University of Oxford, Institute of Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, OX3 7LD, UK.
BMC Med Genet. 2009 Dec 19;10:141. doi: 10.1186/1471-2350-10-141.
In a previous study carried out by our group, the genotyping of 36 microsatellite markers from within a narrow interval of chromosome 6p12.3-q13 generated evidence for linkage and for association to female hip osteoarthritis (OA), with the most compelling association found for a marker within intron 1 of the bone morphogenetic protein 5 gene (BMP5). In this study, we aimed to further categorize the association of variants within intron 1 of BMP5 with OA through an expanded genetic association study of the intron and subsequent functional analysis of associated polymorphisms.
We genotyped 18 common polymorphisms including 8 microsatellites and 9 single nucleotide polymorphisms (SNPs) and 1 insertion/deletion (INDEL) from within highly conserved regions between human and mouse within intron 1 of BMP5. These markers were then tested for association to OA by a two-stage approach in which the polymorphisms were initially genotyped in a case-control cohort comprising 361 individuals with associated polymorphisms (P < or = 0.05) then genotyped in a second case-control cohort comprising 1185 individuals.
Two BMP5 intron 1 polymorphisms demonstrated association in the combined case-control cohort of 1546 individuals (765 cases and 781 controls): microsatellite D6S1276 (P = 0.018) and SNP rs921126 (P = 0.013). Functional analyses in osteoblastic, chondrocytic, and adipocytic cell lines indicated that allelic variants of D6S1276 have significant effects on the transcriptional activity of the BMP5 promoter in vitro.
Variability in gene expression of BMP5 may be an important contributor to OA genetic susceptibility.
在我们小组进行的先前研究中，对染色体 6p12.3-q13 内的 36 个微卫星标记进行基因分型，为女性髋关节骨关节炎（OA）的连锁和关联提供了证据，最引人注目的关联是在骨形态发生蛋白 5 基因（BMP5）的内含子 1 内的一个标记。在这项研究中，我们旨在通过对 BMP5 内含子内变异体的扩展遗传关联研究以及对相关多态性的功能分析，进一步分类 BMP5 内含子 1 内变异体与 OA 的关联。
我们对 BMP5 内含子 1 内的 18 个常见多态性进行了基因分型，包括 8 个微卫星和 9 个单核苷酸多态性（SNP）和 1 个插入/缺失（INDEL），这些标记物在一个两阶段的方法中进行了测试，该方法首先在一个包含 361 名相关多态性患者的病例对照队列中对多态性进行了基因分型（P <或= 0.05），然后在一个包含 1185 名患者的第二个病例对照队列中对多态性进行了基因分型。
两个 BMP5 内含子 1 多态性在包含 1546 名个体的合并病例对照队列中显示出关联（765 例和 781 例对照）：微卫星 D6S1276（P = 0.018）和 SNP rs921126（P = 0.013）。在成骨细胞、软骨细胞和脂肪细胞系中的功能分析表明，D6S1276 的等位变异在体外对 BMP5 启动子的转录活性有显著影响。
BMP5 基因表达的变异性可能是 OA 遗传易感性的一个重要因素。
