Ferrari S, Rizzoli R, Manen D, Slosman D, Bonjour J P
WHO Center for Osteoporosis and Bone Diseases, Department of Internal Medicine, University Hospital, Geneva, Switzerland.
J Bone Miner Res. 1998 Jun;13(6):925-30. doi: 10.1359/jbmr.1998.13.6.925.
Osteoporosis is a polygenic disease, whose determining loci have not yet been identified. Vitamin D receptor (VDR) gene polymorphisms in the 3'-end region (as determined by the enzymes BsmI and ApaI) have been inconsistently associated with bone mineral mass. More recently, VDR start codon polymorphisms (as determined by the enzyme FokI) have been found to be related to adult bone mineral density (BMD) in pre- and postmenopausal American women. We investigated the association between BMD and FokI genotypes in premenopausal European-Caucasian women as well as in prepubertal girls from the same genetic background and examined the interaction with VDR 3'-end region polymorphisms and with dietary calcium intake. Areal BMD (g/cm2) was measured by dual-energy X-ray absorptiometry at the level of the lumbar spine, femoral neck, and femoral shaft in 177 healthy premenopausal women (age range, 18.7-56.0 years) as well as in 155 prepubertal girls (age range, 6.6-11.4 years). Genotyping for FokI, BsmI, and ApaI VDR polymorphisms was performed using polymerase chain reaction methods. FokI genotype-dietary calcium interaction was cross-sectionally analyzed in all subjects and longitudinally in 103 prepubertal girls enrolled in a calcium intervention trial. The prevalence of FokI VDR gene polymorphisms in this cohort was 15% for ff, 50% for Ff, and 35% for FF. In the whole cohort of premenopausal women or prepubertal girls, no significant association was found between FokI VDR gene polymorphisms and BMD, even adjusted for age (Z score), weight, height, and calcium intake. Further analysis of FokI VDR gene polymorphisms and dietary calcium intake suggested a possible interaction in BMD determination, since a trend for an association with FokI genotypes was more evident at high than low calcium intake in both cross-sectional and longitudinal studies. Furthermore, cross-genotyping FokI and either BsmI or ApaI VDR polymorphisms suggested that the ff genotype was associated with a significantly lower lumbar spine BMD in bb and aa prepubertal girls. FokI VDR gene polymorphisms were not significantly associated with BMD in healthy European-Caucasian females. However, cross-genotyping of the VDR 3'-end and start codon polymorphic regions may provide a further insight into the complex determination of BMD.
骨质疏松症是一种多基因疾病，其决定基因座尚未确定。维生素D受体（VDR）基因3'-末端区域的多态性（由BsmI和ApaI酶确定）与骨矿物质含量的关联并不一致。最近，发现VDR起始密码子多态性（由FokI酶确定）与绝经前后美国女性的成人骨矿物质密度（BMD）有关。我们调查了绝经前欧洲白种女性以及来自相同遗传背景的青春期前女孩的BMD与FokI基因型之间的关联，并研究了其与VDR 3'-末端区域多态性和膳食钙摄入量的相互作用。采用双能X线吸收法测量了177名健康绝经前女性（年龄范围18.7 - 56.0岁）以及155名青春期前女孩（年龄范围6.6 - 11.4岁）腰椎、股骨颈和股骨干水平的面积骨密度（g/cm²）。使用聚合酶链反应方法对FokI、BsmI和ApaI VDR多态性进行基因分型。在所有受试者中对FokI基因型 - 膳食钙相互作用进行横断面分析，并在参加钙干预试验的103名青春期前女孩中进行纵向分析。该队列中FokI VDR基因多态性的患病率为ff型15%，Ff型50%，FF型35%。在整个绝经前女性或青春期前女孩队列中，即使对年龄（Z评分）、体重、身高和钙摄入量进行校正后，FokI VDR基因多态性与BMD之间也未发现显著关联。对FokI VDR基因多态性和膳食钙摄入量的进一步分析表明，在BMD的决定中可能存在相互作用，因为在横断面和纵向研究中，高钙摄入量时与FokI基因型的关联趋势比低钙摄入量时更明显。此外，对FokI与BsmI或ApaI VDR多态性进行交叉基因分型表明，在bb和aa基因型的青春期前女孩中，ff基因型与显著更低的腰椎BMD相关。在健康的欧洲白种女性中，FokI VDR基因多态性与BMD无显著关联。然而，对VDR 3'-末端和起始密码子多态性区域进行交叉基因分型可能会为BMD的复杂决定因素提供进一步的见解。
