Evidence for a Major Gene Influence on Tumor Necrosis Factor-α Expression in Tuberculosis: Path and Segregation AnalysisStein C.M. · Nshuti L. · Chiunda A.B. · Boom W.H. · Elston R.C. · Mugerwa R.D. · Iyengar S.K. · Whalen C.C.
aDepartment of Epidemiology and Biostatistics, bTuberculosis Research Unit, and cCenter for Modern Epidemiology of Infectious Diseases, Case Western Reserve University, Cleveland, Ohio, USA; dClinical Epidemiology Unit, Makerere University School of Medicine, Kampala, Uganda
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.
Christopher C. Whalen, MD, MS
Department of Epidemiology and Biostatistics
Case Western Reserve University
10900 Euclid Avenue, Cleveland, OH 44106 (USA)
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CCW and SKI contributed equally as senior authors of this work.
Received: June 21, 2005
Accepted: August 18, 2005
Published online: October 13, 2005
Number of Print Pages : 10
Number of Figures : 2, Number of Tables : 6, Number of References : 51
Human Heredity (International Journal of Human and Medical Genetics)
Vol. 60, No. 2, Year 2005 (Cover Date: 2005)
Journal Editor: Devoto, M. (Wilmington, Del.)
ISSN: 0001–5652 (print), 1423–0062 (Online)
For additional information: http://www.karger.com/hhe