Evidence for a Major Gene Influence on Tumor Necrosis Factor-α Expression in Tuberculosis: Path and Segregation Analysis

Abstract

Objective: Tuberculosis (TB) is a growing global public health problem. Several studies suggest a role for host genetics in disease susceptibility, but studies to date have been inconsistent and a comprehensive genetic model has not emerged. A limitation of previous genetic studies is that they only analyzed the binary trait TB, which does not reflect disease heterogeneity. Furthermore, these studies have not accounted for the influence of shared environment within households on TB risk, which may spuriously inflate estimates of heritability. Methods: We conducted a household contact study in a TB-endemic community in Uganda. Antigen-induced tumor necrosis factor-α (TNFα) expression, a key component of the underlying immune response to TB, was used as an endophenotype for TB. Results: Path analysis, conducted to assess the effect of shared environment, suggested that TNFα is heritable (narrow sense heritability = 34–66%); the effect of shared environment is minimal (1–14%), but gene-environment interaction may be involved. Segregation analysis of TNFα suggested a major gene model that explained one-third of the phenotypic variance, and provided putative evidence of natural selection acting on this phenotype. Conclusion: Our data further support TNFα as an endophenotype for TB, as it may increase power to detect disease-predisposing loci.

Human V-ATPase gene can protect or predispose the host to pulmonary tuberculosis

“…Thus, both the overabundance and deficiency of TNF-a (one of the macrophage-derived cytokines) are both associated with severe tuberculosis. [11][12][13] Given the importance and, at the same time, the potential harmful effect of these cytokines, the biological plausibility of an intermediate level of pro-inflammatory cytokine production becomes obvious: the intermediate phenotype benefits from an optimal inflammatory response. Balanced polymorphism is thus proposed as the mechanism maintaining allele frequencies at the V-ATPase locus, with susceptibility to M. tuberculosis of homozygotes being compensated by the protection afforded to the heterozygotes.…”

“…[8][9][10][11][12][13][14][15] The study was extended to six SNPs (rs36027301, rs4147779, rs2471829, rs4147778, rs4147780 and rs2075609), which are not found in patients affected with osteopetrosis. 4 The corresponding alleles were therefore expected to be present in the population at a reasonable frequency.…”

“…In addition, V-ATPase suppresses the expression of macrophage-derived pro-inflammatory cytokines, in particular of TNF-a, 10 which is essential for the control of M. tuberculosis infection: too little as well as too much production of this cytokine predisposes to pulmonary tuberculosis. [11][12][13] All this evidence points to a role of the V-ATPase gene in conferring resistance against or susceptibility to M. tuberculosis. The article describes two polymorphic sites (A and B) located in the intron 15 and the 5 0 untranslated region of the gene coding for the a3 isoform of human V-ATPase, respectively.…”

Genetic and Shared Environmental Influences on Interferon-γ Production in Response to Mycobacterium tuberculosis Antigens in a Ugandan Population

“…Furthermore, these heritability estimates are depressed when HIV-positive individuals are included in the analysis. Genetic studies of TB susceptibility have overlooked the importance of shared environment in terms of epidemiological risk and exposure to infectious cases 14 and Mtb strain, 13 therefore it is essential to account for shared environment in heritability estimation.…”

“…7 The impact of shared environment is not negligible in studies of genetic susceptibility to TB 13 or the immune response to Mtb. 14 In addition, previous studies were hampered by small sample sizes, which could result in imprecise estimates of these variance components. They also excluded human immunodeficiency virus (HIV)-infected individuals, and therefore could not assess the joint impact of HIV and host genetics.…”