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

Abstract

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.

Common variants in the PARL and PINK1 genes increase the risk to leprosy in Han Chinese from South China

“…3). Note that PINK1 directly interacted with PARK2, which was identified as a leprosy risk gene in several populations424344. However, our NGS analysis for the PARK2 gene revealed no association of this gene with leprosy though we observed positive associations between PARL and leprosy or between PINK1 and leprosy in this relatively small sample.…”

Mycobacterium leprae – der Erreger von Lepra

“…Folgende genetische Faktoren des Menschen beeinflussen den klinischen Verlauf durch Erhöhung der Suszeptibilität: Der Polymorphismus des Interleukin-10 (IL-10)-Promotors [74], Regionen auf dem Chromosom 6 wie PARK2/ PCRG, Parkin, Lymphotoxin alpha und HLA-DR-DQ SNP rs602875 [70,75], Polymorphismus des Toll-like-Rezeptors 1 (TLR-1) [76], Polymorphismus des NOD2 (nucleotide-binding oligomerization domain containing 2) [77]. PARK2 (parkin RBR E3 ubiquitin protein ligase) oder bezeichnet als PINK1 [78] fungiert wie ein Tumorsuppressor, und verschiedene Mutationen (SNP) im PARK2-Gen beeinflussen den Verlauf der Lepra [79]. TLR-2 und TLR-6 dienen dem Eintritt von M leprae in die Zelle [64].…”

PARK2 and proinflammatory/anti-inflammatory cytokine gene interactions contribute to the susceptibility to leprosy: a case–control study of North Indian population

“…16 A subsequent study of the 6q chromosomal region, involving the overlapping regulatory domain of PARK2-PACRG genes, revealed an involvement of significant single-nucleotide polymorphisms (SNPs) and presence of a differential LD structure in Indian populations as compared with Vietnamese. 18 The latter observation and the functional role of PARK2, as a ubiquitin ligase, has recently been shown in providing resistance to intracellular pathogens 19 through ubiquitin-mediated autophagy. Furthermore, the involvement of parkin in regulating production of cytokines upon infection, 20 indeed, provides a strong hint for any functional variations in the gene having a profound effect in modulating the expression of the immune-regulatory genes.…”

“…Furthermore, the involvement of parkin in regulating production of cytokines upon infection, 20 indeed, provides a strong hint for any functional variations in the gene having a profound effect in modulating the expression of the immune-regulatory genes. The importance of all the studied genes [14][15][16][17][18] in the network of immune-response necessitated the analysis of an interaction between these genes as a whole to understand their contribution together towards the susceptibility of the complex disease, leprosy, where the outcome of the infection in all probabilities depends on the nature of gene interactions between the genes with the potential of contributing to the immune pathology.…”

“…These included an overall interaction of the PARK2 gene significant SNPs 18 with the significant SNPs of anti-inflammatory cytokine genes (IL-10, IL-10RB, TGFBR2, IL-6), 14 proinflammatory cytokine genes (TNFα, LT-α, IL-12B) and the genes spanning the HLA region of the chromosome 6p21.3, that is, BAT1 to BTNL2-DR 16 17 to evaluate their combined contribution towards the outcome of the complex infectious disease, leprosy.…”