LARGE-SCALE CANDIDATE GENE STUDY OF LEPROSY SUSCEPTIBILITY IN THE KARONGA DISTRICT OF NORTHERN MALAWI

JODENE FITNESS Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Department of Tropical Hygiene, London School of Hygiene and Tropical Medicine, London, United Kingdom; Karonga Prevention Study, Chilumba, Karonga District, Malawi

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SIAN FLOYD Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Department of Tropical Hygiene, London School of Hygiene and Tropical Medicine, London, United Kingdom; Karonga Prevention Study, Chilumba, Karonga District, Malawi

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DAVID K. WARNDORFF Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Department of Tropical Hygiene, London School of Hygiene and Tropical Medicine, London, United Kingdom; Karonga Prevention Study, Chilumba, Karonga District, Malawi

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LIFTED SICHALI Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Department of Tropical Hygiene, London School of Hygiene and Tropical Medicine, London, United Kingdom; Karonga Prevention Study, Chilumba, Karonga District, Malawi

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LORREN MWAUNGULU Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Department of Tropical Hygiene, London School of Hygiene and Tropical Medicine, London, United Kingdom; Karonga Prevention Study, Chilumba, Karonga District, Malawi

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AMELIA C. CRAMPIN Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Department of Tropical Hygiene, London School of Hygiene and Tropical Medicine, London, United Kingdom; Karonga Prevention Study, Chilumba, Karonga District, Malawi

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PAUL E. M. FINE Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Department of Tropical Hygiene, London School of Hygiene and Tropical Medicine, London, United Kingdom; Karonga Prevention Study, Chilumba, Karonga District, Malawi

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ADRIAN V. S. HILL Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Department of Tropical Hygiene, London School of Hygiene and Tropical Medicine, London, United Kingdom; Karonga Prevention Study, Chilumba, Karonga District, Malawi

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We present a large case-control candidate gene study of leprosy susceptibility. Thirty-eight polymorphic sites from 13 genes were investigated for their role in susceptibility to leprosy by comparing 270 cases with 452 controls in Karonga district, northern Malawi. Homozygotes for a silent T→C change in codon 352 of the vitamin D receptor gene appeared to be at high risk (odds ratio [OR] = 4.3, 95% confidence interval [CI] = 1.6–11.4, P = 0.004), while homozygotes for the McCoy b blood group defining variant K1590E in exon 29 of the complement receptor 1 (formerly CD35) gene appeared to be protected (OR = 0.3, 95% CI = 0.1–0.8, P = 0.02). Borderline evidence for association with leprosy susceptibility was found for seven polymorphic sites in an additional six genes. Some of these apparent associations may be false-positive results from multiple comparisons, and several associations suggested by studies in other populations were not replicated here. These data provide evidence of inter-population heterogeneity in leprosy susceptibility.

  • 1

    Fine PE, 1988. Implications of genetics for the epidemiology and control of leprosy. Philos Trans R Soc Lond B Biol Sci 321 :365–376.

  • 2

    Chakravartti MR, Vogel F, 1973. A twin study on leprosy. Top Hum Genet 1 :1–123.

  • 3

    Fitness J, Tosh K, Hill AV, 2002. Genetics of susceptibility to leprosy. Genes Immun 3 :441–453.

  • 4

    Tosh K, Meisner S, Siddiqui MR, Balakrishnan K, Ghei S, Golding M, Sengupta U, Pitchappan RM, Hill AV, 2002. A region of chromosome 20 is linked to leprosy susceptibility in a south Indian population. J Infect Dis 186 :1190–1193.

    • Search Google Scholar
    • Export Citation
  • 5

    Todd JR, West BC, McDonald JC, 1990. Human leukocyte antigen and leprosy: study in northern Louisiana and review. Rev Infect Dis 12 :63–74.

    • Search Google Scholar
    • Export Citation
  • 6

    Shaw MA, Donaldson IJ, Collins A, Peacock CS, Lins-Lainson Z, Shaw JJ, Ramos F, Silveira F, Blackwell JM, 2001. Association and linkage of leprosy phenotypes with HLA class II and tumour necrosis factor genes. Genes Immun 2 :196–204.

