Linkage and association analysis of candidate genes for TB and TNFα cytokine expression:: evidence for association with IFNGR1, IL-10, and TNF receptor 1 genes

被引:52
作者
Stein, Catherine M.
Zalwango, Sarah
Chiunda, Allan B.
Millard, Christopher
Leontiev, Dmitry V.
Horvath, Amanda L.
Cartier, Kevin C.
Chervenak, Keith
Boom, W. Henry
Elston, Robert C.
Mugerwa, Roy D.
Whalen, Christopher C.
Iyengar, Sudha K.
机构
[1] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Tuberculosis Res Unit, Cleveland, OH 44106 USA
[3] Case Western Reserve Univ, Ctr Modern Epidemiol Infect Dis, Cleveland, OH 44106 USA
[4] Makerere Univ, Sch Med, Clin Epidemiol Unit, Kampala, Uganda
关键词
D O I
10.1007/s00439-007-0357-8
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Tuberculosis (TB) is a growing public health threat globally and several studies suggest a role of host genetic susceptibility in increased TB risk. As part of a household contact study in Kampala, Uganda, we have taken a unique approach to the study of genetic susceptibility to TB by developing an intermediate phenotype model for TB susceptibility, analyzing levels of tumor necrosis factor-alpha (TNF alpha) in response to culture filtrate as the phenotype. In the present study, we analyzed candidate genes related to TNF alpha regulation and found that interleukin (IL)-10, interferon-gamma receptor 1 (IFNGR1), and TNF alpha receptor 1 (TNFR1) genes were linked and associated to both TB and TNF alpha. We also show that these associations are with progression to active disease and not susceptibility to latent infection. This is the first report of an association between TB and TNFR1 in a human population and our findings for IL-10 and IFNGR1 replicate previous findings. By observing pleiotropic effects on both phenotypes, we show construct validity of our intermediate phenotype model, which enables the characterization of the role of these genetic polymorphisms on TB pathogenesis. This study further illustrates the utility of such a model for disentangling complex traits.
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收藏
页码:663 / 673
页数:11
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