HLA class II locus and susceptibility to podoconiosis

Abstract

Background: 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.).

Figure 1. Podoconiosis (Endemic Nonfilarial Elephantiasis)

Podoconiosis is a noninfectious geochemical disease. Panel A shows early-stage podoconiosis, characterized by “slipper-distribution” mossy lesions (covering the tops of the toes and the sides and soles of the feet, much as a typical slipper does), as well as bilateral and asymmetric below-the-knee swelling. At this stage, the condition is reversible with the use of footwear and foot hygiene. Panel B shows two examples of advanced-stage podoconiosis, characterized by bilateral below-the-knee swelling, visible discrete lumps, deformed toes, and pigmented, shiny, thickened skin. At this stage, the disease can be ameliorated, but not completely reversed, with the use of conventional treatment: foot hygiene and compression bandages.

Figure 2 (facing page). Association of Single-Nucleotide Polymorphisms (SNPs) with Podoconiosis

In Panels A and B, each of the 551,840 SNPs in autosomal chromosomes is represented by a point. The higher the point (the higher the negative log₁₀ P value), the more significant the association with podoconiosis. Points above the blue horizontal line represent SNPs with a P value of less than 10⁻⁵. Points above the red horizontal line indicate SNPs with a P value of less than 5×10⁻⁸. Panel A shows results from the allelic genetic model that tests associations with the individual alleles. Panel B shows the additive genetic model that uses the Armitage trend test. Panel C shows association signals over a 1-Mb HLA class II region on chromosome 6 surrounding rs17612858 (purple diamond); each of the other SNPs is represented by a gray circle indicating low linkage disequilibrium (r²<0.20). The left y axis represents negative log₁₀ P values calculated with the use of the Armitage trend test. The right y axis represents the recombination rate (in centimorgans [cM] per megabase [Mb]), indicated by the blue curve. Genes found in the region are shown in relative position under the plot; arrows indicate the direction of transcription.