COL1A1 Sp1 polymorphism predicts perimenopausal and early postmenopausal spinal bone loss
COL1A1 Sp1 polymorphism predicts perimenopausal and early postmenopausal spinal bone loss
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DOI：
10.1359/jbmr.2001.16.9.1634
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发表时间：
2001-09-01
影响因子：
6.2
通讯作者：
Reid, DM
中科院分区：
文献类型：
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作者：
MacDonald, HM;McGuigan, FA;Reid, DM
遗传因素在骨质疏松症的发病机制中起着重要作用，但决定骨健康不良易感性的基因定义尚不完整。先前的工作表明，在一些人群中，影响COL1A1基因Sp1结合位点的多态性与骨密度(BMD)降低和骨质疏松性骨折风险增加有关。来自横断面研究的数据表明，COL1A1 Sp1等位基因也可能与随年龄增加的骨丢失有关，但研究了与COL1A1基因有关的骨丢失的纵向研究得出了相互矛盾的结果。在这项研究中，我们研究了COL1A1 Sp1等位基因与通过双能X射线骨密度仪(DXA)测量的绝经后早期骨丢失的关系，对734名苏格兰女性进行了为期5至7年的随访。在白人群体中，484名“SS”纯合子(65.9%)、225名“SS”杂合子(30.7%)和25名“SS”纯合子(3.4%)的基因分布与预期一致。与未使用激素替代疗法的女性(n=352；脊柱，-1.36+/-0.06%/年；髋部，-1.21+/-0.06%/年，p<；0.001)相比，接受激素替代疗法(n=239)的女性脊柱(-0.40+/-0.06%/年)和髋部(-0.56+/-0.06%/年)的骨丢失率显著降低。在HRT使用者中，不同基因型之间腰椎(LS)或股骨颈TM的基础骨密度值或不同基因型之间的骨丢失率没有显著差异。然而，在非激素替代疗法使用者(n=352)中，我们发现SS纯合子(n=12)在腰椎部位丢失的骨明显多于其他基因型组，SS=-2.26+/-0.31%/年，SS=-1.38+/-0.07%/年和SS=-1.22+/-0.10%/年(p=0.004；方差分析[ANOVA])，FN的SS=-1.78+/-0.19%/年，SS=-1.21+/-0.06%/年，SS=-1.16+/-0.08%/年(P=0.06；ANOVA)。在校正混杂因素后，脊柱骨密度丢失的差异仍然显著。逐步多元回归分析显示，在年龄(4.0%)、体重(5.0%)和基线骨密度(2.8%)之后，COL1A1基因单独解释了脊柱骨密度变化的3.0%。我们的结论是，Sp1多态纯合子的女性在脊柱过度骨质丢失的风险显著增加，但这种影响可能被HRT的使用所抵消。
Genetic factors play an important role in the pathogenesis of osteoporosis but the genes that determine susceptibility to poor bone health are defined incompletely. Previous work has shown that a polymorphism that affects an Sp1 binding site in the COL1A1 gene is associated with reduced bone mineral density (BMD) and an increased risk of osteoporotic fracture in several populations. Data from cross-sectional studies have indicated that COL1A1 Sp1 alleles also may be associated with increased rates of bone loss with age, but longitudinal studies, which have examined bone loss in relation to COL1A1 genotype, have yielded conflicting results. In this study, we examined the relationship between COL1A1 Sp1 alleles and early postmenopausal bone loss measured by dual-energy X-ray absorptiometry (DXA) in a population-based cohort of 734 Scottish women who were followed up over a 5- to 7-year period. The distribution of genotypes was as expected in a white population with 484 "SS" homozygotes (65.9%); 225 "Ss" heterozygotes (30.7%), and 25 "ss" homozygotes (3.4%). Women taking hormone-replacement therapy (HRT, n = 239) had considerably reduced rates of bone loss at the spine (-0.40 +/- 0.06%/year) and hip (-0.56 +/- 0.06%/year) when compared with non-HRT users (n = 352; spine, -1.36 +/- 0.06%/year; hip, -1.21 +/- 0.05%/year, p < 0.001 for both sites). There was no significant difference in baseline BMD values at the lumbar spine (LS) or femoral neck TM between genotypes or in the rates of bone loss between genotypes in HRT users. However, in non-HRT users (n = 352), we found that ss homozygotes (n = 12) lost significantly more bone at the lumbar site than the other genotype groups in which ss = -2.26 +/- 0.31%/year compared with SS = -1.38 +/- 0.07%/year and Ss = -1.22 +/- 0.10%/year (p = 0.004; analysis of variance [ANOVA]) and a similar trend was observed at the FN in which ss = -1.78 +/- 0.19%/year compared with SS = -1.21 +/- 0.06%/year and Ss = -1.16 +/- 0.08%/year (p = 0.06; ANOVA). The differences in spine BMD loss remained significant after correcting for confounding factors. Stepwise multiple regression analysis showed that COL1A1 genotype independently accounted for a further 3.0% of the variation in spine BMD change after age (4.0%), weight (5.0%), and baseline BMD (2.8%). We conclude that women homozygous for the Sp1 polymorphism are at significantly increased risk of excess rates of bone loss at the spine, but this effect may be nullified by the use of HRT.