Abstract
BackgroundHuman genetic variants may affect tuberculosis susceptibility, but the immunologic correlates of the genetic variants identified are often unclear.MethodsWe conducted a pilot case-control study to identify genetic variants associated with extrapulmonary tuberculosis in patients with previously characterized immune defects: low CD4+ lymphocytes and low unstimulated cytokine production. Two genetic association approaches were used: 1) variants previously associated with tuberculosis risk; 2) single nucleotide polymorphisms (SNPs) in candidate genes involved in tuberculosis pathogenesis. Single locus association tests and multifactor dimensionality reduction (MDR) assessed main effects and multi-locus interactions.ResultsThere were 24 extrapulmonary tuberculosis cases (18 black), 24 pulmonary tuberculosis controls (19 black) and 57 PPD+ controls (49 black). In approach 1, 22 SNPs and 3 microsatellites were assessed. In single locus association tests, interleukin (IL)-1β +3953 C/T was associated with extrapulmonary tuberculosis compared to PPD+ controls (P = 0.049). Among the sub-set of patients who were black, genotype frequencies of the vitamin D receptor (VDR) Fok1 A/G SNP were significantly different in extrapulmonary vs. pulmonary TB patients (P = 0.018). In MDR analysis, the toll-like receptor (TLR) 2 microsatellite had 76% prediction accuracy for extrapulmonary tuberculosis in blacks (P = 0.002). In approach 2, 613 SNPs in 26 genes were assessed. None were associated with extrapulmonary tuberculosis.ConclusionsIn this pilot study among extrapulmonary tuberculosis patients with well-characterized immune defects, genetic variants in IL-1β, VDR Fok1, and TLR2 were associated with an increased risk of extrapulmonary disease. Additional studies of the underlying mechanism of these genetic variants are warranted.
Highlights
Human genetic variants may affect tuberculosis susceptibility, but the immunologic correlates of the genetic variants identified are often unclear
We have sought to first identify immunologic defects that may predispose to tuberculosis, assess for genetic polymorphisms associated with these immunologic defects
In previous studies we noted that HIV-seronegative adults with prior extrapulmonary tuberculosis had lower levels of CD4+ lymphocytes, unstimulated cytokine production, and tumor necrosis factor (TNF)-a production in response to lipopolysaccharide (LPS) or LPS + interferon (IFN)-g than persons with prior pulmonary tuberculosis or latent M. tuberculosis infection [6,7]
Summary
Human genetic variants may affect tuberculosis susceptibility, but the immunologic correlates of the genetic variants identified are often unclear. A possible genetic predisposition to tuberculosis has been suggested in several studies,[1,2,3] but the functional immunologic correlate of the genetic polymorphisms identified is often unclear[4]. We have sought to first identify immunologic defects that may predispose to tuberculosis, assess for genetic polymorphisms associated with these immunologic defects. In the current study we have combined two previous study populations in which cytokine responses were well-characterized, [6,7] to identify genetic polymorphisms associated with extrapulmonary tuberculosis, and by extension, the associated immunologic abnormalities. We make use of a candidate gene approach utilizing single nucleotide polymorphisms (SNPs) and microsatellites previously reported to be associated with tuberculosis, and we include SNPs in candidate genes that are hypothesized to play a role in tuberculosis pathogenesis
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