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.
Stein
Catherine M
CM
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA.
Guwatudde
David
D
Nakakeeto
Margaret
M
Peters
Pierre
P
Elston
Robert C
RC
Tiwari
Hemant K
HK
Mugerwa
Roy
R
Whalen
Christopher C
CC
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