Evidence for a major gene influence on tumor necrosis factor-alpha expression in tuberculosis: path and segregation analysis.
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. We conducted a household contact study in a TB-endemic community in Uganda. Antigen-induced tumor necrosis factor-alpha (TNFalpha) expression, a key component of the underlying immune response to TB, was used as an endophenotype for TB. Path analysis, conducted to assess the effect of shared environment, suggested that TNFalpha 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 TNFalpha suggested a major gene model that explained one-third of the phenotypic variance, and provided putative evidence of natural selection acting on this phenotype. Our data further support TNFalpha as an endophenotype for TB, as it may increase power to detect disease-predisposing loci.