Genome-Wide Association Study of Cardiovascular Resilience Identifies Protective Variation in the CETP Gene.
Genome-Wide Association Study of Cardiovascular Resilience Identifies Protective Variation in the CETP Gene.
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DOI：
10.1161/jaha.123.031459
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发表时间：
2023-11-07
影响因子：
5.4
通讯作者：
中科院分区：
文献类型：
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作者：
动脉粥样硬化性心血管疾病（ASCVD）的风险随着年龄的增长而急剧增加。然而，一些老年人尽管预测风险很高，但仍然不受影响。这些人可能携带有助于恢复力的心脏保护基因变异。我们的目的是评估无症状的老年人是否携带有助于ASCVD恢复的心脏保护性遗传变异。我们进行了一项全基因组关联研究，使用10年预测ASCVD风险评分作为定量特征，仅在年龄≥70岁且无ASCVD流行的无症状老年人中计算。我们对ASPREE（阿司匹林减少老年人事件）试验中的N=12 031例ASCVD无事件个体进行的全基因组关联研究发现了CETP（胆固醇酯转移蛋白）基因中的2个独立变体rs 9939224（P<5×10−8）和rs 56156922（P<10−6）。CETP基因是血浆高密度脂蛋白胆固醇、低密度脂蛋白胆固醇和脂蛋白（a）水平的调节剂，并且是治疗药物靶标。在英国生物样本库（N= 13888例年龄≥69岁且无ASCVD流行的个体的亚群）中复制了相关性。已鉴定的CETP变异体携带者（与非携带者相比）在随访期间具有较高的血浆高密度脂蛋白胆固醇水平，较低的血浆低密度脂蛋白胆固醇水平和降低的ASCVD事件发生风险。表达数量性状基因座分析预测所鉴定的CETP变体降低CETP基因在各种组织中的表达。在3917例有视网膜成像和遗传数据的ASPREE试验参与者中，未观察到先前报道的遗传CETP抑制与年龄相关性黄斑变性风险增加之间的相关性。CETP基因区域的常见遗传变异与衰老过程中的心血管弹性相关。URL：https://www.clinicaltrials.gov;唯一标识符：NCT 01038583。
The risk of atherosclerotic cardiovascular disease (ASCVD) increases sharply with age. Some older individuals, however, remain unaffected despite high predicted risk. These individuals may carry cardioprotective genetic variants that contribute to resilience. Our aim was to assess whether asymptomatic older individuals without prevalent ASCVD carry cardioprotective genetic variants that contribute to ASCVD resilience. We performed a genome‐wide association study using a 10‐year predicted ASCVD risk score as a quantitative trait, calculated only in asymptomatic older individuals aged ≥70 years without prevalent ASCVD. Our discovery genome‐wide association study of N=12 031 ASCVD event‐free individuals from the ASPREE (Aspirin in Reducing Events in the Elderly) trial identified 2 independent variants, rs9939224 (P<5×10−8) and rs56156922 (P<10−6), in the CETP (cholesteryl ester transfer protein) gene. The CETP gene is a regulator of plasma high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol, and lipoprotein(a) levels, and it is a therapeutic drug target. The associations were replicated in the UK Biobank (subpopulation of N=13 888 individuals aged ≥69 years without prevalent ASCVD). Carriers of the identified CETP variants (versus noncarriers) had higher plasma high‐density lipoprotein cholesterol levels, lower plasma low‐density lipoprotein cholesterol levels, and reduced risk of incident ASCVD events during follow‐up. Expression quantitative trait loci analysis predicted the identified CETP variants reduce CETP gene expression across various tissues. Previously reported associations between genetic CETP inhibition and increased risk of age‐related macular degeneration were not observed among the 3917 ASPREE trial participants with retinal imaging and genetic data available. Common genetic variants in the CETP gene region are associated with cardiovascular resilience during aging. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583.
影响因子：
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作者：
Nunn JS;Sulovski M;Tiller J;Holloway B;Ayton D;Lacaze P
通讯作者：
Lacaze P
DOI：
10.1093/ehjopen/oeab015
发表时间：
2021-09
期刊：
European heart journal open
影响因子：
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作者：
Christensen, Daniel Molager;Phelps, Matthew;Gerds, Thomas;Malmborg, Morten;Schjerning, Anne-Marie;Strange, Jarl Emanuel;El-Chouli, Mohamad;Larsen, Lars Bruun;Fosbol, Emil;Kober, Lars;Torp-Pedersen, Christian;Mehta, Suneela;Jackson, Rod;Gislason, Gunnar
通讯作者：
Gislason, Gunnar