Agueda Lídia, Bustamante Mariona, Jurado Susana, Garcia-Giralt Natalia, Ciria Manel, Saló Guillem, Carreras Ramon, Nogués Xavier, Mellibovsky Leonardo, Díez-Pérez Adolfo, Grinberg Daniel, Balcells Susana
Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
J Bone Miner Res. 2008 Dec;23(12):1954-63. doi: 10.1359/jbmr.080806.
LRP5 encodes the low-density lipoprotein receptor-related protein 5, a transmembrane protein involved in Wnt signaling. LRP5 is an important regulator of osteoblast growth and differentiation, affecting bone mass in vertebrates. Whether common variations in LRP5 are associated with normal BMD variation or osteoporotic phenotypes is of great relevance. We used a haplotype-based approach to search for common disease-associated variants in LRP5 in a cohort of 964 Spanish postmenopausal women. Twenty-four SNPs were selected, covering the LRP5 region, including the missense changes p.V667M and p.A1330V. The SNPs were genotyped and evaluated for association with BMD at the lumbar spine (LS) or femoral neck (FN) and with osteoporotic fracture, at single SNP and haplotype levels, by regression methods. Association with LS BMD was found for SNP 1, rs312009, located in the 5'-flanking region (p = 0.011, recessive model). SNP 6, rs2508836, in intron 1, was also associated with BMD, both at LS (p = 0.025, additive model) and FN (p = 0.031, recessive model). Two polymorphisms were associated with fracture: SNP 11, rs729635, in intron 1, and SNP 15, rs643892, in intron 5 (p = 0.007 additive model and p = 0.019 recessive model, respectively). Haplotype analyses did not provide additional information, except for haplotype "GC" of the block located at the 3'end of the gene. This haplotype spans intron 22 and the 3' untranslated region and was associated with FN BMD (p = 0.029, one copy of the haplotype versus none). In silico analyses showed that SNP 1 (rs312009) lies in a putative RUNX2 binding site. Electro-mobility shift assays confirmed RUNX2 binding to this site.
LRP5基因编码低密度脂蛋白受体相关蛋白5，这是一种参与Wnt信号传导的跨膜蛋白。LRP5是成骨细胞生长和分化的重要调节因子，影响脊椎动物的骨量。LRP5的常见变异是否与正常骨密度变化或骨质疏松表型相关具有重大意义。我们采用基于单倍型的方法，在964名西班牙绝经后女性队列中寻找LRP5中与疾病相关的常见变异。选择了24个单核苷酸多态性（SNP），覆盖LRP5区域，包括错义突变p.V667M和p.A1330V。通过回归方法对这些SNP进行基因分型，并在单SNP和单倍型水平上评估其与腰椎（LS）或股骨颈（FN）骨密度以及骨质疏松性骨折的相关性。位于5'侧翼区域的SNP 1（rs312009）与LS骨密度相关（p = 0.011，隐性模型）。内含子1中的SNP 6（rs2508836）也与骨密度相关，在LS处（p = 0.025，加性模型）和FN处（p = 0.031，隐性模型）均如此。两个多态性与骨折相关：内含子1中的SNP 11（rs729635）和内含子5中的SNP 15（rs643892）（分别为p = 0.007加性模型和p = 0.019隐性模型）。单倍型分析未提供额外信息，但位于基因3'端的区域的单倍型“GC”除外。该单倍型跨越内含子22和3'非翻译区，与FN骨密度相关（p = 0.029，有一个该单倍型拷贝与无拷贝相比）。计算机分析表明SNP 1（rs312009）位于一个假定的RUNX2结合位点。电泳迁移率变动分析证实RUNX2与该位点结合。
