INT J TUBERC LUNG DIS 8(12):1464–1471 © 2004 IUATLD SLC11A1 (NRAMP1) but not SLC11A2 (NRAMP2) polymorphisms are associated with susceptibility to tuberculosis in a high-incidence community in South Africa E. G. Hoal,* L-A. Lewis,* S. E. Jamieson, § F. Tanzer,* M. Rossouw,* T. Victor,* R. Hillerman, † N. Beyers, ‡ J. M. Blackwell, § P. D. Van Helden* * Medical Biochemistry and MRC Centre for Molecular and Cellular Biology, † Department of Genetics, ‡ Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg, South Africa; § Cambridge Institute for Medical SUMMARY Research, Addenbrooke’s Hospital, Cambridge, United Kingdom SETTING: Stellenbosch University Faculty of Health Sci- ences, and metropolitan Cape Town, Western Cape, South Africa. OBJECTIVE: To investigate whether the reported associ- ation between SLC11A1 (also NRAMP1) polymorphisms and susceptibility to tuberculosis (TB) can be confirmed in a different population, and whether polymorphisms in SLC11A2 (also NRAMP2, DCT1, DMT1) are associ- ated with TB. DESIGN: A case-control study design was used to compare the frequencies of five polymorphisms in SLC11A1 and three in SLC11A2 between a group of bacteriologically confirmed TB patients and healthy community controls. RESULTS: The 59 (GT) 9 allele in the promoter of SLC11A1 was found at significantly higher frequencies among 265 controls than in 224 pulmonary TB (PTB) patients (P 5 0.002; OR 0.6; 95%CI 0.43–0.83). Ho- mozygotes for the TGTG deletion (1729155del4) in the 39UTR of SLC11A1 were over-represented among PTB patients (P 5 0.013; OR 5.19; 95%CI 1.42–18.94). Step- wise logistic regression analysis indicated that the 59 and 39 polymorphisms contribute separate main effects. Tu- berculous meningitis patients (n 5 22) showed the same allele and genotype frequency as PTB patients. No SLC11A2 polymorphisms tested were associated with TB. CONCLUSION: The 59 (GT) n allele driving the highest rate of transcription of SLC11A1 appears to be associ- ated with protection against TB in the majority of the populations studied. KEY WORDS: association; SLC11A1; SLC11A2; sus- ceptibility; tuberculosis THE TUBERCULOSIS (TB) epidemic in developing countries shows no signs of slowing down and is in fact growing worldwide, with the death toll still be- tween 2 and 3 million people per year. It is thought that in some populations this can be ascribed to un- derlying genetic susceptibility to the pathogen which, combined with frequent adverse socio-economic fac- tors, acts to exacerbate the incidence and severity of TB disease. A number of genes, the subject of many reviews, 1–4 have been found to play a role in TB sus- ceptibility, and the relative importance of these genes in causing disease, or even different forms of disease, is often modulated by the ethnicity of the population studied. Before any genetic association can be used to indi- cate a pathway providing a potential target for antimi- crobial therapy, it should be confirmed and strength- ened by replication of results in a number of different population groups. As fewer than 10% of infected individuals develop clinical TB disease in the absence of immunosuppression, immunomodulation may be a viable alternative to chemotherapy. Novel anti- tuberculosis treatment may follow this path, as both a new vaccine and a new drug have thus far proved elusive. New ways to combat TB may come from the study of the natural resistance of certain individuals to this disease, and these natural defence mechanisms should thus be investigated to determine their univer- sality and the practicality of their implementation in treatment. The most extensively studied of the non-major his- tocompatibility complex TB susceptibility genes is SLC11A1 (solute carrier family 11A member 1), 5,6 formerly known as NRAMP1 (natural resistance- associated macrophage protein 1) and located on chromosome 2q35. This is the human homologue of Correspondence to: Dr Eileen G Hoal, Medical Biochemistry, P O Box 19063, Stellenbosch University, Tygerberg 7505, South Africa. Tel: (127) 219389412. Fax: (127) 219317841. e-mail: egvh@sun.ac.za Article submitted 1 August 2003. Final version accepted 25 March 2004.