The genetic basis of podoconiosis - a model for gene environment interactions. (360G-Wellcome-079791_Z_06_Z)

Podoconiosis (endemic non-filarial elephantiasis) is a common geochemical disease resulting in severe lower limb deformity, debilitation and economic loss for affected families. Our studies to date provide convincing evidence that the disease results from the interaction between a host gene (or possibly genes) and an environmental factor, probably silica, found in the red clay soils to which susceptible individuals are exposed. The aim of this study is to identify the gene(s) responsible for this condition using a robust affected sibling pair genetic linkage study design. The high familial aggregation of cases, the distinctive phenotype and lack of phenocopies, coupled with the evidence for a single major gene mode of inheritance in this population significantly enhance the likelihood of successful outcome. Identification of the gene(s) involved will lead to better understanding of the pathogenesis of this condition including mechanisms of fibrosis that are common to other disorders such as filiarial elephantiasis and causes of pulmonary fibrosis, including silicosis. Elucidation of the molecular mechanisms involved in podoconiosis could also broaden our understanding of gene-environment interactions in the development of complex disorders more generally where the genetic and environmental factors are less clearly defined.