Excessive fat accumulation is associated with the TNF alpha-308 G/A promoter polymorphism in women but not in men

Aims/hypothesis. Tumour necrosis factor alpha (TNF alpha) is a candidate gene for the development of obesity, which in turn is a major risk factor for diabetes mellitus. The aim of our study was to investigate whether a previously known NcoI-sensitive polymorphism (-308 G/A) in the promoter region of the TNF alpha gene was related to body weight. Methods. Genotyping was done in 239 male and 342 female non-diabetic subjects with a marked variation in body mass index (BMI). Results. We found three genotypes; AA (n = 13), AG (n = 158) and GG (n = 410). When the material was divided according to sex, allele specific phenotypic differences were confined to women. The female subjects carrying the AA genotype were markedly more obese than both the AG and GG carriers (mean BMI = 41.4 vs 32.3 and 31.7 kg/m(2), respectively, p = 0.02), The body fat content of female AA carriers was increased by one-third compared with AG/GG carriers (p = 0.02). We found no differences between genotypes with respect to waist-to-hip ratio, blood pressure or metabolic variables. Among obese female subjects (BMI > 27 kg/m(2)), we also found that the BMI and body fat content of AA carriers (n = 7) were also higher than for AG/GG carriers. Conclusion/interpretation. The AA-variant at position -308 in the promoter region of the TNF alpha gene could be an important genetic factor behind excessive fat accumulation in women.