Variants of the CD40 ligand gene are not associated with increased susceptibility to tuberculosis in West Africa
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Evidence for linkage between tuberculosis and human chromosomal region Xq26 has previously been described. The costimulatory molecule CD40 ligand, encoded by TNFSF5 and located at Xq26.3, is a promising positional candidate. Interactions between CD40 ligand and CD40 are involved in the development of humoral- and cell-mediated immunity, as well as the activation of macrophages, which are the primary host and effector cells for Mycobacterium tuberculosis. We hypothesised that common variation within TNFSF5 might affect susceptibility to tuberculosis disease and, thus, might be responsible for the observed linkage to Xq26. Sequencing 32 chromosomes from a Gambian population identified nine common polymorphisms within the coding, 3′ and 5′ regulatory sequences of the gene. Six single nucleotide polymorphisms (SNPs) and a 3′ microsatellite were genotyped in 121 tuberculosis patients and their available parents. No association with tuberculosis was detected for these variants using a transmission disequilibrium test, although one SNP at −726 showed some evidence of association in males. This finding, however, did not replicate in a separate case control study of over 1,200 West African individuals. We conclude that common genetic variation in TNFSF5 is not likely to affect tuberculosis susceptibility in West Africa and the linkage observed in this region is not due to variation in TNFSF5.
KeywordsTuberculosis Genetic susceptibility Polymorphism CD40 ligand
SJC is supported by a Wellcome Trust Prize Fellowship and AVSH is Wellcome Trust Principal Research Fellow. SB and KF are members of the MRC Tropical Epidemiology Group. The samples of the case-control study were collected as part of an EU-funded project (contract number IC18CT980375). Ethical approval was provided by the joint Gambian Government/Medical Research Council Ethical Committee, Ministry of Public Health (MINSAP, Guinea-Bissau) and National Ethics committee, Ministry of Health, Conakry, République de Guinée. The experiments comply with current laws of the countries in which the work was carried out. We are very grateful for the help of Cyril Ruwende and Hilton C. Whittle in the collection of the family samples and Simon Donkor and Sadio Diallo in data management. We would like to thank all study individuals for their participation.
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