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.
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, r2 = 1.0000, chi2 = 192.000, p = 1.2 x 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.
Ishida
Ryota
R
Department of Molecular Biology, Institute of Gerontology, Kawasaki, Japan.
Emi
Mitsuru
M
Ezura
Yoichi
Y
Iwasaki
Hironori
H
Yoshida
Hideyo
H
Suzuki
Takao
T
Hosoi
Takayuki
T
Inoue
Satoshi
S
Shiraki
Masataka
M
Ito
Hiromoto
H
Orimo
Hajime
H
D001483:Base Sequence; D015519:Bone Density / Q000235:genetics*; D017931:DNA Primers; D006239:Haplotypes; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases; D010649:Phenylalanine / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics*; D011884:Radius / Q000378:metabolism*; D012694:Serine / Q000235:genetics
D017931:DNA Primers; D012694:Serine; D010649:Phenylalanine; D011494:Protein Kinases; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases