Abdominal Aortic Aneurysm Is Associated with a Variant in Low-Density Lipoprotein Receptor-Related Protein 1
Abdominal Aortic Aneurysm Is Associated with a Variant in Low-Density Lipoprotein Receptor-Related Protein 1
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DOI：
10.1016/j.ajhg.2011.10.002
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发表时间：
2011-11-11
影响因子：
9.8
通讯作者：
Samani, Nilesh J.
中科院分区：
文献类型：
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作者：
Bown, Matthew J.;Jones, Gregory T.;Samani, Nilesh J.
腹主动脉瘤（AAA）是一种常见的发病率和死亡率的原因，并具有显着的遗传性。我们对1866名AAA患者和5435名对照进行了全基因组关联发现研究，并在另外2871名病例和32,687名对照中复制了有希望的信号（p值< 1 x 10（-5）的前导SNP），并对1491名AAA和11,060名对照进行了进一步随访。在发现研究中，9个位点与AAA相关（p < 1 x 10（-5））。在复制样本中，位于低密度脂蛋白受体相关蛋白1（LRP 1）内含子1内的这些位点之一rs 1466535的前导SNP表现出显著的相关性（p = 0.0042）。我们在随访研究中证实了rs 1466535与AAA的相关性（p = 0.035）。在一项合并分析中（6228例AAA和49182例对照），rs 1466535在所有样本集中具有一致的效应大小和方向（合并p = 4.52 x 10（-10），比值比1.15 [1.10-1.21]）。在冠状动脉疾病、血压、糖尿病或腹主动脉瘤的独立关联研究中，没有发现rs 1466535或12q13.3位点的相关性，这表明该位点对AAA具有特异性。基因表达研究表明，动脉组织中rs 1466535 CC基因型的LRP 1表达呈增加趋势;主动脉外膜中CC纯合子的LRP 1表达比TT纯合子显著增加（p = 0.029）1.19倍（1.04-1.36）。功能研究表明，rs 1466535可能会改变SREBP-1的结合位点，并影响增强子在该位点的活性。总之，这项研究已经确定了一个生物学合理的遗传变异与AAA的具体相关，我们认为，这种变异有可能在LRP 1表达的功能作用。
Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 x 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 x 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 x 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.