Genetic Association of Lipids and Lipid Drug Targets With Abdominal Aortic Aneurysm: A Meta-analysis.
Genetic Association of Lipids and Lipid Drug Targets With Abdominal Aortic Aneurysm: A Meta-analysis.
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DOI：
10.1001/jamacardio.2017.4293
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发表时间：
2018-01-01
期刊：
影响因子：
24
通讯作者：
Humphries SE
中科院分区：
文献类型：
--
作者：
Harrison SC;Holmes MV;Burgess S;Asselbergs FW;Jones GT;Baas AF;van 't Hof FN;de Bakker PIW;Blankensteijn JD;Powell JT;Saratzis A;de Borst GJ;Swerdlow DI;van der Graaf Y;van Rij AM;Carey DJ;Elmore JR;Tromp G;Kuivaniemi H;Sayers RD;Samani NJ;Bown MJ;Humphries SE
这项荟萃分析检查了5项国际全基因组关联研究的数据集，以确定血脂升高与腹主动脉瘤风险之间的关联。遗传性血脂水平升高与腹主动脉瘤风险之间有何关联？在这项荟萃分析中，在5项全基因组关联研究中，多达4,914例病例和48名 002对照，低密度脂蛋白胆固醇和甘油三酯水平的遗传升高与腹主动脉瘤风险增加相关，高密度脂蛋白胆固醇水平与腹主动脉瘤风险降低相关。腹主动脉瘤患者有很高的遗传决定的血脂异常的负担；在这一高危人群中靶向血脂可能会改善长期结果。腹主动脉瘤(AAA)的危险因素在很大程度上是未知的，这阻碍了非手术治疗的发展，以改变疾病的自然历史。目的：探讨脂质相关单核苷酸多态(SNPs)与AAA风险的关系。利用传统的孟德尔随机化(MR)和国际AAA全基因组关联研究的数据，构建了由脂质性状相关的SNPs组成的遗传风险分数，并测试了它们与AAA的相关性。对潜在遗传多效性的敏感性分析包括MR-Egger和加权中位数MR，多变量MR方法用于检验血脂与AAA风险的独立关联。还评估了可作为药物靶点代理的基因座上AAA和SNPs之间的关联。数据收集发生在2015年1月9日至2016年1月4日之间。数据分析在2015年1月4日至2016年12月31日之间进行。低密度脂蛋白胆固醇(低密度脂蛋白胆固醇)、高密度脂蛋白胆固醇(高密度脂蛋白胆固醇)和甘油三酯(TG)的遗传升高。脂质相关SNPs的遗传风险分数与AAA风险之间的关联，以及脂类药物靶点(HMGCR、CETP和PCSK9)中的SNPs与AAA风险之间的关联。我们的分析包括4914例病例和48例 002对照。低密度脂蛋白胆固醇的1-SD基因升高与腹主动脉瘤风险增加相关(优势比[OR]为1.66；95%可信区间为1.41-1.96；P = 为1.1 × 10−9)。对于高密度脂蛋白胆固醇，1-SD增加与AA风险降低相关(OR，0.67；95%CI，0.55-0.82；P = 8.3 × 10−5)，而甘油三酯增加1-SD与AA风险增加相关(OR，1.6 9；95%CI，1.38-2.07；P = 5.2 × 10−7)。在多变量MR分析以及MR-Egger和加权中位数MR方法中，每种脂组分与AAA风险的相关性基本保持不变。低密度脂蛋白胆固醇降低等位基因rs12916与腹主动脉硬化风险相关(OR，0.93；95%CI，0.89~0.98；P = .009)。等位基因rs3764261高密度脂蛋白胆固醇与较低的腹主动脉硬化风险相关(OR，0.89；95%CI，0.85~0.94；P = 3.7 × 10−7)。PCSK9的rs11206510等位基因降低低密度脂蛋白胆固醇的风险较低(OR为0.94；95%CI为0.88-1.00；P = 为0.04)，但第二个独立的低密度脂蛋白胆固醇变异(Rs2479409)与AA风险无关(OR为0.97；95%CI为0.92-1.02；P = 为0.28)。本研究中的MR分析支持血脂在AAA的病因学中起重要作用的假设。对作为药物靶标替代物的单个基因变异的分析支持，降低低密度脂蛋白是预防和管理AAA的潜在有效治疗策略。
This meta-analysis examines data sets from 5 international genome-wide association studies to determine the association between elevated lipids and the risk for abdominal aortic aneurysm. What is the association between genetically elevated lipid levels and the risk for abdominal aortic aneurysm? In this meta-analysis of up to 4914 cases and 48 002 controls in 5 genome-wide association studies, genetic elevation of low-density lipoprotein cholesterol and triglyceride levels were associated with an elevated risk of abdominal aortic aneurysm and high-density lipoprotein cholesterol level was associated with a lower risk of abdominal aortic aneurysm. Patients with abdominal aortic aneurysm have a high burden of genetically determined dyslipidemia; targeting lipids in this high-risk group may improve longer-term outcomes. Risk factors for abdominal aortic aneurysm (AAA) are largely unknown, which has hampered the development of nonsurgical treatments to alter the natural history of disease. To investigate the association between lipid-associated single-nucleotide polymorphisms (SNPs) and AAA risk. Genetic risk scores, composed of lipid trait–associated SNPs, were constructed and tested for their association with AAA using conventional (inverse-variance weighted) mendelian randomization (MR) and data from international AAA genome-wide association studies. Sensitivity analyses to account for potential genetic pleiotropy included MR-Egger and weighted median MR, and multivariable MR method was used to test the independent association of lipids with AAA risk. The association between AAA and SNPs in loci that can act as proxies for drug targets was also assessed. Data collection took place between