    • Search Google Scholar
    • Export Citation
  • 7

    Siddiqui MR, Meisner S, Tosh K, Balakrishnan K, Ghei S, Fisher SE, Golding M, Shanker Narayan NP, Sitaraman T, Sengupta U, Pitchappan R, Hill AV, 2001. A major susceptibility locus for leprosy in India maps to chromosome 10p13. Nat Genet 27 :439–441.

    • Search Google Scholar
    • Export Citation
  • 8

    Mira MT, Alcais A, van Thuc N, Thai VH, Huong NT, Ba NN, Verner A, Hudson TJ, Abel L, Schurr E, 2003. Chromosome 6q25 is linked to susceptibility to leprosy in a Vietnamese population. Nat Genet 33 :412–415.

    • Search Google Scholar
    • Export Citation
  • 9

    Santos AR, Suffys PN, Vanderborght PR, Moraes MO, Vieira LM, Cabello PH, Bakker AM, Matos HJ, Huizinga TW, Ottenhoff TH, Sampaio EP, Sarno EN, 2002. Role of tumor necrosis factor-alpha and interleukin-10 promoter gene polymorphisms in leprosy. J Infect Dis 186 :1687–1691.

    • Search Google Scholar
    • Export Citation
  • 10

    Fitness J, Floyd S, Warndorff DK, Sichali L, Malema S, Crampin AC, Fine PEM, Hill AVS, 2004. Large-scale candidate gene study of tuberculosis susceptibility in the Karonga district of northern Malawi. Am J Trop Med Hyg 70 : (in press).

    • Search Google Scholar
    • Export Citation
  • 11

    Fernandez-Reyes D, Craig AG, Kyes SA, Peshu N, Snow RW, Berendt AR, Marsh K, Newbold CI, 1997. A high frequency African coding polymorphism in the N-terminal domain of ICAM-1 predisposing to cerebral malaria in Kenya. Hum Mol Genet 6 :1357–1360.

    • Search Google Scholar
    • Export Citation
  • 12

    Shin HD, Winkler C, Stephens JC, Bream J, Young H, Goedert JJ, O’Brien TR, Vlahov D, Buchbinder S, Giorgi J, Rinaldo C, Donfield S, Willoughby A, O’Brien SJ, Smith MW, 2000. Genetic restriction of HIV-1 pathogenesis to AIDS by promoter alleles of IL10. Proc Natl Acad Sci U S A 97 :14467–14472.

    • Search Google Scholar
    • Export Citation
  • 13

    Lorenz E, Mira JP, Cornish KL, Arbour NC, Schwartz DA, 2000. A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection. Infect Immun 68 :6398–6401.

    • Search Google Scholar
    • Export Citation
  • 14

    Ponnighaus JM, Fine PE, Sterne JA, Bliss L, Wilson RJ, Malema SS, Kileta S, 1994. Incidence rates of leprosy in Karonga District, northern Malawi: patterns by age, sex, BCG status and classification. Int J Lepr Other Mycobact Dis 62 :10–23.

    • Search Google Scholar
    • Export Citation
  • 15

    Ponninghaus JM, Fine PE, Bliss L, Sliney IJ, Bradley DJ, Rees RJ, 1987. The Lepra Evaluation Project (LEP), an epidemiological study of leprosy in northern Malawi. I. Methods. Lepr Rev 58 :359–375.

    • Search Google Scholar
    • Export Citation
  • 16

    Ponnighaus JM, Fine PE, Bliss L, 1987. Certainty levels in the diagnosis of leprosy. Int J Lepr Other Mycobact Dis 55 :454–462.

  • 17

    Ponnighaus JM, Mwanjasi LJ, Fine PE, Shaw MA, Turner AC, Oxborrow SM, Lucas SB, Jenkins PA, Sterne JA, Bliss L, 1991. Is HIV infection a risk factor for leprosy? Int J Lepr Other Mycobact Dis 59 :221–228.

    • Search Google Scholar
    • Export Citation
  • 18

    van Heel DA, McGovern DP, Cardon LR, Dechairo BM, Lench NJ, Carey AH, Jewell DP, 2002. Fine mapping of the IBD1 locus did not identify Crohn disease-associated NOD2 variants: implications for complex disease genetics. Am J Med Genet 111 :253–259.

