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

Twenty-seven polymorphisms from 12 genes have been investigated for association with tuberculosis (TB) in up to 514 cases and 913 controls from Karonga district, northern Malawi. Homozygosity for the complement receptor 1 (CR1) Q1022H polymorphism was associated with susceptibility to TB in this population (odds ratio [OR] = 3.12, 95% Confidence interval [CI] = 1.13–8.60, P = 0.028). This association was not observed among human immunodeficiency virus (HIV)–positive TB cases, suggesting either chance association or that HIV status may influence genetic associations with TB susceptibility. Heterozygosity for a newly studied CAAA insertion/deletion polymorphism in the 3'-untranslated region of solute carrier family 11, member 1 (SLC11A1, formerly NRAMP1) was associated with protection against TB in both HIV-positive (OR = 0.70, 95% CI = 0.49–0.99, P = 0.046) and HIV-negative (OR = 0.65, 95% CI = 0.46–0.92, P = 0.014) TB cases, suggesting that the SLC11A1 protein may have a role in innate TB immune responses that influence susceptibility even in immunocompromised individuals. However, associations of other variants of SCLA11A with TB reported from other populations were not replicated in Malawi. Furthermore, associations with vitamin D receptor, interferon-, and mannose-binding lectin observed elsewhere were not observed in this Karonga study. Genetic susceptibility to TB in Africans appears polygenic. The relevant genes and variants may vary significantly between populations, and may be affected by HIV infection status.

Received August 28, 2003. Accepted for publication March 11, 2004.

Acknowledgments: We thank the many field, laboratory, and data management staff of the KPS who have carried out the 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 Christophe Aucan, Kerrie Tosh, and Branwen Hennig for various assistance.

Financial support: 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, Simon Malema, 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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