A phenome-wide association study of a lipoprotein-associated phospholipase A2 loss-of-function variant in 90 000 Chinese adults
A phenome-wide association study of a lipoprotein-associated phospholipase A2 loss-of-function variant in 90 000 Chinese adults
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DOI：
10.1093/ije/dyw087
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发表时间：
2016-10-01
影响因子：
7.7
通讯作者：
Chen, Zhengming
中科院分区：
文献类型：
--
作者：
Millwood, Iona Y.;Bennett, Derrick A.;Chen, Zhengming
背景：脂蛋白相关磷脂酶 A(2) (Lp-PLA(2)) 与动脉粥样硬化的发生有关。然而，最近 Lp-PLA(2) 抑制的随机试验报告称对血管疾病没有有益作用。在东亚人中，PLA2G7 基因中的功能缺失变异可用于评估基因决定的较低 Lp-PLA(2) 的影响。方法：对从中国嘉道理生物库中随机选出的 91 428 名个体进行 PLA2G7 V279F (rs76863441) 的基因分型，该样本包括 2004-08 年从中国 10 个地区招募的 0.5 M 参与者，其中 7年的后续行动。使用线性回归评估 V279F 对基线性状的影响。对一系列血管和非血管疾病进行逻辑回归，包括 41 个 ICD-10 编码疾病类别。结果：PLA2G7 V279F 频率总体为 5%（按地区范围为 3-7%），9691 名 (11%) 参与者至少有一种功能丧失变异。 V279F 与基线血压、肥胖、血糖或肺功能无关。 V279F 与主要血管事件无关[7141 事件；每个 F 变体的比值比 (OR) = 0.98，95% 置信区间 (CI) 0.90-1.06] 或其他血管结局，包括主要冠状动脉事件（922 起事件；0.96，0.79-1.18）和中风（5967 起事件；1.00，0.92-1.09）。 V279F 个体患糖尿病（7031 例事件；0.91，0.84-0.98）和哮喘（182 例事件；0.53，0.28-0.98）的风险较低，但在调整多重测试后没有关联。 结论：终生较低的 Lp-PLA(2) 活性与中国成年人血管或非血管疾病的主要风险无关。在与一系列健康结果相关的大规模前瞻性研究中使用功能性遗传变异是为药物开发和重新定位提供信息的宝贵方法。
Background: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) has been implicated in development of atherosclerosis; however, recent randomized trials of Lp-PLA(2) inhibition reported no beneficial effects on vascular diseases. In East Asians, a loss-of-function variant in the PLA2G7 gene can be used to assess the effects of genetically determined lower Lp-PLA(2).Methods: PLA2G7 V279F (rs76863441) was genotyped in 91 428 individuals randomly selected from the China Kadoorie Biobank of 0.5 M participants recruited in 2004-08 from 10 regions of China, with 7 years' follow-up. Linear regression was used to assess effects of V279F on baseline traits. Logistic regression was conducted for a range of vascular and non-vascular diseases, including 41 ICD-10 coded disease categories.Results: PLA2G7 V279F frequency was 5% overall (range 3-7% by region), and 9691 (11%) participants had at least one loss-of-function variant. V279F was not associated with baseline blood pressure, adiposity, blood glucose or lung function. V279F was not associated with major vascular events [7141 events; odds ratio (OR) = 0.98 per F variant, 95% confidence interval (CI) 0.90-1.06] or other vascular outcomes, including major coronary events (922 events; 0.96, 0.79-1.18) and stroke (5967 events; 1.00, 0.92-1.09). Individuals with V279F had lower risks of diabetes (7031 events; 0.91, 0.84-0.98) and asthma (182 events; 0.53, 0.28-0.98), but there was no association after adjustment for multiple testing.Conclusions: Lifelong lower Lp-PLA(2) activity was not associated with major risks of vascular or non-vascular diseases in Chinese adults. Using functional genetic variants in large-scale prospective studies with linkage to a range of health outcomes is a valuable approach to inform drug development and repositioning.