LRRK2 and RIPK2 variants in the NOD 2-mediated signaling pathway are associated with susceptibility to Mycobacterium leprae in Indian populations

Patrick Marcinek; Aditya Nath Jha; Vidyagouri Shinde; Arun Sundaramoorthy; Raja Rajkumar; Naveen Chandra Suryadevara; Sanjeev Kumar Neela; Hoang van Tong; Vellingiri Balachander; Vijaya Lakshmi Valluri; Kumarasamy Thangaraj; Thirumalaisamy P Velavan

doi:10.1371/journal.pone.0073103

LRRK2 and RIPK2 variants in the NOD 2-mediated signaling pathway are associated with susceptibility to Mycobacterium leprae in Indian populations

PLoS One. 2013 Aug 28;8(8):e73103. doi: 10.1371/journal.pone.0073103. eCollection 2013.

Authors

Patrick Marcinek¹, Aditya Nath Jha, Vidyagouri Shinde, Arun Sundaramoorthy, Raja Rajkumar, Naveen Chandra Suryadevara, Sanjeev Kumar Neela, Hoang van Tong, Vellingiri Balachander, Vijaya Lakshmi Valluri, Kumarasamy Thangaraj, Thirumalaisamy P Velavan

Affiliation

¹ Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.

Abstract

In recent years, genome wide association studies have discovered a large number of gene loci that play a functional role in innate and adaptive immune pathways associated with leprosy susceptibility. The immunological control of intracellular bacteria M. leprae is modulated by NOD2-mediated signaling of Th1 responses. In this study, we investigated 211 clinically classified leprosy patients and 230 ethnically matched controls in Indian population by genotyping four variants in NOD2 (rs9302752A/G), LRRK2 (rs1873613A/G), RIPK2 (rs40457A/G and rs42490G/A). The LRRK2 locus is associated with leprosy outcome. The LRRK2 rs1873613A minor allele and respective rs1873613AA genotypes were significantly associated with an increased risk whereas the LRRK2 rs1873613G major allele and rs1873613GG genotypes confer protection in paucibacillary and leprosy patients. The reconstructed GA haplotypes from RIPK2 rs40457A/G and rs42490G/A variants was observed to contribute towards increased risk whereas haplotypes AA was observed to confer protective role. Our results indicate that a possible shared mechanisms underlying the development of these two clinical forms of the disease as hypothesized. Our findings confirm and validates the role of gene variants involved in NOD2-mediated signalling pathways that play a role in immunological control of intracellular bacteria M. leprae.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Female
Genetic Predisposition to Disease*
Haplotypes / genetics
Haplotypes / immunology
Humans
India / epidemiology
Leprosy / epidemiology
Leprosy / genetics*
Leprosy / immunology
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Male
Mycobacterium leprae*
Nod2 Signaling Adaptor Protein / genetics*
Nod2 Signaling Adaptor Protein / immunology
Polymorphism, Genetic / genetics
Polymorphism, Genetic / immunology
Protein Serine-Threonine Kinases / genetics*
Protein Serine-Threonine Kinases / immunology
Receptor-Interacting Protein Serine-Threonine Kinase 2 / genetics*
Receptor-Interacting Protein Serine-Threonine Kinase 2 / immunology
Signal Transduction / genetics*
Signal Transduction / immunology
Th1 Cells / immunology

Substances

NOD2 protein, human
Nod2 Signaling Adaptor Protein
LRRK2 protein, human
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Protein Serine-Threonine Kinases
RIPK2 protein, human
Receptor-Interacting Protein Serine-Threonine Kinase 2

Grants and funding

This study was funded by fortüne grant (1916-1-1), DFG PA 1974/3-1 and BMBF IND 10/A18 to Velavan TP. This study was also funded by LEPRA-BPHRC institutional grant and by ICMR (5/8/3(13)/2009-ECD-I (A) grant to Valluri VL. This work was supported by the Council of Scientific and Industrial Research, New Delhi (www.csir.res.in) to KT. The authors acknowledge the support by the Deutsche Forschungsgemeinschaft (DFG) and Open Access Publishing Fund of Tuebingen University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.