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

Tewodros Gebresilase,Konstantinos Hatzikotoulas,Daniel Suveges,Fasil Tekola-Ayele,Abraham Aseffa,Tesfaye Sisay Tessema,Melanie J Newport,Eleftheria Zeggini,Chris Finan,Gail Davey

doi:10.1038/s41598-021-81836-x

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 < 5.0 × 10−8) 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.

Highlights

Podoconiosis, a debilitating lymphoedema of the leg, results from barefoot exposure to volcanic clay soil in genetically susceptible individuals
We identified five HLA class II single-nucleotide polymorphism (SNP) that reached genome-wide significance and the lead SNP was rs17205647 (P = 6.469E-09; Odds Ratio (OR) = 1.56; 95% CI = 1.35–1.82; Fig. 2B and Supplementary Table 5)
We found significant genome-wide association with 14 common variants in the HLA class II region on chromosome 6p21.3

Summary

Introduction

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. The neglected tropical disease podoconiosis is a type of progressive tropical lymphoedema that mainly affects the lower leg. It results from long term exposure of bare feet to red clay soil derived from volcanic r ock[1]. The lymph vessels gradually become obstructed causing progressive lymphoedema with corresponding skin changes in the lower limb that are typical of podoconiosis These include dermal nodules and a rough, velvet-like appearance to the skin known as mossy changes which are pathognomonic for the disease. Differences in particle and mineral composition between soil from endemic and non-endemic regions have been described, but correlation with the ability of the different soils to induce inflammation measured by haemolytic activity was not demonstrated[13]

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