title: Association of variants in BAT1-LTA-TNF-BTNL2 genes within 6p21.3 region show graded risk to leprosy in unrelated cohorts of Indian population.
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.
authors.affiliation: National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Shafat
authors.initials: S
authors.lastname: Ali
authors.forename: Rupali
authors.initials: R
authors.lastname: Chopra
authors.forename: Shweta
authors.initials: S
authors.lastname: Aggarwal
authors.forename: Amit Kumar
authors.initials: AK
authors.lastname: Srivastava
authors.forename: Ponnusamy
authors.initials: P
authors.lastname: Kalaiarasan
authors.forename: Dheeraj
authors.initials: D
authors.lastname: Malhotra
authors.forename: Sailesh
authors.initials: S
authors.lastname: Gochhait
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Garg
authors.forename: S N
authors.initials: SN
authors.lastname: Bhattacharya
authors.forename: Rameshwar N K
authors.initials: RN
authors.lastname: Bamezai
mesh_terms: D044466:Asian People / Q000235:genetics; D005075:Biological Evolution; D000071797:Butyrophilins; D002896:Chromosomes, Human, Pair 6; D053487:DEAD-box RNA Helicases / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007194:India; D007918:Leprosy / Q000235:genetics*; D008233:Lymphotoxin-alpha / Q000235:genetics; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: C408263:BTNL2 protein, human; D000071797:Butyrophilins; D008233:Lymphotoxin-alpha; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; C487886:DDX39B protein, human; D053487:DEAD-box RNA Helicases
references.citation: J Infect Dis. 2011 May 1;203(9):1274-81
references.pmid: 21459816
references.citation: Breast Cancer Res Treat. 2011 Apr;126(2):333-43
references.pmid: 20443055
references.citation: Science. 2002 Jun 21;296(5576):2225-9
references.pmid: 12029063
references.citation: Nat Genet. 2007 Apr;39(4):517-22
references.pmid: 17353895
references.citation: Int J Lepr Other Mycobact Dis. 1995 Jun;63(2):241-8
references.pmid: 7602219
references.citation: Nat Genet. 2006 Nov;38(11):1298-303
references.pmid: 17057720
references.citation: Annu Rev Genet. 2006;40:469-86
references.pmid: 17094741
references.citation: Cytokine. 2001 Jun 21;14(6):316-23
references.pmid: 11497492
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: Genes Cells. 2001 May;6(5):487-94
references.pmid: 11380625
references.citation: PLoS Pathog. 2010 Jul 01;6:e1000979
references.pmid: 20617178
references.citation: Nat Genet. 2005 Apr;37(4):357-64
references.pmid: 15735647
references.citation: Microbes Infect. 2007 Apr;9(4):522-8
references.pmid: 17347014
references.citation: Int J Immunogenet. 2007 Jun;34(3):201-8
references.pmid: 17504510
references.citation: Eur J Hum Genet. 2006 Apr;14(4):438-42
references.pmid: 16391553
references.citation: J Clin Invest. 1987 Apr;79(4):1139-43
references.pmid: 3549780
references.citation: Tissue Antigens. 1998 Aug;52(2):147-52
references.pmid: 9756403
references.citation: Nat Genet. 2009 Dec;41(12):1282-9
references.pmid: 19881526
references.citation: J Exp Med. 1996 Mar 1;183(3):829-36
references.pmid: 8642287
references.citation: Tissue Antigens. 1997 Feb;49(2):168-72
references.pmid: 9062973
references.citation: Int J Lepr Other Mycobact Dis. 1966 Jul-Sep;34(3):255-73
references.pmid: 5950347
references.citation: J Immunol. 2006 Jun 15;176(12):7354-60
references.pmid: 16751379
references.citation: Infect Genet Evol. 2010 May;10(4):517-21
references.pmid: 20176143
references.citation: N Engl J Med. 2009 Dec 31;361(27):2609-18
references.pmid: 20018961
references.citation: J Infect Dis. 2002 Dec 1;186(11):1687-91
references.pmid: 12447749
references.citation: N Engl J Med. 2010 Apr 15;362(15):1446-7; author reply 1447-8
references.pmid: 20393182
references.citation: Bioinformatics. 2005 Jan 15;21(2):263-5
references.pmid: 15297300
references.citation: Genet Epidemiol. 1995;12(1):63-82
references.pmid: 7713401
references.citation: Hum Genet. 2005 Nov;118(2):295-300
references.pmid: 16163478