Volume 11 Supplement 1

Beyond the Genome: The true gene count, human evolution and disease genomics

Open Access

A replicative association study of Chromosome 6p21.3 with susceptibility to leprosy in an Indian population - 'a string hypothesis'

  • Shafat Ali1,
  • Rupali Chopra1,
  • Shweta Aggarwal1,
  • Dheeraj Malhotra1,
  • Vijay K Garg2,
  • S N Bhattacharya3 and
  • Rameshwar NK Bamezai1
Genome Biology201011(Suppl 1):P5

https://doi.org/10.1186/gb-2010-11-s1-p5

Published: 11 October 2010

Introduction

Leprosy is a chronic infectious disease, caused by Mycobacterium leprae, which affects mainly the skin and nerves of the host and results in characteristic deformity and disability. The role of host genetic factors in conferring susceptibility to this disease has long been a focus of research, with the discovery of many loci by segregation, twin and case-control studies [1, 2]. Here we propose how a perturbation involving a 'string' of DNA, co-evolved with a cluster of genes, provides a basis to the susceptibility to a this complex disease.

Materials and methods

We conducted a systematic three-stage, high resolution scan of the 6p21.3 chromosomal region of 177kb, within HLA class I and III region, with 111 SNPs genotyped using Sequenom Mass Array. We included a total of 2301 individuals, including patients and controls from the North Indian population and replicated our results in an East Indian population, from the geographically distinct state of Orissa.

Results

We identified SNP variants along the length of the 'string' of 6p21.3 with multiple genes from HLA class III and HLA class II that were significantly associated with leprosy and its polar subgroups. Table 1
Table 1

Significant P-values for SNPs in 6p21.3 region

SNP (rs-ID)

Function

Significant P-value

rs2523504

BAT1 promoter

5.1 E-05

rs2230365

NFKBIL1 exon3

8.6E-06

rs13192469

LTA 13kb upstream

1.5E-04

rs36221459

LTA promoter

4.9E-04

rs1800629

TNF-308 promoter

5.5E-04

rs769178

TNF-LTB downstream

8.8E-04

rs3135365

HLA class II BTNL2-DRA

1.73E-22

rs7773756

HLA class II BTNL2-DRA

2.8E-17

Conclusion

In addition to discovering the function of the genes BAT1 and BTNL2, we also established the functional status of the SNPs through in-vitroreporter assays. Furthermore, our assessment of an interaction of multiple genes in unison within the 'string' provided us with a graded risk to leprosy, which is dependant on the combination of genotypes of the significantly associated functional SNPs. Our results provide the first demonstration of the genome combinations of the polar forms of leprosy and the role of independent SNPs/genes in reaction states of the leprosy.

Authors’ Affiliations

(1)
National Centre of Applied Human Genetics, School of life Sciences, Jawaharlal Nehru University
(2)
Department of Dermatology and Sexually Transmitted Diseases, Maulana Azad Medical College, Lok Nayak Jai Prakash Hospital
(3)
Department of Dermatology and Venereology, University College of Medical Sciences and GTB Hospital

References

  1. Abel L, Vu DL, Oberti J, Nguyen VT, Van VC, Guilloud-Bataille M, Schurr E, Lagrange PH: Complex segregation analysis of leprosy in southern Vietnam. Genet Epidemiol. 1995, 12: 63-82. 10.1002/gepi.1370120107.PubMedView ArticleGoogle Scholar
  2. Shields ED, Russell DA, Pericak-Vance MA: Genetic epidemiology of the susceptibility to leprosy. J Clin Invest. 1987, 79: 1139-1143. 10.1172/JCI112930.PubMedPubMed CentralView ArticleGoogle Scholar

Copyright

© Ali et al; licensee BioMed Central Ltd. 2010

This article is published under license to BioMed Central Ltd.