Although bone mineral density (BMD) is a complex trait that is influenced by both genetic and environmental factors, heritability studies in twins and families have shown that genetic factors account for 60-85% of the variance in BMD. We examined the relations of six candidate gene polymorphisms to BMD in community-dwelling women and men. The 2238 subjects (1110 women, 1128 men) were aged 40-79 years and were randomly recruited to a population-based prospective cohort study of aging and age-related diseases in Japan. BMD at the distal and proximal radius was measured by peripheral quantitative computed tomography, and BMD for the total body, lumbar spine (L2-L4), right femoral neck, and right trochanter was measured by dual-energy X-ray absorptiometry. Genotypes for the 1019C↷T (Pro319Ser) polymorphism of GJA4 and the 1462A↷G (Lys469Glu) polymorphism of ICAM1 were determined with a fluorescence-based allele-specific DNA primer assay system, and those for the 386G↷A (Ala99Thr) polymorphism of PLOD1, the A↷G polymorphism of CNR2, the 1583G↷A (Arg528Lys) polymorphism of ALAP, and the -514C↷T polymorphism of LIPC were determined by melting curve analysis. The polymorphisms of ALAP and PLOD1 were associated with BMD in premenopausal women; those of ICAM1 and LIPC with BMD in postmenopausal women; that of CNR2 with BMD in premenopausal and postmenopausal women; and that of GJA4 with BMD in men. Among these polymorphisms, those of ICAM1, CNR2, and GJA4 were markedly associated with BMD. These results suggest that ALAP, PLOD1, ICAM1, LIPC, and CNR2 are susceptibility loci for reduced bone mass in Japanese women and that GJA4 constitutes such a locus in Japanese men. The polymorphisms of ICAM1 and CNR2 may confer susceptibility to postmenopausal osteoporosis in women, and that of GJA4 to osteoporosis in men.

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