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Association of a Haplotype (196Phe/532Ser) in the Interleukin‐1‐Receptor‐Associated Kinase ( IRAK1 ) Gene With Low Radial Bone Mineral Density in Two Independent Populations
Author(s) -
Ishida Ryota,
Emi Mitsuru,
Ezura Yoichi,
Iwasaki Hironori,
Yoshida Hideyo,
Suzuki Takao,
Hosoi Takayuki,
Inoue Satoshi,
Shiraki Masataka,
Ito Hiromoto,
Orimo Hajime
Publication year - 2003
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.2003.18.3.419
Subject(s) - bone mineral , haplotype , osteoporosis , linkage disequilibrium , bone density , medicine , genetics , cohort , biology , endocrinology , genotype , gene
Osteoporosis, a multifactorial common disease, is believed to result from the interplay of multiple environmental and genetic determinants, including factors that regulate bone mineral density. Interleukin‐1 (IL‐1) is one of the most potent bone‐resorbing factors, and interleukin‐1‐associated kinase 1 (IRAK1) is an essential effector of the IL‐1 receptor signaling cascade. In genetic studies of two independent populations of postmenopausal women (cohort A: 220 individuals and cohort T: 126 individuals) from separated geographical regions of Japan, we found that radial bone mineral density levels had similar associations with IRAK1 genotypes in both populations. Two amino acid‐substituting variations in the gene, encoding Phe196Ser and Ser532Leu, were in complete linkage disequilibrium (D′ = 1.0000, r 2 = 1.0000, χ 2 = 192.000, p = 1.2 × 10 −43 ), and we found two exclusive haplotypes (196F/532S, frequency 0.74; 196S/532L, frequency 0.26) of the IRAK1 gene among our test subjects. In both populations, a significant association with decreased radial bone mineral density was identified with haplotype 196F/532S (in cohort A: r = 0.21, p = 0.0017; in cohort T: r = 0.23, p = 0.011). Radial bone mineral density was lowest among 196F/532S homozygotes, highest among 196S/532L homozygotes, and intermediate among heterozygotes. Accelerated bone loss also correlated with the 196F/532S haplotype in a 5‐year follow‐up. These results suggest that variation of IRAK1 may be an important determinant of postmenopausal osteoporosis, in part through the mechanism of accelerated postmenopausal bone loss.