Heritability analysis of cytokines as intermediate phenotypes of tuberculosis.
Numerous studies have provided support for genetic susceptibility to tuberculosis (TB); however, heterogeneity in disease expression has hampered previous genetic studies. The purpose of this work was to investigate possible intermediate phenotypes for TB. A set of cytokine profiles, including antigen-stimulated whole-blood assays for interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, and the ratio of IFN to TNF, were analyzed in 177 pedigrees from a community in Uganda with a high prevalence of TB. The heritability of these variables was estimated after adjustment for covariates, and TNF-alpha, in particular, had an estimated heritability of 68%. A principal component analysis of IFN-gamma, TNF-alpha, and TGF-beta reflected the immunologic model of TB. In this analysis, the first component explained >38% of the variation in the data. This analysis illustrates the value of such intermediate phenotypes in mapping susceptibility loci for TB and demonstrates that this area deserves further research.
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA.
Catherine M
CM
Stein
David
D
Guwatudde
Margaret
M
Nakakeeto
Pierre
P
Peters
Robert C
RC
Elston
Hemant K
HK
Tiwari
Roy
R
Mugerwa
Christopher C
CC
Whalen
D000293:Adolescent; D000328:Adult; D016207:Cytokines / Q000097:blood* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics; D016014:Linear Models; D008297:Male; D009169:Mycobacterium tuberculosis; D010375:Pedigree; D010641:Phenotype; D019655:Quantitative Trait, Heritable; D015291:Transforming Growth Factors / Q000097:blood / Q000235:genetics; D014376:Tuberculosis / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics; D014454:Uganda
D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D015291:Transforming Growth Factors; D007371:Interferon-gamma