    • Search Google Scholar
    • Export Citation
  • 19

    Pravica V, Perrey C, Stevens A, Lee JH, Hutchinson IV, 2000. A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production. Hum Immunol 61 :863–866.

    • Search Google Scholar
    • Export Citation
  • 20

    Jongeneel CV, Briant L, Udalova IA, Sevin A, Nedospasov SA, Cambon-Thomsen A, 1991. Extensive genetic polymorphism in the human tumor necrosis factor region and relation to extended HLA haplotypes. Proc Natl Acad Sci U S A 88 :9717–9721.

    • Search Google Scholar
    • Export Citation
  • 21

    Al-Sharif FM, Makki RF, Ollier WE, Hajeer AH, 1999. A new microsatellite marker within the promoter region of the MIP-1A gene. Immunogenetics 49 :740–741.

    • Search Google Scholar
    • Export Citation
  • 22

    Kang TJ, Chae GT, 2001. Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients. FEMS Immunol Med Microbiol 31 :53–58.

    • Search Google Scholar
    • Export Citation
  • 23

    Day DJ, Speiser PW, White PC, Barany F, 1995. Detection of steroid 21-hydroxylase alleles using gene-specific PCR and a multiplexed ligation detection reaction. Genomics 29 :152–162.

    • Search Google Scholar
    • Export Citation
  • 24

    Rogers L, 1921. Chaulmoogra oil in leprosy and tuberculosis. Lancet 1 :1178–1180.

  • 25

    Roy S, Frodsham A, Saha B, Hazra SK, Mascie-Taylor CG, Hill AV, 1999. Association of vitamin D receptor genotype with leprosy type. J Infect Dis 179 :187–191.

    • Search Google Scholar
    • Export Citation
  • 26

    Verbeek W, Gombart AF, Shiohara M, Campbell M, Koeffler HP, 1997. Vitamin D receptor: no evidence for allele-specific mRNA stability in cells which are heterozygous for the Taq I restriction enzyme polymorphism. Biochem Biophys Res Commun 238 :77–80.

    • Search Google Scholar
    • Export Citation
  • 27

    Mocharla H, Butch AW, Pappas AA, Flick JT, Weinstein RS, De Togni P, Jilka RL, Roberson PK, Parfitt AM, Manolagas SC, 1997. Quantification of vitamin D receptor mRNA by competitive polymerase chain reaction in PBMC: lack of correspondence with common allelic variants. J Bone Miner Res 12 :726–733.

    • Search Google Scholar
    • Export Citation
  • 28

    Schlesinger LS, Horwitz MA, 1990. Phagocytosis of leprosy bacilli is mediated by complement receptors CR1 and CR3 on human monocytes and complement component C3 in serum. J Clin Invest 85 :1304–1314.

    • Search Google Scholar
    • Export Citation
  • 29

    Hirsch CS, Ellner JJ, Russell DG, Rich EA, 1994. Complement receptor-mediated uptake and tumor necrosis factor-alpha-mediated growth inhibition of Mycobacterium tuberculosis by human alveolar macrophages. J Immunol 152 :743–753.

    • Search Google Scholar
    • Export Citation
  • 30

    Moulds JM, Zimmerman PA, Doumbo OK, Kassambara L, Sagara I, Diallo DA, Atkinson JP, Krych-Goldberg M, Hauhart RE, Hourcade DE, McNamara DT, Birmingham DJ, Rowe JA, Moulds JJ, Miller LH, 2001. Molecular identification of Knops blood group polymorphisms found in long homologous region D of complement receptor 1. Blood 97 :2879–2885.

    • Search Google Scholar
    • Export Citation
  • 31

    Xiang L, Rundles JR, Hamilton DR, Wilson JG, 1999. Quantitative alleles of CR1: coding sequence analysis and comparison of haplotypes in two ethnic groups. J Immunol 163 :4939–4945.

    • Search Google Scholar
    • Export Citation
  • 32

    Zimmerman PA, Fitness J, Moulds JM, McNamara DT, Kasehagen LJ, Rowe JA, Hill AV, 2003. CR1 Knops blood group alleles are not associated with severe malaria in the Gambia. Genes Immun 4 :368–373.

