van Meurs Joyce B J, Schuit Stephanie C E, Weel Angélique E A M, van der Klift Marjolein, Bergink Arjan P, Arp Pascal P, Colin Edgar M, Fang Yue, Hofman Albert, van Duijn Cornelia M, van Leeuwen Johannes P T M, Pols Huibert A P, Uitterlinden André G
Department of Internal Medicine, Erasmus Medical Centre, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
Hum Mol Genet. 2003 Jul 15;12(14):1745-54. doi: 10.1093/hmg/ddg176.
This study investigates the influence of genetic variation of the estrogen receptor alpha (ESR1) gene locus on several bone parameters in 2042 individuals of The Rotterdam Study, a prospective population-based cohort study of elderly subjects. We analysed three polymorphic sites in the 5' region of the ESR1 gene; a (TA)(n)-repeat in the promoter region, and molecular haplotypes of the PvuII and XbaI RFLPs in intron 1, and inferred long-range haplotypes (LRH) thereof. We observed only three of the possible four PvuII-XbaI haplotypes in our population. A comparison with other Caucasian populations showed similar haplotype frequencies, while in Asian and African populations these were different. Linkage disequilibrium (LD) analysis between the PvuII-XbaI haplotype and the (TA)(n) repeat showed strong LD between the two sites. Reconstruction of long range haplotypes over the entire 5' region, revealed six frequent LRH. In men, we did not observe an association between the ESR1 polymorphisms studied and bone parameters. In women, we demonstrated an allele dose effect of haplotype "px" (P=0.003) and a low number of (TA)(n) repeats (P=0.008) with decreased lumbar spine bone mineral density (BMD) (4.8% lower BMD in women homozygous for haplotype "px", representing 28% of the population, compared with homozygous non-carriers) and decreased vertebral bone area (2.3% difference between extreme genotypes; P=0.016). Most importantly, we found an increased vertebral fracture risk with evidence for an allele dose effect with an odds ratio of 2.2 (95%CI 1.3-3.5) for haplotype "px", and 2.0 (1.5-3.2) for a low number of (TA)(n) repeats. The ESR1 genotype dependent fracture risk is largely independent of BMD and bone area. Combination of risk alleles at both loci by long-range haplotyping improved the associations slightly, but because of the strong LD between the two polymorphic sites, we were unable to determine if any particular polymorphic site is driving the associations found. We conclude that ESR1 polymorphism in the 5' (promoter) region is associated with vertebral fracture risk, lumbar spine BMD and vertebral bone area in postmenopausal women, but not in men. The molecular mechanism underlying this association needs further study.
本研究在鹿特丹研究的2042名个体中，调查雌激素受体α（ESR1）基因位点的遗传变异对多个骨参数的影响。鹿特丹研究是一项基于人群的前瞻性队列研究，研究对象为老年受试者。我们分析了ESR1基因5'区域的三个多态性位点：启动子区域的（TA）（n）重复序列，以及内含子1中PvuII和XbaI限制性片段长度多态性（RFLP）的分子单倍型，并推断了其远距离单倍型（LRH）。我们在研究人群中仅观察到四种可能的PvuII - XbaI单倍型中的三种。与其他白种人群体的比较显示单倍型频率相似，而在亚洲和非洲人群体中则有所不同。PvuII - XbaI单倍型与（TA）（n）重复序列之间的连锁不平衡（LD）分析显示这两个位点之间存在强LD。对整个5'区域的远距离单倍型进行重建，发现了六种常见的LRH。在男性中，我们未观察到所研究的ESR1多态性与骨参数之间存在关联。在女性中，我们证明单倍型“px”（P = 0.003）和（TA）（n）重复序列数量较少（P = 0.008）与腰椎骨矿物质密度（BMD）降低有关（单倍型“px ”纯合子女性的BMD比非携带者纯合子女性低4.8%，该单倍型纯合子女性占人群的28%），并且与椎骨面积减小有关（极端基因型之间相差2.3%；P = 0.016）。最重要的是，我们发现椎骨骨折风险增加，有证据表明存在等位基因剂量效应，单倍型“px”的比值比为2.2（95%CI 1.3 - 3.5），（TA）（n）重复序列数量较少时的比值比为2.0（1.5 - 3.2）。ESR1基因型依赖性骨折风险在很大程度上独立于BMD和骨面积。通过远距离单倍型分析对两个位点的风险等位基因进行组合，使关联性略有改善，但由于两个多态性位点之间存在强LD，我们无法确定是否有任何特定的多态性位点驱动了所发现的关联性。我们得出结论，5'（启动子）区域的ESR1多态性与绝经后女性的椎骨骨折风险、腰椎BMD和椎骨面积有关，但与男性无关。这种关联背后的分子机制需要进一步研究。
