A study of host genetic risk factors for leprosy susceptibility

Leprosy, a chronic infectious disease caused by Mycobacterium leprae, is the leading cause of non-traumatic neuropathies in the world. Although a genetic component for leprosy susceptibility has been demonstrated by several studies, the exact nature and extent of this component is still unknown. Here, we applied linkage and association analysis in a combined candidate region and genome-wide approach to further investigate the nature of host genetic factors controlling leprosy susceptibility. First, we used 20 Vietnamese multiplex leprosy families to perform linkage analysis on selected genomic candidate regions harbouring genes previously known to be either linked or associated with leprosy phenotypes. We found significant evidence for linkage between markers of the TNFA gene located on chromosomal region 6p21 and clinical subtype of the disease (P = 0.00021). Next, we performed a genome-wide scan in a sample of 86 Vietnamese multiplex leprosy families. We identified a new leprosy "per se" susceptibility locus on chromosome 6q25--q27 (LOD = 4.31, P = 5 x 10-6). Linkage results were reproduced by family-based association analysis in an independent sample of 208 Vietnamese simplex leprosy pedigrees (P = 5.9 x 10 -5). A linkage homogeneity test confirmed chromosomal region 10p13 as modifier for paucibacillary leprosy in the Vietnamese population. Finally, we applied SNP-based association analysis to construct a high density linkage disequilibrium (LD) map of chromosome 6q25--q27. We identified genetic polymorphisms clustered in a 80 Kb LD block overlapping the 5-prime regulatory region shared by two genes, Parkinson's disease susceptibility gene PARK2 and PACRG, as risk factors for leprosy "per se" in the Vietnamese population (OR = 3.15--5.72). All associated SNPs can be distributed in three frequency haplotypes, with two SNPs capturing all the association information between the PARK2/PACRG 5-prime regulatory region and leprosy in the Vietnamese families. The same polymorphisms were found associated with leprosy in a large case-control sample from Southeast Brazil (P = 0.023--0.0002), indicating a universal role for the PARK2/PACRG variants in the control of leprosy "per se" susceptibility. These results indicate that current methods for gene mapping can be successfully applied to the identification of genetic risk factors in complex traits.