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Sequencing the IL4 locus in African Americans implicates rare noncoding variants in asthma susceptibility.

ABSTRACT: Common genetic variations in the IL4 gene have been associated with asthma and atopy in European and Asian populations, but not in African Americans.Because populations of African descent have increased levels of genetic variation compared with other populations, particularly with respect to low frequency or rare variants, we hypothesized that rare variants in the IL4 gene contribute to the development of asthma in African Americans.To test this hypothesis, we sequenced the IL4 locus in 72 African Americans with asthma and 70 African American controls without asthma to identify novel and rare polymorphisms in the IL4 gene that may be contributing to asthma susceptibility.We report an excess of private noncoding single nucleotide polymorphisms (SNPs) in the subjects with asthma compared with control subjects without asthma (P = .031). Tajima's D is significantly more negative in subjects with asthma (-0.375) than controls (-0.073; P = .04), reflecting an excess of rare variants in the subjects with asthma.Our findings indicate that SNPs at the IL4 locus that are potentially exclusive to African Americans are associated with susceptibility to asthma. Only 3 of the 26 private SNPs (ie, SNPs present only in the subjects with asthma or only in the controls) are tagged by single SNPs on one of the common genotyping platforms used in genome-wide association studies. We also find that most of the private SNPs cannot be reliably imputed, highlighting the importance of sequencing to identify genetic variants contributing to common diseases in African Americans.

SUBMITTER: Haller G

PROVIDER: S-EPMC3984460 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Sequencing the IL4 locus in African Americans implicates rare noncoding variants in asthma susceptibility.

Haller Gabe G Torgerson Dara G DG Ober Carole C Thompson Emma E EE

The Journal of allergy and clinical immunology 20091201 6

<h4>Background</h4>Common genetic variations in the IL4 gene have been associated with asthma and atopy in European and Asian populations, but not in African Americans.<h4>Objective</h4>Because populations of African descent have increased levels of genetic variation compared with other populations, particularly with respect to low frequency or rare variants, we hypothesized that rare variants in the IL4 gene contribute to the development of asthma in African Americans.<h4>Methods</h4>To test th ...[more]

PMID: 19910025

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Project description:The genetic architecture of late-onset Alzheimer disease (AD) in African Americans (AAs) differs from that in persons of European ancestry. In addition to APOE, genome-wide association studies (GWASs) of AD in AA samples have implicated ABCA7, COBL, and SLC10A2 as AA-AD risk genes. Previously, we identified by whole exome sequencing a small number of AA AD cases and subsequent genotyping in a large AA sample of AD cases and controls association of AD risk with a pair of rare missense variants in AKAP9. In this study, we performed targeted deep sequencing (including both introns and exons) of approximately 100 genes previously linked to AD or AD-related traits in an AA cohort of 489 AD cases and 472 controls to find novel AD risk variants. We observed association with an 11 base-pair frame-shift loss-of-function (LOF) variant in ABCA7 (rs567222111) for which the evidence was bolstered when combined with data from a replication AA cohort of 484 cases and 484 controls (OR = 2.42, p = 0.022). We also found association of AD with a rare 9 bp deletion (rs371245265) located very close to the AKAP9 transcription start site (rs371245265, OR = 10.75, p = 0.0053). The most significant findings were obtained with a rare protective variant in F5 (OR = 0.053, p = 6.40 × 10-5), a gene that was previously associated with a brain MRI measure of hippocampal atrophy, and two common variants in KIAA0196 (OR = 1.51, p<8.6 × 10-5). Gene-based tests of aggregated rare variants yielded several nominally significant associations with KANSL1, CNN2, and TRIM35. Although no associations passed multiple test correction, our study adds to a body of literature demonstrating the utility of examining sequence data from multiple ethnic populations for discovery of new and impactful risk variants. Larger sample sizes will be needed to generate well-powered epidemiological investigations of rare variation, and functional studies are essential for establishing the pathogenicity of variants identified by sequencing.

Project description:Background and objectivesPresumed genetic risk for diabetic and nondiabetic end stage renal disease is strong in African Americans.Design, setting, participants, & measurementsExome sequencing data from African Americans with type 2 diabetic end stage renal disease and nondiabetic, non-nephropathy controls in the T2D-GENES study (Discovery, n=529 patients and n=535 controls) were evaluated, focusing on missense variants in NPHS1. Associated variants were then evaluated in independent type 2 diabetic end stage renal disease (Replication, n=1305 patients and n=760 controls), nondiabetic end stage renal disease (n=1705), and type 2 diabetes-only, non-nephropathy samples (n=503). All participants were recruited from dialysis facilities and internal medicine clinics across the southeastern United States from 1991 to present. Additional NPHS1 missense variants were identified from exome sequencing resources, genotyped, and sequence kernel association testing was then performed.ResultsInitial analysis identified rs35238405 (T233A; minor allele frequency=0.0096) as associated with type 2 diabetic end stage renal disease (adjustment for admixture P=0.042; adjustment for admixture+APOL1 P=0.080; odds ratio, 2.89 and 2.36, respectively); with replication in independent type 2 diabetic end stage renal disease samples (P=0.018; odds ratio, 4.30) and nondiabetic end stage renal disease samples (P=0.016; odds ratio, 4.48). In a combined analysis (all patients with end stage renal disease versus all controls), T233A was associated with all-cause end stage renal disease (P=0.0038; odds ratio, 2.82; n=3270 patients and n=1187 controls). A P-value of <0.001 was obtained after adjustment for admixture and APOL1 in sequence kernel association testing. Two additional variants (H800R and Y1174H) were nominally associated with protection from end stage renal disease (P=0.036; odds ratio, 0.44; P=0.0084; odds ratio, 0.040, respectively) in the locus-wide single-variant association tests.ConclusionsCoding variants in NPHS1 are associated with both risk for and protection from common forms of nephropathy in African Americans.

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Sequencing the IL4 locus in African Americans implicates rare noncoding variants in asthma susceptibility.

Publications

Sequencing the IL4 locus in African Americans implicates rare noncoding variants in asthma susceptibility.

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