Qureshi A M, Herd R J, Blake G M, Fogelman I, Ralston S H
Department of Medicine and Therapeutics, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom.
Calcif Tissue Int. 2002 Mar;70(3):158-63. doi: 10.1007/s00223-001-1035-9. Epub 2002 Feb 19.
Genetic factors are important in the pathogenesis of osteoporosis but less is known about their possible role in predicting response to anti-osteoporotic therapy. Previous studies have shown that a polymorphic Sp1 binding site in the collagen type 1 alpha 1 gene (COLIA1) is associated with bone mineral density (BMD) and osteoporotic vertebral fracture. In this study we sought to determine if the COLIA1 Sp1 polymorphism might also act as a predictor of the response to treatment of osteoporosis with bisphosphonate therapy. The study group comprised 108 perimenopausal women with osteopenia who had been randomized to receive cyclical etidronate therapy for 2 years with a 1-year treatment-free follow-up as part of a randomized placebo controlled trial. Bone mineral density was measured at the lumbar spine and femoral neck by dual X-ray absorptiometry and genotyping performed on DNA extracted from peripheral blood leukocytes using standard techniques. The distribution of COLIA1 genotypes was similar to that previously reported in Caucasians with 69 (63.9%) "SS" homozygotes, 38 (35.2%) "Ss" heterozygotes, and 1 (0.9%) "ss" homozygote. There was no association between COLIA1 genotype and response of lumbar spine BMD during etidronate treatment or the follow-up phase. The response of femoral neck (FN) BMD, however, differed significantly between the genotype groups throughout the study period, such that FN BMD increased by 0.56%, 2.36%, 1.82%, and 1.32 % after 1, 2, 2.5, and 3 years, respectively in the "SS" genotype group, compared with -1.56%, -0.62%, -0.37%, and -0.66% in the "Ss/ss" genotype groups (P = 0.002). The data presented here show that site-specific heterogeneity exists in the response of BMD to cyclical etidronate therapy, which is related to COLIA1 genotype. Our data raise the possibility that COLIA1 genotyping could be used to target etidronate therapy to those most likely to respond in terms of FN BMD, with potential benefits in terms of economic cost and clinical outcome.
遗传因素在骨质疏松症的发病机制中起着重要作用，但对于它们在预测抗骨质疏松治疗反应方面可能发挥的作用，人们了解较少。先前的研究表明，I型胶原α1基因（COLIA1）中的一个多态性Sp1结合位点与骨密度（BMD）及骨质疏松性椎体骨折相关。在本研究中，我们试图确定COLIA1 Sp1多态性是否也可能作为双膦酸盐治疗骨质疏松症反应的预测指标。研究组包括108名围绝经期骨质减少的女性，她们被随机分组，接受为期2年的周期性依替膦酸治疗，并进行为期1年的无治疗随访，这是一项随机安慰剂对照试验的一部分。通过双能X线吸收法测量腰椎和股骨颈的骨密度，并使用标准技术对从外周血白细胞中提取的DNA进行基因分型。COLIA1基因型的分布与先前在白种人中报道的相似，有69名（63.9%）“SS”纯合子、38名（35.2%）“Ss”杂合子和1名（0.9%）“ss”纯合子。在依替膦酸治疗期间或随访阶段，COLIA1基因型与腰椎骨密度反应之间没有关联。然而，在整个研究期间，股骨颈（FN）骨密度的反应在基因型组之间存在显著差异，“SS”基因型组在1年、2年、2.5年和3年后FN骨密度分别增加0.56%、2.36%、1.82%和1.32%，而“Ss/ss”基因型组分别为-1.56%、-0.62%、-0.37%和-0.66%（P = 0.002）。此处呈现的数据表明，骨密度对周期性依替膦酸治疗的反应存在位点特异性异质性，这与COLIA1基因型有关。我们的数据提出了一种可能性，即COLIA1基因分型可用于将依替膦酸治疗靶向至那些在FN骨密度方面最可能有反应的患者，在经济成本和临床结果方面可能带来益处。