    • Search Google Scholar
    • Export Citation
  • 33

    Knight JC, Udalova I, Hill AV, Greenwood BM, Peshu N, Marsh K, Kwiatkowski D, 1999. A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria. Nat Genet 22 :145–150.

    • Search Google Scholar
    • Export Citation
  • 34

    Cabrera M, Shaw MA, Sharples C, Williams H, Castes M, Convit J, Blackwell JM, 1995. Polymorphism in tumor necrosis factor genes associated with mucocutaneous leishmaniasis. J Exp Med 182 :1259–1264.

    • Search Google Scholar
    • Export Citation
  • 35

    Sashio H, Tamura K, Ito R, Yamamoto Y, Bamba H, Kosaka T, Fukui S, Sawada K, Fukuda Y, Satomi M, Shimoyama T, Furuyama J, 2002. Polymorphisms of the TNF gene and the TNF receptor superfamily member 1B gene are associated with susceptibility to ulcerative colitis and Crohn’s disease, respectively. Immunogenetics 53 :1020–1027.

    • Search Google Scholar
    • Export Citation
  • 36

    Santos AR, Almeida AS, Suffys PN, Moraes MO, Filho VF, Mattos HJ, Nery JA, Cabello PH, Sampaio EP, Sarno EN, 2000. Tumor necrosis factor promoter polymorphism (TNF2) seems to protect against development of severe forms of leprosy in a pilot study in Brazilian patients. Int J Lepr Other Mycobact Dis 68 :325–327.

    • Search Google Scholar
    • Export Citation
  • 37

    Moraes MO, Duppre NC, Suffys PN, Santos AR, Almeida AS, Nery JA, Sampaio EP, Sarno EN, 2001. Tumor necrosis factor-alpha promoter polymorphism TNF2 is associated with a stronger delayed-type hypersensitivity reaction in the skin of borderline tuberculoid leprosy patients. Immunogenetics 53 :45 −47.

    • Search Google Scholar
    • Export Citation
  • 38

    Roy S, McGuire W, Mascie-Taylor CG, Saha B, Hazra SK, Hill AV, Kwiatkowski D, 1997. Tumor necrosis factor promoter polymorphism and susceptibility to lepromatous leprosy. J Infect Dis 176 :530–532.

    • Search Google Scholar
    • Export Citation
  • 39

    Bayley JP, de Rooij H, van den Elsen PJ, Huizinga TW, Verweij CL, 2001. Functional analysis of linker-scan mutants spanning the −376, −308, −244, and −238 polymorphic sites of the TNF-alpha promoter. Cytokine 14 :316–323.

    • Search Google Scholar
    • Export Citation
  • 40

    Udalova IA, Richardson A, Denys A, Smith C, Ackerman H, Foxwell B, Kwiatkowski D, 2000. Functional consequences of a polymorphism affecting NF-kappaB p50-p50 binding to the TNF promoter region. Mol Cell Biol 20 :9113–9119.

    • Search Google Scholar
    • Export Citation
  • 41

    Gibson AW, Edberg JC, Wu J, Westendorp RG, Huizinga TW, Kimberly RP, 2001. Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus. J Immunol 166 :3915–3922.

    • Search Google Scholar
    • Export Citation
  • 42

    Rees LE, Wood NA, Gillespie KM, Lai KN, Gaston K, Mathieson PW, 2002. The interleukin-10-1082 G/A polymorphism: allele frequency in different populations and functional significance. Cell Mol Life Sci 59 :560–569.

    • Search Google Scholar
    • Export Citation
  • 43

    Krutzik SR, Ochoa MT, Sieling PA, Uematsu S, Ng YW, Legaspi A, Liu PT, Cole ST, Godowski PJ, Maeda Y, Sarno EN, Norgard MV, Brennan PJ, Akira S, Rea TH, Modlin RL, 2003. Activation and regulation of Toll-like receptors 2 and 1 in human leprosy. Nat Med 9 :525–532.

    • Search Google Scholar
    • Export Citation
  • 44

    Means TK, Wang S, Lien E, Yoshimura A, Golenbock DT, Fenton MJ, 1999. Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. J Immunol 163 :3920–3927.

