Liu Yao-Zhong, Wilson Scott G, Wang Liang, Liu Xiao-Gang, Guo Yan-Fang, Li Jian, Yan Han, Deloukas Panos, Soranzo Nicole, Chinappen-Horsley Usha, Cervino Alessandra, Williams Frances M, Xiong Dong-Hai, Zhang Yin-Ping, Jin Tian-Bo, Levy Shawn, Papasian Christopher J, Drees Betty M, Hamilton James J, Recker Robert R, Spector Tim D, Deng Hong-Wen
School of Medicine, University of Missouri - Kansas City, Kansas City, Missouri, United States of America.
PLoS One. 2008 Sep 8;3(9):e3160. doi: 10.1371/journal.pone.0003160.
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 approximately 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 3.72x10(-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 8.62x10(-3) and 2.44x10(-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 approximately 0.6 kb apart from the most significant SNP detected in our GWAS (rs7595412), achieved a p value of 7.66x10(-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.
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，而此类骨折与高发病率和高死亡率相关。髋部骨大小（BS）已被确定为HF的关键可测量风险因素之一。尽管髋部BS在很大程度上由基因决定，但该性状背后的遗传因素仍未明确。在此，我们对髋部BS进行了首次全基因组关联研究（GWAS），在1000名无亲缘关系的白人受试者中，使用Affymetrix平台检测了约380,000个单核苷酸多态性（SNP），其中包括501名女性和499名男性。我们发现了一个基因，即PLCL1（磷脂酶c样1），在我们的女性受试者中，有4个SNP与髋部BS相关，且达到或接近全基因组显著性水平；最显著的SNP，rs7595412，p值为3.72×10⁻⁷。在一个包含1216名白人女性的独立英国队列中，使用Illumina基因分型平台对该基因对髋部BS的重要性进行了验证。PLCL1基因的两个SNP，rs892515和rs9789480，被我们GWAS中鉴定的4个SNP所包围，与髋部BS关联的p值分别为8.62×10⁻³和2.44×10⁻³。对我们的GWAS和英国样本进行的插补分析进一步证实了验证信号；该基因的8个SNP在两个样本中的合并插补p值<10⁻⁵。在一个包含403名女性的中国样本中也观察到了PLCL1基因与HF的相关性，其中包括266名HF患者和177名对照受试者。PLCL1基因的一个SNP，rs3771362，与我们GWAS中检测到的最显著SNP（rs7595412）仅相距约0.6 kb，与HF关联的p值为7.66×10⁻³（优势比 = 0.26）。先前已有研究表明PLCL1蛋白可抑制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，这为PLCL1在骨大小方面的作用提供了额外的生物学支持。我们的研究结果表明，PLCL1是一个与髋部BS变异相关的新基因，并为HF的发病机制提供了新的见解。
