Linkage and association analysis of candidate genes for TB and TNFalpha cytokine expression: evidence for association with IFNGR1, IL-10, and TNF receptor 1 genes.
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 (TNFalpha) in response to culture filtrate as the phenotype. In the present study, we analyzed candidate genes related to TNFalpha regulation and found that interleukin (IL)-10, interferon-gamma receptor 1 (IFNGR1), and TNFalpha receptor 1 (TNFR1) genes were linked and associated to both TB and TNFalpha. 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.
Stein
Catherine M
CM
Department of Epidemiology and Biostatistics, Case Western Reserve University, Wolstein Research Building Room 1303, 2103 Cornell Rd, Cleveland, OH 44106, USA.
Zalwango
Sarah
S
Chiunda
Allan B
AB
Millard
Christopher
C
Leontiev
Dmitry V
DV
Horvath
Amanda L
AL
Cartier
Kevin C
KC
Chervenak
Keith
K
Boom
W Henry
WH
Elston
Robert C
RC
Mugerwa
Roy D
RD
Whalen
Christopher C
CC
Iyengar
Sudha K
SK
D005260:Female; D015870:Gene Expression; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats; D008957:Models, Genetic; D010641:Phenotype; D017471:Receptors, Interferon / Q000235:genetics*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D014376:Tuberculosis / Q000235:genetics* / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D014454:Uganda; D000096743:Interferon gamma Receptor
D016753:Interleukin-10; D017471:Receptors, Interferon; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor; C508609:IL10 protein, human