Association of a promoter haplotype (−1542G/−525C) in the tumor necrosis factor receptor associated factor-interacting protein gene with low bone mineral density in Japanese women

Abstract

Osteoporosis, a multifactorial common disease, is believed to result from the interplay of multiple environmental and genetic factors that regulate bone mineral density (BMD). Tumor necrosis factor receptor associated factor-interacting protein (I-TRAF) is an essential effecter of the tumor necrosis factor receptor-signaling cascade, one of the most potent bone-resorbing systems. In genetic studies of 382 Japanese adult women, we found that genotypes of two promoter variations of I-TRAF gene, −1542T/G and −525G/C, were similarly associated with radial BMD levels. Two variations were in almost complete linkage disequilibrium ( D′ = 0.978, r 2 = 0.917, χ 2 = 695, 2, P = 3.4 × 10 −153), and there were two exclusive haplotypes (−1542T/−525C, frequency 0.74, and −1542G/−525G, frequency 0.24) among our test subjects. When BMD values were compared among the three haplotypic categories (−1542G/−525G homozygotes, heterozygotes, and −1542T/−525C homozygotes), BMD was lowest among −1542G/−525C homozygotes (mean ± SD = 0.382 ± 0.060 g/cm 2), highest among −1542T/−525G homozygotes (0.405 ± 0.051 g/cm 2), and intermediate among heterozygotes (0.395 ± 0.056 g/cm 2) ( r = 0.11, P = 0.030). The observed trend supported a codominant effect of the relevant haplotype of I-TRAF gene in determination of radial BMD. These results suggested that variation of I-TRAF might be an important determinant for postmenopausal osteoporosis.