Genetic Predisposition to Low-Density Lipoprotein Cholesterol and Incident Type 2 Diabetes.

IF 14.8 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS JAMA cardiology Pub Date : 2025-01-15 DOI:10.1001/jamacardio.2024.5072

Akshaya Ravi, Satoshi Koyama, So Mi Jemma Cho, Sara Haidermota, Whitney Hornsby, Patrick T Ellinor, Pradeep Natarajan

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引用次数: 0

Abstract

Importance: Treatment to lower high levels of low-density lipoprotein cholesterol (LDL-C) reduces incident coronary artery disease (CAD) risk but modestly increases the risk for incident type 2 diabetes (T2D). The extent to which genetic factors across the cholesterol spectrum are associated with incident T2D is not well understood.

Objective: To investigate the association of genetic predisposition to increased LDL-C levels with incident T2D risk.

Design, setting, and participants: In this large prospective, population-based cohort study, UK Biobank participants who underwent whole-exome sequencing and genome-wide genotyping were included. Participants were separated into 7 groups with familial hypercholesterolemia (FH), predicted loss of function (pLOF) in APOB or PCSK9 variants, and LDL-C polygenic risk score (PRS) quintiles. Data were collected between 2006 and 2010, with a median follow-up of 13.7 (IQR, 12.9-14.5) years. Data were analyzed from March 1 to November 1, 2024.

Exposures: LDL-C level, LDL-C PRS, FH, or pLOF variant status.

Main outcomes and measures: Cox proportional hazards regression models adjusted for age, sex, genotyping array, lipid-lowering medication use, and the first 10 genetic principal components were fitted to assess the association between LDL-C genetic factors and incident T2D and CAD risks.

Results: Among the 361 082 participants, mean (SD) age was 56.8 (8.0) years, 194 751 (53.9%) were female, and mean (SD) baseline LDL-C level was 138.0 (33.6) mg/dL. During the follow-up period, 22 619 (6.3%) participants developed incident T2D and 17 966 (5.0%) developed incident CAD. The hazard ratio for incident T2D was lowest in the FH group (0.65; 95% CI, 0.54-0.77), while the highest risk was in the pLOF group (1.48; 95% CI, 1.18-1.86). The association between LDL-C PRS and incident T2D was 0.72 (95% CI, 0.66-0.79) for very high LDL-C PRS, 0.87 (95% CI, 0.84-0.90) for high LDL-C PRS, 1.13 (95% CI, 1.09-1.17) for low LDL-C PRS, and 1.26 (95% CI, 1.15-1.38) for very low LDL-C PRS. CAD risk increased directly with the LDL-C PRS.

Conclusions and relevance: In this cohort study, LDL-C and T2D risks were inversely associated across genetic mechanisms for LDL-C variation. Further elucidation of the mechanisms associating low LDL-C risk with increased risk of T2D is warranted.

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低密度脂蛋白胆固醇和2型糖尿病的遗传易感性。

重要性：降低低密度脂蛋白胆固醇（LDL-C）的治疗降低了冠心病（CAD）的发生风险，但适度增加了2型糖尿病（T2D）的发生风险。在多大程度上，胆固醇谱上的遗传因素与T2D的发生有关尚不清楚。目的：探讨LDL-C水平升高的遗传易感性与T2D发生风险的关系。设计、环境和参与者：在这项大型前瞻性、基于人群的队列研究中，英国生物银行的参与者接受了全外显子组测序和全基因组基因分型。参与者按家族性高胆固醇血症（FH）、APOB或PCSK9变异的预测功能丧失（pLOF）和LDL-C多基因风险评分（PRS）五分位数分为7组。数据收集于2006年至2010年，中位随访时间为13.7年（IQR, 12.9-14.5）年。数据分析时间为2024年3月1日至11月1日。暴露：LDL-C水平，LDL-C PRS， FH或pLOF变异状态。主要结局和测量方法：采用Cox比例风险回归模型，对年龄、性别、基因分型阵列、降脂药物使用和前10个遗传主成分进行校正，以评估LDL-C遗传因素与T2D和CAD事件风险之间的关系。结果：在361 082名参与者中，平均（SD）年龄为56.8（8.0）岁，194 751（53.9%）为女性，平均（SD）基线LDL-C水平为138.0 (33.6)mg/dL。在随访期间，22 619名（6.3%）参与者发生T2D事件，17 966名（5.0%）参与者发生CAD事件。FH组发生T2D的风险比最低(0.65；95% CI, 0.54-0.77)，而pLOF组的风险最高(1.48；95% ci, 1.18-1.86)。LDL-C PRS与T2D事件之间的关联：非常高的LDL-C PRS为0.72 (95% CI, 0.66-0.79)，高的LDL-C PRS为0.87 (95% CI, 0.84-0.90)，低LDL-C PRS为1.13 (95% CI, 1.09-1.17)，极低LDL-C PRS为1.26 （95% CI, 1.15-1.38）。冠心病风险随着LDL-C PRS的升高而直接增加。结论和相关性：在这项队列研究中，LDL-C和T2D风险在LDL-C变异的遗传机制中呈负相关。进一步阐明低LDL-C风险与T2D风险增加相关的机制是有必要的。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

JAMA cardiology Medicine-Cardiology and Cardiovascular Medicine

CiteScore

45.80

自引率

1.70%

发文量

264

期刊介绍： JAMA Cardiology, an international peer-reviewed journal, serves as the premier publication for clinical investigators, clinicians, and trainees in cardiovascular medicine worldwide. As a member of the JAMA Network, it aligns with a consortium of peer-reviewed general medical and specialty publications. Published online weekly, every Wednesday, and in 12 print/online issues annually, JAMA Cardiology attracts over 4.3 million annual article views and downloads. Research articles become freely accessible online 12 months post-publication without any author fees. Moreover, the online version is readily accessible to institutions in developing countries through the World Health Organization's HINARI program. Positioned at the intersection of clinical investigation, actionable clinical science, and clinical practice, JAMA Cardiology prioritizes traditional and evolving cardiovascular medicine, alongside evidence-based health policy. It places particular emphasis on health equity, especially when grounded in original science, as a top editorial priority.