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. 2013;9(7):e1003578.
doi: 10.1371/journal.pgen.1003578. Epub 2013 Jul 4.

Mapping of PARK2 and PACRG overlapping regulatory region reveals LD structure and functional variants in association with leprosy in unrelated indian population groups

Rupali Chopra  1 , Shafat Ali, Amit K Srivastava, Shweta Aggarwal, Bhupender Kumar, Siddharth Manvati, Ponnusamy Kalaiarasan, Mamta Jena, Vijay K Garg, Sambit N Bhattacharya, Rameshwar N K Bamezai
Affiliations

Mapping of PARK2 and PACRG overlapping regulatory region reveals LD structure and functional variants in association with leprosy in unrelated indian population groups

Rupali Chopra et al. PLoS Genet. 2013.

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. A partial map of Chromosome-6q26 expanded to show the position and distribution of 11 significant SNPs (shown with rs numbers) in the regulatory region of the PARK2 and PACRG genes.
Figure 2
Figure 2. The association statistics of the 11 significant SNPs in the regulatory region of the PARK2 and PACRG genes; presented as negative logarithm of the P-Value and their linkage disequilibrium (LD) plot based on pairwise LD for r2 cut off value ≥0.80.
Figure 3
Figure 3. A schematic lay-out of the BIN structure (r2≥0.80) in the regulatory region of the PARK2 and PACRG genes in North Indian and East Indian-Orissa and Vietnamese population for 41 SNPs spanning 148 Kb region of Chromosome 6q26, where 36 SNPs are common to both Vietnamese and Indian population and 5 significant SNPs (No. 20, 22, 23, 26, 32) are exclusively studied in the Indian population.
[It may be noted that a similar BIN structure was observed in the North-Indian and East-Indian-Orissa populations]. Physical location of the studied chromosomal region is given in Mb on top. Vietnamese population information of Mira et al, 2004 and common SNPs between Indian and Vietnamese population (Alter et al, 2012) was shared by Prof. Schurr. Rest of the SNPs & BIN structure information was retrieved from Alter et al (2012). SNPs in star shape indicate the significant association (in two respective populations-Indian and Vietnamese). 11 significantly associated SNPs in studied Indian populations are distributed in two BINs (BIN 1 with 8 and BIN 2 with 3 SNPs). Distribution of significant SNPs in Vietnamese population is shown in BIN 1, BIN 2 and BIN3. SNPs, rs10945859 (No. 1) and rs9347684 (No. 9), although shared significance in both the Indian and Vietnamese population, but these showed no significant difference in expression in in vitro reporter assay for the alternative alleles. Each SNP is designated by a No. ranging from 1 to 41 according to increasing order of the chromosomal position. Filled Black Star - Significant SNPs in Indian (North and East Indian-Orissa) population, Unfilled Star - Significant SNPs in Vietnamese population, Filled Black Dot - Non-Significant SNPs in North and East Indian-Orissa population, Unfilled Dot - Non-Significant SNPs in Vietnamese population, Black Circled Dot and Black Circled Star SNPs (No. 5, 7, 8, 24, 35) studied by us earlier .
Figure 4
Figure 4. Luciferase expression assay of upstream SNPs of PARK2 gene (rs9365492 (T/C) and rs9355403 (G/A)): C & A respectively represent risk allele for the SNP.
Bar with standard error shows the mean expression values in three different cell lines (HepG2, MCF7 and HeLa) for different Clones in PGL3 promoter vector: Clone1, with protective allele combination - rs9365492(T)-rs9355403(G); Clone2, with risk and protective allele combination - rs9365492(C)-rs9355403(G); Clone3, with protective and risk allele combination - rs9365492(T)-rs9355403(A) and Clone4, with risk allele combination - rs9365492(C)-rs9355403(A). P-Values for comparison of mean (one way ANOVA) expression between clones with different allele combination of 2 SNPs is also shown.
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Grants and funding

Financial support for the production of the manuscript was provided by Shri Mata Vaishno Devi University and University Grants Commission and DBT to the National Centre of Applied Human Genetics. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.