Mapping of PARK2 and PACRG Overlapping Regulatory Region Reveals LD Structure and Functional Variants in Association with Leprosy in Unrelated Indian Population Groups

Leprosy is a chronic infectious disease caused by Mycobacterium Leprae, where the host genetic background plays an important role toward the disease pathogenesis. Various studies have identified a number of human genes in association with leprosy or its clinical forms. However, non-replication of results has hinted at the heterogeneity among associations between different population groups, which could be due to differently evolved LD structures and differential frequencies of SNPs within the studied regions of the genome. A need for systematic and saturated mapping of the associated regions with the disease is warranted to unravel the observed heterogeneity in different populations. Mapping of the PARK2 and PACRG gene regulatory region with 96 SNPs, with a resolution of 1 SNP per 1 Kb for PARK2 gene regulatory region in a North Indian population, showed an involvement of 11 SNPs in determining the susceptibility towards leprosy. The association was replicated in a geographically distinct and unrelated population from Orissa in eastern India. In vitro reporter assays revealed that the two significantly associated SNPs, located 63.8 kb upstream of PARK2 gene and represented in a single BIN of 8 SNPs, influenced the gene expression. A comparison of BINs between Indian and Vietnamese populations revealed differences in the BIN structures, explaining the heterogeneity and also the reason for non-replication of the associated genomic region in different populations.Author Summary: Leprosy is a chronic granulomatous infection caused by the intracellular organism Mycobacterium leprae. The disease affects the skin and the peripheral nerves and can cause irreversible impairment of the nerve function with consequent chronic disabilities. The prevalence of leprosy has declined dramatically after the introduction of Multidrug therapy in the 1980s. However, the infection continues to survive as a major public health problem with more than 200,000 new cases reported globally every year, especially in China and India. The disease is governed by host genetic background, where several genes have been identified in association with leprosy or its clinical forms. The involvement of the PARK2 and PACRG genes with leprosy susceptibility in two distinct populations of the world, Vietnamese and Brazilian, and its non-replication in other populations suggests unravelling the reasons of heterogeneity between different population groups. The possibility of involvement of other variants and a differential LD structure for the PARK2 regulatory region in Indian populations as compared to Brazilian and Vietnamese provides an answer to the heterogeneity among associations observed previously in different population groups.