January 9, 2015, and January 4, 2016. Data analysis was conducted between January 4, 2015, and December 31, 2016. Genetic elevation of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). The association between genetic risk scores of lipid-associated SNPs and AAA risk, as well as the association between SNPs in lipid drug targets (HMGCR, CETP, and PCSK9) and AAA risk. Up to 4914 cases and 48 002 controls were included in our analysis. A 1-SD genetic elevation of LDL-C was associated with increased AAA risk (odds ratio [OR], 1.66; 95% CI, 1.41-1.96; P = 1.1 × 10−9). For HDL-C, a 1-SD increase was associated with reduced AAA risk (OR, 0.67; 95% CI, 0.55-0.82; P = 8.3 × 10−5), whereas a 1-SD increase in triglycerides was associated with increased AAA risk (OR, 1.69; 95% CI, 1.38-2.07; P = 5.2 × 10−7). In multivariable MR analysis and both MR-Egger and weighted median MR methods, the association of each lipid fraction with AAA risk remained largely unchanged. The LDL-C–reducing allele of rs12916 in HMGCR was associated with AAA risk (OR, 0.93; 95% CI, 0.89-0.98; P = .009). The HDL-C–raising allele of rs3764261 in CETP was associated with lower AAA risk (OR, 0.89; 95% CI, 0.85-0.94; P = 3.7 × 10−7). Finally, the LDL-C–lowering allele of rs11206510 in PCSK9 was weakly associated with a lower AAA risk (OR, 0.94; 95% CI, 0.88-1.00; P = .04), but a second independent LDL-C–lowering variant in PCSK9 (rs2479409) was not associated with AAA risk (OR, 0.97; 95% CI, 0.92-1.02; P = .28). The MR analyses in this study lend support to the hypothesis that lipids play an important role in the etiology of AAA. Analyses of individual genetic variants used as proxies for drug targets support LDL-C lowering as a potential effective treatment strategy for preventing and managing AAA.
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腹主动脉瘤的全基因组关联研究的荟萃分析确定了四个新的疾病特异性风险基因座。
影响因子：
20.1
作者：
Jones GT;Tromp G;Kuivaniemi H;Gretarsdottir S;Baas AF;Giusti B;Strauss E;Van't Hof FN;Webb TR;Erdman R;Ritchie MD;Elmore JR;Verma A;Pendergrass S;Kullo IJ;Ye Z;Peissig PL;Gottesman O;Verma SS;Malinowski J;Rasmussen-Torvik LJ;Borthwick KM;Smelser DT;Crosslin DR;de Andrade M;Ryer EJ;McCarty CA;Böttinger EP;Pacheco JA;Crawford DC;Carrell DS;Gerhard GS;Franklin DP;Carey DJ;Phillips VL;Williams MJ;Wei W;Blair R;Hill AA;Vasudevan TM;Lewis DR;Thomson IA;Krysa J;Hill GB;Roake J;Merriman TR;Oszkinis G;Galora S;Saracini C;Abbate R;Pulli R;Pratesi C;Saratzis A;Verissimo AR;Bumpstead S;Badger SA;Clough RE;Cockerill G;Hafez H;Scott DJ;Futers TS;Romaine SP;Bridge K;Griffin KJ;Bailey MA;Smith A;Thompson MM;van Bockxmeer FM;Matthiasson SE;Thorleifsson G;Thorsteinsdottir U;Blankensteijn JD;Teijink JA;Wijmenga C;de Graaf J;Kiemeney LA;Lindholt JS;Hughes A;Bradley DT;Stirrups K;Golledge J;Norman PE;Powell JT;Humphries SE;Hamby SE;Goodall AH;Nelson CP;Sakalihasan N;Courtois A;Ferrell RE;Eriksson P;Folkersen L;Franco-Cereceda A;Eicher JD;Johnson AD;Betsholtz C;Ruusalepp A;Franzén O;Schadt EE;Björkegren JL;Lipovich L;Drolet AM;Verhoeven EL;Zeebregts CJ;Geelkerken RH;van Sambeek MR;van Sterkenburg SM;de Vries JP;Stefansson K;Thompson JR;de Bakker PI;Deloukas P;Sayers RD;Harrison SC;van Rij AM;Samani NJ;Bown MJ
通讯作者：
Bown MJ
DOI：
10.1097/maj.0000000000000292
发表时间：
2014-08
期刊：
The American journal of the medical sciences
影响因子：
--
作者：
Gamboa CM;Safford MM;Levitan EB;Mann DM;Yun H;Glasser SP;Woolley JM;Rosenson R;Farkouh M;Muntner P
通讯作者：
Muntner P
影响因子：
2.1
作者：
Bowden J;Davey Smith G;Haycock PC;Burgess S
通讯作者：
Burgess S
影响因子：
9.8
作者：
Bown, Matthew J.;Jones, Gregory T.;Samani, Nilesh J.
通讯作者：
Samani, Nilesh J.
影响因子：
--
作者：
Bradley, Declan T.;Hughes, Anne E.;Bown, Matthew J.
通讯作者：
Bown, Matthew J.