Gorai Itsuo, Inada Mae, Morinaga Hiroko, Uchiyama Yukimi, Yamauchi Hideko, Hirahara Fumiki, Chaki Osamu
Department of Obstetrics and Gynecology International University of Health and Welfare Atami Hospital, Shizuoka Prefecture 413-0012, Japan.
Bone. 2007 Jan;40(1):28-36. doi: 10.1016/j.bone.2006.07.017. Epub 2006 Sep 12.
We aimed to assess whether circulating sex steroids would influence bone density and bone loss, whether part of this influence could be explained by genetic variation measured as polymorphisms in candidate genes affecting circulating hormone levels, or whether gene polymorphisms would have direct effects on bone in 229 postmenopausal Japanese women aged 46 years and over who had been followed for eight years (Yokohama Cohort). Bone mineral density (BMD) in the lumbar spine (L), femoral neck (FN), total hip (T) and distal radius (R) was measured every year, and endogenous sex steroid levels were determined at the start of the study. We investigated the polymorphisms of estrogen-metabolizing enzyme gene, CYP17; estrogen biosynthesis (high activity, A2/A2), CYP1A1; hydroxylation (high inducibility, vt/vt) and COMT; inactivation (low activity, L/L) with PCR-based restriction fragment length polymorphism assays. Dehydroepiandrosterone (DHEA) and androstenedione (AND) levels significantly correlated with bone density in both the axial (L) and the appendicular skeleton (FN, T and R) (r=0.194-0.229; P<0.05) whereas estradiol (E2) and AND showed significant correlations with bone change only at the axial skeleton (r=0.205 and r=-0.139, respectively; P<0.05) on the total cohort. These correlations remained significant in thin/normal-weight women [body mass index (BMI) <25 kg/m2)] even after adjustment for years since menopause (YSM) and BMI or age and BMI, suggesting an interaction of BMI and sex steroid/BMD association. On the total cohort, a difference in endogenous DHEA levels between CYP17 homozygote A2 and non-homozygote A2; an increasing trend in AND levels from COMT L/L, L/H, to H/H; and a difference in TS level between COMT homozygote L and non-homozygote L were separately observed. All observations were significant for unadjusted and adjusted analysis, except for COMT and TS. In thin/normal-weight women (BMI <25 kg/m2), the same effects of CYP17 genotypes on DHEA were observed as on the total cohort. CYP17 and COMT genes showed some direct influence on bone density. Mean percent change in T-BMD was negative for CYP17 non-homozygote A2 in contrast to a positive value for homozygote A2. Mean percent change in R-BMD showed the difference between COMT homozygote L and non-homozygote L with a larger decrease for the homozygote L. Together, CYP17 and COMT genotypes might have some effect on bone both directly and indirectly through their effects on endogenous sex steroids in postmenopausal Japanese women.
我们旨在评估循环性激素是否会影响骨密度和骨质流失，这种影响的部分原因是否可以通过影响循环激素水平的候选基因中的多态性所测量的基因变异来解释，或者基因多态性是否会对229名年龄在46岁及以上、已随访八年的绝经后日本女性（横滨队列）的骨骼产生直接影响。每年测量腰椎（L）、股骨颈（FN）、全髋（T）和桡骨远端（R）的骨矿物质密度（BMD），并在研究开始时测定内源性性激素水平。我们采用基于聚合酶链反应的限制性片段长度多态性分析方法，研究了雌激素代谢酶基因CYP17；雌激素生物合成（高活性，A2/A2）、CYP1A1；羟基化（高诱导性，vt/vt）和儿茶酚-O-甲基转移酶（COMT）；失活（低活性，L/L）的多态性。脱氢表雄酮（DHEA）和雄烯二酮（AND）水平与轴向骨骼（L）和附属骨骼（FN、T和R）的骨密度均显著相关（r = 0.194 - 0.229；P < 0.05），而雌二醇（E2）和AND仅与轴向骨骼的骨变化显著相关（分别为r = 0.205和r = -0.139；P < 0.05），在整个队列中均如此。即使在调整绝经年限（YSM）、体重指数（BMI）或年龄和BMI后，这些相关性在体重过轻/正常体重的女性[体重指数（BMI）< 25 kg/m²]中仍然显著，表明BMI与性激素/BMD关联之间存在相互作用。在整个队列中，分别观察到CYP17纯合子A2和非纯合子A2之间内源性DHEA水平的差异；从COMT L/L、L/H到H/H，AND水平呈上升趋势；以及COMT纯合子L和非纯合子L之间TS水平的差异。除了COMT和TS外，所有观察结果在未调整和调整分析中均具有显著性。在体重过轻/正常体重的女性（BMI < 25 kg/m²）中，观察到CYP17基因型对DHEA的影响与整个队列相同。CYP17和COMT基因对骨密度有一些直接影响。与纯合子A2的正值相比，CYP17非纯合子A2的T-BMD平均百分比变化为负值。R-BMD的平均百分比变化显示了COMT纯合子L和非纯合子L之间的差异，纯合子L的下降幅度更大。总之，CYP17和COMT基因型可能通过对内源性性激素的影响，对绝经后日本女性的骨骼产生直接和间接的影响。
