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Association of variants in BAT1-LTA-TNF-BTNL2 genes within 6p21.3 region show graded risk to leprosy in unrelated cohorts of Indian population

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Abstract

Host immune response against Mycobacterium leprae plays an important role in providing resistance to infection and disease progression. Genome-wide linkage and association studies suggest the possibility of multiple risk loci within HLA (6p21.3) region. Any systematic study of relevance within the histocompatibility complex of importance in host immune response would be pertinent because of non-replication of the known loci and unavailable information on some of the unexplored genes and regions. A systematic scan was performed of the selected region involving LTA-TNF-LTB genes within 6p21.3 with a resolution of 1SNP/127 bp; and the SNPs in flanking BAT1, NFKBIL and BTNL2-DRA genes on the basis of their tag status or their presence in promoter/exonic regions with MAF of >5%. Nine SNPs located in BAT1, LTA, TNF genes and BTNL2-DRA interval showed strong association with leprosy susceptibility in two independent sets of North Indian population which was replicated in a geographically distinct East Indian population. Conditional logistic regression showed at least one functional SNP remaining significant in each gene, suggesting an independent role of each of the disease associated SNPs. In vitro reporter assay revealed that two SNPs located at BAT1 promoter and 13 kb upstream to LTA gene affected the transcription factor binding site, hence the gene expression. We unravel the role of unexplored immunologically important genes, BAT1 and BTNL2, in addition to known LTA and TNF genes, and the haplotypes of the significantly associated SNPs therein, to understand susceptibility to the disease, leprosy and its differential severity.

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Acknowledgments

We thank all who participated in the study. Authors thank Anita Behura, Subhendu Acharya, Bhupender Kumar and Rajnish Singh for their assistance; Dr. Shobit Caroli and Dr. Sudhanshu, the attending physicians at LNJP Hospital and Prof. Jason P. Sinnwell for his invaluable support in providing Haplo.Stats package. Acknowledgement is due for providing genotypic data of HLA region by Fredrick Vannberg, The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK. Financial support provided to the National Centre of Applied Human Genetics by the University Grants Commission, New Delhi, India and high-throughput-project funding from DBT is acknowledged. The fellowship support to S.A. from Council for Scientific and Industrial Research (CSIR) is also acknowledged.

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Author notes

  1. Rameshwar N. K. Bamezai

    Present address: SMVDU, Katra, Jammu, Jammu and Kashmir, India

Authors and Affiliations

  1. National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India

    Shafat Ali, Rupali Chopra, Shweta Aggarwal, Amit Kumar Srivastava, Ponnusamy Kalaiarasan, Dheeraj Malhotra, Sailesh Gochhait & Rameshwar N. K. Bamezai

  2. Department of Dermatology and Sexually Transmitted Diseases, Maulana Azad Medical College, Lok Nayak Jai Prakash Hospital, New Delhi, 110002, India

    Vijay K. Garg

  3. Department of Dermatology and Venereology, University College of Medical Sciences and GTB Hospital, Delhi, 110095, India

    S. N. Bhattacharya

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  1. Shafat Ali
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  2. Rupali Chopra
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Correspondence to Rameshwar N. K. Bamezai.

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The authors wish it to be known that, in their opinion, authors R. Chopra and S. Aggarwal should be regarded as joint second authors.

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Ali, S., Chopra, R., Aggarwal, S. et al. Association of variants in BAT1-LTA-TNF-BTNL2 genes within 6p21.3 region show graded risk to leprosy in unrelated cohorts of Indian population. Hum Genet 131, 703–716 (2012). https://doi.org/10.1007/s00439-011-1114-6

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