Leprosy is an infectious disease caused by the obligate intracellular pathogen Mycobacterium leprae and remains endemic in many parts of the world. Despite several major studies on susceptibility to leprosy, few genomic loci have been replicated independently. We have conducted an association analysis of more than 1,500 individuals from different case-control and family studies, and observed consistent associations between genetic variants in both TLR1 and the HLA-DRB1/DQA1 regions with susceptibility to leprosy (TLR1 I602S, case-control P = 5.7×10−8, OR = 0.31, 95% CI = 0.20–0.48, and HLA-DQA1 rs1071630, case-control P = 4.9×10−14, OR = 0.43, 95% CI = 0.35–0.54). The effect sizes of these associations suggest that TLR1 and HLA-DRB1/DQA1 are major susceptibility genes in susceptibility to leprosy. Further population differentiation analysis shows that the TLR1 locus is extremely differentiated. The protective dysfunctional 602S allele is rare in Africa but expands to become the dominant allele among individuals of European descent. This supports the hypothesis that this locus may be under selection from mycobacteria or other pathogens that are recognized by TLR1 and its co-receptors. These observations provide insight into the long standing host-pathogen relationship between human and mycobacteria and highlight the key role of the TLR pathway in infectious diseases.
Mycobacterium leprae is an obligate intracellular pathogen that causes leprosy, a disease that shares a long history with the human population but which remains endemic in many parts of the world. Despite the fact that the genome of M. leprae has been sequenced, our understanding of its pathogenesis and interaction with the human host is limited, in part due to the inability to culture the bacterium in vitro. In this gene-centric microarray study, we have genotyped SNPs in over 2,000 genes and identified TLR1 and HLA-DRB1/DQA1 as major leprosy susceptibility genes. Studying the geographical distribution of this hypo-functional TLR1 variant demonstrated extreme population differentiation at this locus. These results suggest that leprosy may have contributed to the evolution of this genomic region, and provide insight into the long history of the host-pathogen relationship between humans and M. leprae.