Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density.
Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density.
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DOI：
10.1136/annrheumdis-2017-212469
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发表时间：
2018-03
影响因子：
27.4
通讯作者：
Ralston SH
中科院分区：
文献类型：
--
作者：
Alonso N;Estrada K;Albagha OME;Herrera L;Reppe S;Olstad OK;Gautvik KM;Ryan NM;Evans KL;Nielson CM;Hsu YH;Kiel DP;Markozannes G;Ntzani EE;Evangelou E;Feenstra B;Liu X;Melbye M;Masi L;Brandi ML;Riches P;Daroszewska A;Olmos JM;Valero C;Castillo J;Riancho JA;Husted LB;Langdahl BL;Brown MA;Duncan EL;Kaptoge S;Khaw KT;Usategui-Martín R;Del Pino-Montes J;González-Sarmiento R;Lewis JR;Prince RL;D'Amelio P;García-Giralt N;Nogués X;Mencej-Bedrac S;Marc J;Wolstein O;Eisman JA;Oei L;Medina-Gómez C;Schraut KE;Navarro P;Wilson JF;Davies G;Starr J;Deary I;Tanaka T;Ferrucci L;Gianfrancesco F;Gennari L;Lucas G;Elosua R;Uitterlinden AG;Rivadeneira F;Ralston SH
确定临床椎体骨折易感性的遗传决定因素，这是骨质疏松症的重要并发症。在此，我们对1553名绝经后临床椎体骨折妇女和4340名对照进行了全基因组关联研究，两阶段重复研究涉及1028例病例和3762名对照。潜在的因果变异，确定使用表达数量性状基因座（eQTL）的数据transliac骨活检和生物信息学研究。在染色体2 q13上发现了一个标记为rs 10190845的位点，该位点与临床椎骨骨折显著相关（P=1.04×10−9），效应量较大（OR 1.74，95%CI 1.06 - 2.6）。该基因座的生物信息学分析鉴定了几种与位置候选基因TTL（微管蛋白酪氨酸连接酶）和SLC 20 A1（溶质载体家族20成员1）的表达相关的潜在功能性SNP。在染色体1 p31、11 q12和15 q11上发现了另外三个可能的位点。所有这些位点都是新的，以前没有与骨密度或临床骨折。我们已经确定了一种新的遗传变异，与临床椎骨骨折的机制是独立的骨密度。目前正在进行进一步的研究，以验证这种关联并评估潜在的机制。
To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies. A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10−9) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures. We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism.
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