Zmuda Joseph M, Yerges Laura M, Kammerer Candace M, Cauley Jane A, Wang Xiaojing, Nestlerode Cara S, Wheeler Victor W, Patrick Alan L, Bunker ClareAnn H, Moffett Susan P, Ferrell Robert E
Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
J Bone Miner Res. 2009 Mar;24(3):437-47. doi: 10.1359/jbmr.081106.
Wnts comprise a family of secreted growth factors that regulate the development and maintenance of many organs. Recently, Wnt10b was shown to stimulate osteoblastogenesis and bone formation in mice. To evaluate further the role of Wnt10b in bone health in humans, we performed bidirectional sequencing of approximately 8 kb of the WNT10B gene region in 192 individuals (96 African, 96 white) to identify single nucleotide polymorphisms (SNPs). We identified 19 SNPs with minor allele frequency (MAF) > or =0.01. Ten of these SNPs were not present in the NCBI dbSNP database (build 127), whereas 10 of the 20 SNPs (50%) reported in dbSNP were not verified. We initially genotyped seven tagging SNPs that captured common (MAF > or = 0.05) variation in the region with r (2) > 0.80 and a potentially functional SNP in exon 5 in 1035 Afro-Caribbean men > or =40 yr of age. Association analysis showed three SNPs in a 3' region of linkage disequilibrium that were associated with DXA measures of hip BMD. Associations between two of these three SNPs (rs1051886, rs3741627) with hip BMD were replicated in an additional 980 Afro-Caribbean men (p < 0.05), in the combined sample of 2015 men (p < or = 0.006), and in 416 individuals > or =18 yr of age (mean, 44 yr) belonging to eight extended, multigenerational Afro-Caribbean families with mean family size >50 (3535 relative pairs; p < 0.05). Further analysis showed that rs1051886 and rs3741627 were associated with cortical cross-sectional area, periosteal circumference, and BMC in the radius, such that individuals with the minor alleles had lower biomechanical indices of long-bone bending strength. This analysis implicates the WNT10B locus as a genetic element in the regulation of bone mass and structural geometry.
Wnt 是一类分泌型生长因子家族，可调节多个器官的发育和维持。最近研究表明，Wnt10b 能刺激小鼠成骨细胞生成和骨形成。为进一步评估 Wnt10b 在人类骨骼健康中的作用，我们对 192 名个体（96 名非洲人、96 名白人）的 WNT10B 基因区域约 8kb 进行双向测序，以鉴定单核苷酸多态性（SNP）。我们鉴定出 19 个次要等位基因频率（MAF）≥0.01 的 SNP。其中 10 个 SNP 不在 NCBI 的 dbSNP 数据库（构建版本 127）中，而 dbSNP 中报告的 20 个 SNP 中有 10 个（50%）未得到验证。我们最初对 1035 名年龄≥40 岁的非洲裔加勒比男性中的 7 个标签 SNP 进行基因分型，这些标签 SNP 捕获了该区域常见（MAF≥0.05）的变异，r（2）>0.80，以及外显子 5 中的一个潜在功能性 SNP。关联分析显示，在一个连锁不平衡的 3'区域中有 3 个 SNP 与双能 X 线吸收法（DXA）测量的髋部骨密度相关。在另外 980 名非洲裔加勒比男性（p<0.05）、2015 名男性的合并样本（p≤0.006）以及 416 名年龄≥18 岁（平均 44 岁）、属于八个平均家庭规模>50 的多代非洲裔加勒比大家庭（3535 个亲属对；p<0.05）中，这三个 SNP 中的两个（rs1051886、rs3741627）与髋部骨密度的关联得到了重复验证。进一步分析表明，rs1051886 和 rs3741627 与桡骨的皮质横截面积、骨膜周长和骨矿含量相关，携带次要等位基因的个体长骨弯曲强度的生物力学指标较低。该分析表明 WNT10B 基因座是调节骨量和结构几何形状的一个遗传因素。
