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The HLA class II locus confers susceptibility to podoconiosis
journal contribution
posted on 2023-06-07, 16:05 authored by Fasil Tekola Ayele, Adebowale Adeyemo, Christopher Finan, Elena Hailu, Paul Sinnott, Natalia Diaz Burlington, Aseffa Aseffa, Charles N. Rotimi, Melanie NewportMelanie Newport, Gail DaveyGail DaveyBackground: Podoconiosis is a tropical lymphedema resulting from long-term barefoot exposure to red-clay soil derived from volcanic rock. The World Health Organization recently designated it as a neglected tropical disease. Podoconiosis develops in only a subgroup of exposed people, and studies have shown familial clustering with high heritability (63%). Methods: We conducted a genomewide association study of 194 case patients and 203 controls from southern Ethiopia. Findings were validated by means of family-based association testing in 202 family trios and HLA typing in 94 case patients and 94 controls. Results: We found a genomewide significant association of podoconiosis with the single-nucleotide polymorphism (SNP) rs17612858, located 5.8 kb from the HLA-DQA1 locus (in the allelic model: odds ratio, 2.44; 95% confidence interval [CI], 1.82 to 3.26; P=1.42×10-9; and in the additive model: odds ratio, 2.19; 95% CI, 1.66 to 2.90; P=3.44×10-8), and suggestive associations (P<1.0×10-5) with seven other SNPs in or near HLA-DQB1, HLA-DQA1, and HLA-DRB1. We confirmed these associations using family-based association testing. HLA typing showed the alleles HLA-DRB1*0701 (odds ratio, 2.00), DQA1*0201 (odds ratio, 1.91), and DQB1*0202 (odds ratio, 1.79) and the HLA-DRB1*0701–DQB1*0202 haplotype (odds ratio, 1.92) were risk variants for podoconiosis. Conclusions: Association between variants in HLA class II loci with podoconiosis (a noncommunicable disease) suggests that the condition may be a T-cell–mediated inflammatory disease and is a model for gene–environment interactions that may be relevant to other complex genetic disorders. (Funded by the Wellcome Trust and others.)
History
Publication status
- Published
Journal
New England Journal of MedicineISSN
0028-4793Publisher
Massachusetts Medical SocietyExternal DOI
Issue
13Volume
366Page range
1200-1208Department affiliated with
- Clinical and Experimental Medicine Publications
Full text available
- No
Peer reviewed?
- Yes