    • Search Google Scholar
    • Export Citation
  • 45

    Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, Frees K, Watt JL, Schwartz DA, 2000. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 25 :187–191.

    • Search Google Scholar
    • Export Citation
  • 46

    Lorenz E, Mira JP, Frees KL, Schwartz DA, 2002. Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med 162 :1028–1032.

    • Search Google Scholar
    • Export Citation
  • 47

    Garred P, Madsen HO, Kurtzhals JA, Lamm LU, Thiel S, Hey AS, Svejgaard A, 1992. Diallelic polymorphism may explain variations of the blood concentration of mannan-binding protein in Eskimos, but not in black Africans. Eur J Immunogenet 19 :403–412.

    • Search Google Scholar
    • Export Citation
  • 48

    Garred P, Harboe M, Oettinger T, Koch C, Svejgaard A, 1994. Dual role of mannan-binding protein in infections: another case of heterosis? Eur J Immunogenet 21 :125–131.

    • Search Google Scholar
    • Export Citation
  • 49

    Lio D, Marino V, Serauto A, Gioia V, Scola L, Crivello A, Forte GI, Colonna-Romano G, Candore G, Caruso C, 2002. Genotype frequencies of the +874T→A single nucleotide polymorphism in the first intron of the interferon-gamma gene in a sample of Sicilian patients affected by tuberculosis. Eur J Immunogenet 29 :371–374.

    • Search Google Scholar
    • Export Citation
  • 50

    Rossouw M, Nel HJ, Cooke GS, van Helden PD, Hoal EG, 2003. Association between tuberculosis and a polymorphic NFkappaB binding site in the interferon gamma gene. Lancet 361 :1871–1872.

    • Search Google Scholar
    • Export Citation
  • 51

    Abel L, Sanchez FO, Oberti J, Thuc NV, Hoa LV, Lap VD, Skamene E, Lagrange PH, Schurr E, 1998. Susceptibility to leprosy is linked to the human NRAMP1 gene. J Infect Dis 177 :133–145.

    • Search Google Scholar
    • Export Citation
  • 52

    Shaw MA, Atkinson S, Dockrell H, Hussain R, Lins-Lainson Z, Shaw J, Ramos F, Silveira F, Mehdi SQ, Kaukab F, 1993. An RFLP map for 2q33–q37 from multicase mycobacterial and leishmanial disease families: no evidence for an Lsh/Ity/Bcg gene homologue influencing susceptibility to leprosy. Ann Hum Genet 57 :251–271.

    • Search Google Scholar
    • Export Citation
  • 53

    Meisner SJ, Mucklow S, Warner G, Sow SO, Lienhardt C, Hill AV, 2001. Association of NRAMP1 polymorphism with leprosy type but not susceptibility to leprosy per se in west Africans. Am J Trop Med Hyg 65 :733–735.

    • Search Google Scholar
    • Export Citation
  • 54

    Medina E, Rogerson BJ, North RJ, 1996. The Nramp1 antimicrobial resistance gene segregates independently of resistance to virulent Mycobacterium tuberculosis.Immunology 88 :479–481.

    • Search Google Scholar
    • Export Citation
  • 55

    Alcais A, Sanchez FO, Thuc NV, Lap VD, Oberti J, Lagrange PH, Schurr E, Abel L, 2000. Granulomatous reaction to intra-dermal injection of lepromin (Mitsuda reaction) is linked to the human NRAMP1 gene in Vietnamese leprosy sibships. J Infect Dis 181 :302–308.

    • Search Google Scholar
    • Export Citation
  • 56

    Bellamy R, Ruwende C, Corrah T, McAdam KP, Whittle HC, Hill AV, 1998. Variations in the NRAMP1 gene and susceptibility to tuberculosis in west Africans. N Engl J Med 338 :640–644.

    • Search Google Scholar
    • Export Citation
  • 57

    Wallace C, Clayton D, Fine P, 2003. Estimating the relative recurrence risk ratio for leprosy in Karonga District, Malawi. Lepr Rev 74 :133–140.

    • Search Google Scholar
    • Export Citation
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