome, and increased homozygosity for the I405V variant in CETP. These findings suggest that lipoprotein particle sizes are heritable and promote a healthy aging phenotype.

Comparison of statistical approaches to rare variant analysis for quantitative traits.

With recent advances in technology, deep sequencing data will be widely used to further the understanding of genetic influence on traits of interest. Therefore not only common variants but also rare variants need to be better used to exploit the new information provided by deep sequencing data. Recently, statistical approaches for analyzing rare variants in genetic association studies have been proposed, but many of them were designed only for dichotomous outcomes. We compare the type I error and power of several statistical approaches applicable to quantitative traits for collapsing and analyzing rare variant data within a defined gene region. In addition to comparing methods that consider only rare variants, such as indicator, count, and data-adaptive collapsing methods, we also compare methods that incorporate the analysis of common variants along with rare variants, such as CMC and LASSO regression. We find that the three methods used to collapse rare variants perform similarly in this simulation setting where all risk variants were simulated to have effects in the same direction. Further, we find that incorporating common variants is beneficial and using a LASSO regression to choose which common variants to include is most useful when there is are few common risk variants compared to the total number of risk variants.