Dataset Information

Replication of HLA class II locus association with susceptibility to podoconiosis in three Ethiopian ethnic groups.

ABSTRACT: Podoconiosis, a debilitating lymphoedema of the leg, results from barefoot exposure to volcanic clay soil in genetically susceptible individuals. A previous genome-wide association study (GWAS) conducted in the Wolaita ethnic group from Ethiopia showed association between single nucleotide polymorphisms (SNPs) in the HLA class II region and podoconiosis. We aimed to conduct a second GWAS in a new sample (N?=?1892) collected from the Wolaita and two other Ethiopian populations, the Amhara and the Oromo, also affected by podoconiosis. Fourteen SNPs in the HLA class II region showed significant genome-wide association (P?-8) with podoconiosis. The lead SNP was rs9270911 (P?=?5.51?×?10^-10; OR 1.53; 95% CI 1.34-1.74), located near HLA-DRB1. Inclusion of data from the first GWAS (combined N?=?2289) identified 47 SNPs in the class II HLA region that were significantly associated with podoconiosis (lead SNP also rs9270911 (P?=?2.25?×?10^-12). No new loci outside of the HLA class II region were identified in this more highly-powered second GWAS. Our findings confirm the HLA class II association with podoconiosis suggesting HLA-mediated abnormal induction and regulation of immune responses may have a direct role in its pathogenesis.

SUBMITTER: Gebresilase T

PROVIDER: S-EPMC7870958 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Replication of HLA class II locus association with susceptibility to podoconiosis in three Ethiopian ethnic groups.

Gebresilase Tewodros T Finan Chris C Suveges Daniel D Tessema Tesfaye Sisay TS Aseffa Abraham A Davey Gail G Hatzikotoulas Konstantinos K Zeggini Eleftheria E Newport Melanie J MJ Tekola-Ayele Fasil F

Scientific reports 20210208 1

Podoconiosis, a debilitating lymphoedema of the leg, results from barefoot exposure to volcanic clay soil in genetically susceptible individuals. A previous genome-wide association study (GWAS) conducted in the Wolaita ethnic group from Ethiopia showed association between single nucleotide polymorphisms (SNPs) in the HLA class II region and podoconiosis. We aimed to conduct a second GWAS in a new sample (N = 1892) collected from the Wolaita and two other Ethiopian populations, the Amhara and the ...[more]

PMID: 33558538

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Project description:In Northern European descended populations, genetic susceptibility for multiple sclerosis (MS) is associated with alleles of the human leukocyte antigen (HLA) Class II gene DRB1. Whether other major histocompatibility complex (MHC) genes contribute to MS susceptibility is controversial.A case control analysis was performed using 958 single nucleotide polymorphisms (SNPs) spanning the MHC assayed in two independent datasets. The discovery dataset consisted of 1,018 cases and 1,795 controls and the replication dataset was composed of 1,343 cases and 1,379 controls. The most significantly MS-associated SNP in the discovery dataset was rs3135391, a Class II SNP known to tag the HLA-DRB1*15:01 allele, the primary MS susceptibility allele in the MHC (O.R. = 3.04, p < 1 x 10(-78)). To control for the effects of the HLA-DRB1*15:01 haplotype, case control analysis was performed adjusting for this HLA-DRB1*15:01 tagging SNP. After correction for multiple comparisons (false discovery rate = .05) 52 SNPs in the Class I, II and III regions were significantly associated with MS susceptibility in both datasets using the Cochran Armitage trend test. The discovery and replication datasets were merged and subjects carrying the HLA-DRB1*15:01 tagging SNP were excluded. Association tests showed that 48 of the 52 replicated SNPs retained significant associations with MS susceptibility independently of the HLA-DRB1*15:01 as defined by the tagging SNP. 20 Class I SNPs were associated with MS susceptibility with p-values < or = 1 x 10(-8). The most significantly associated SNP was rs4959039, a SNP in the downstream un-translated region of the non-classical HLA-G gene (Odds ratio 1.59, 95% CI 1.40, 1.81, p = 8.45 x 10(-13)) and is in linkage disequilibrium with several nearby SNPs. Logistic regression modeling showed that this SNP's contribution to MS susceptibility was independent of the Class II and Class III SNPs identified in this screen.A MHC Class I locus contributes to MS susceptibility independently of the HLA-DRB1*15:01 haplotype.

Dataset Information

Replication of HLA class II locus association with susceptibility to podoconiosis in three Ethiopian ethnic groups.

Publications

Replication of HLA class II locus association with susceptibility to podoconiosis in three Ethiopian ethnic groups.

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