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 < 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.

Determinants of Podoconiosis in Bensa District, Sidama Region, Ethiopia: A case control study

“…This may indicate the role of genetic background in the development of podoconiosis [ 3 ]. There are studies which indicated relationship between some HLA Class II variants and occurrence of podoconiosis [ 22 , 23 ].…”

Evidence for immune activation in pathogenesis of the HLA class II associated disease, podoconiosis

“…The upregulation of HLA-DQB1 in this study is of interest due to the documented association between this gene (as well as HLA-DRB1 ) and podoconiosis 9 , 10 . Variation in the HLA-DQB1 gene and its upregulation have been linked with susceptibility to different solid organ and tissue fibrosis 45 , 46 .…”

“…Podoconiosis is a noncommunicable disease caused by exposure to an environmental factor on the background of genetic susceptibility associated with variation in HLA-DR and HLA-DQ genotypes 9 , 10 . Little is known about the environmental trigger or the pathogenic immune response it induces in podoconiosis.…”

“…Segregation analysis of multigenerational podoconiosis-affected families in Wolaita, southern Ethiopia, showed an estimated sibling recurrence risk ratio (λs) and heritability of 5.07 and 0.63, respectively 8 . These findings led to the undertaking of genome-wide association study (GWAS) in the Wolaita population 9 and a second larger GWAS in three ethnic populations in Ethiopia 10 . Both these studies reported that variation in HLA class II genes ( DRB1 , DQA1 , and DQB1 ) was significantly associated with susceptibility to podoconiosis.…”

A geochemical and mineralogical characterization of soils associated with podoconiosis

“…The last decade has seen a significant increase in studies of Podoconiosis. Improvements are occurring in the understanding of its medical and public health aspects, such as prevention and management, genetic factors, and even community understanding (Alcantara et al, 2020 ; Davey et al, 2007 ; Deribe et al, 2018 ; Florence & Fuller, 2017 ; Gebresilase et al, 2021 ; Molla et al, 2012 ; Tora et al, 2016 ; van‘t Noordende et al, 2020 ). However, research into the soils has not received the same attention, though recent years suggest growing interest (Cooper et al, 2019 ; Gislam et al, 2020 ; Le Blond et al, 2015 ; Molla et al, 2014 ).…”