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

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 TC 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.

Received August 28, 2003. Accepted for publication January 19, 2004.

Acknowledgments: We thank the many field, laboratory, and data management staff of the KPS who have carried out the leprosy work in Karonga District since 1979, the people of Karonga District, and the Ministry of Health and Population and the National Health Sciences Research Committee of Malawi for their encouragement of the KPS over many years. We also thank past and present Wellcome Trust Centre for Human Genetics (WTCHG) researchers and collaborators including Peter Zimmerman, Patricia Ramaley, and Graham Cooke for their role in developing the genotyping methods used here, as well as WTCHG core facilities staff, and Kerrie Tosh, Christophe Aucan, and Dr. Branwen Hennig, for their assistance.

Financial support: The leprosy work of the KPS has been funded since its inception by the British Leprosy Relief Association, with contributions from the International Federation of Anti-Leprosy Associations. This study was supported by the Wellcome Trust. Adrian V. S. Hill is a Wellcome Trust Principal Research Fellow.

Authors’ addresses: Jodene Fitness, School of Biological Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand, E-mail: jodene.fitness{at}vuw.ac.nz. Sian Floyd and Paul E. M. Fine, Department of Tropical Hygiene, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom, E-mails: sian.floyd{at}lshtm.ac.uk and paul.fine{at}lshtm.ac.uk. David K. Warndorff, Lifted Sichali, Lorren Mwaungulu, and Amelia C. Crampin, Karonga Prevention Study, PO Box 46, Chilumba, Karonga District, Malawi. Adrian V. S. Hill, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, United Kingdom, E-mail: adrian.hill{at}molecular-medicine.oxford.ac.uk.

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