Identification of PLCL1 gene for hip bone size variation in females in a genome-wide association study.
Identification of PLCL1 gene for hip bone size variation in females in a genome-wide association study.
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在全基因组关联研究中，女性的髋骨大小变异的PLCL1基因的鉴定。
DOI：
10.1371/journal.pone.0003160
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发表时间：
2008-09-08
期刊：
影响因子：
3.7
通讯作者：
Deng HW
中科院分区：
文献类型：
--
作者：
Liu YZ;Wilson SG;Wang L;Liu XG;Guo YF;Li J;Yan H;Deloukas P;Soranzo N;Chinappen-Horsley U;Cervino A;Williams FM;Xiong DH;Zhang YP;Jin TB;Levy S;Papasian CJ;Drees BM;Hamilton JJ;Recker RR;Spector TD;Deng HW
骨质疏松症是老年人中最常见的代谢性骨病，会增加低创伤性髋部骨折 (HF) 的风险，而低创伤性髋部骨折 (HF) 的发病率和死亡率较高。髋骨大小 (BS) 已被确定为心力衰竭的关键可测量危险因素之一。尽管髋关节 BS 是高度遗传决定的，但该特征背后的遗传因素仍不清楚。在这里，我们在 Affymetrix 平台上对 1,000 名同质的无关白人受试者（包括 501 名女性和 499 名男性）进行了首次髋关节 BS 全基因组关联研究 (GWAS)，询问了约 380,000 个 SNP。我们鉴定出一个基因 PLCL1（磷脂酶 c 样 1），该基因具有四个与髋部 BS 相关的 SNP，在我们的女性受试者中处于或接近全基因组显着性水平；最显着的 SNP rs7595412 的 p 值为 3.72×10−7。使用 Illumina 基因分型平台在一个包含 1,216 名白人女性的独立英国队列中复制了该基因对髋关节 BS 的重要性。 PLCL1 基因的两个 SNP，rs892515 和 rs9789480，被我们的 GWAS 中鉴定的四个 SNP 包围，与髋关节 BS 的关联分别达到 8.62×10−3 和 2.44×10−3 的 p 值。对我们的 GWAS 和英国样本的插补分析进一步证实了复制信号；该基因的 8 个 SNP 在两个样本中实现了组合估算 p 值<10−5。 PLCL1 基因与心力衰竭的相关性也在包含 403 名女性的中国样本中观察到，其中包括 266 名心力衰竭患者和 177 名对照受试者。 PLCL1 基因的一个 SNP rs3771362 与我们的 GWAS 中检测到的最显着的 SNP (rs7595412) 仅相距约 0.6 kb，与 HF 相关的 p 值为 7.66×10−3（比值比 = 0.26）。 PLCL1 在 BS 中的作用的额外生物学支持来自先前的证明，即 PLCL1 蛋白抑制 IP3（肌醇 1,4,5-三磷酸）介导的钙信号传导，这是调节骨细胞机械传感的重要途径。我们的研究结果表明 PLCL1 是一种与髋关节 BS 变异相关的新基因，并为 HF 的发病机制提供了新的见解。
Osteoporosis, the most prevalent metabolic bone disease among older people, increases risk for low trauma hip fractures (HF) that are associated with high morbidity and mortality. Hip bone size (BS) has been identified as one of the key measurable risk factors for HF. Although hip BS is highly genetically determined, genetic factors underlying the trait are still poorly defined. Here, we performed the first genome-wide association study (GWAS) of hip BS interrogating ∼380,000 SNPs on the Affymetrix platform in 1,000 homogeneous unrelated Caucasian subjects, including 501 females and 499 males. We identified a gene, PLCL1 (phospholipase c-like 1), that had four SNPs associated with hip BS at, or approaching, a genome-wide significance level in our female subjects; the most significant SNP, rs7595412, achieved a p value of 3.72×10−7. The gene's importance to hip BS was replicated using the Illumina genotyping platform in an independent UK cohort containing 1,216 Caucasian females. Two SNPs of the PLCL1 gene, rs892515 and rs9789480, surrounded by the four SNPs identified in our GWAS, achieved p values of 8.62×10−3 and 2.44×10−3, respectively, for association with hip BS. Imputation analyses on our GWAS and the UK samples further confirmed the replication signals; eight SNPs of the gene achieved combined imputed p values<10−5 in the two samples. The PLCL1 gene's relevance to HF was also observed in a Chinese sample containing 403 females, including 266 with HF and 177 control subjects. A SNP of the PLCL1 gene, rs3771362 that is only ∼0.6 kb apart from the most significant SNP detected in our GWAS (rs7595412), achieved a p value of 7.66×10−3 (odds ratio = 0.26) for association with HF. Additional biological support for the role of PLCL1 in BS comes from previous demonstrations that the PLCL1 protein inhibits IP3 (inositol 1,4,5-trisphosphate)-mediated calcium signaling, an important pathway regulating mechanical sensing of bone cells. Our findings suggest that PLCL1 is a novel gene associated with variation in hip BS, and provide new insights into the pathogenesis of HF.
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