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

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, r2 _ 0.917, _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/cm2), highest among _1542T/_525G homozygotes (0.405 _ 0.051 g/cm2), and intermediate among heterozygotes (0.395 _ 0.056 g/cm2) (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.