Association of Genetic Variants Related to Combined Exposure to Lower Low-Density Lipoproteins and Lower Systolic Blood Pressure With Lifetime Risk of Cardiovascular Disease,JAMA

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Association of Genetic Variants Related to Combined Exposure to Lower Low-Density Lipoproteins and Lower Systolic Blood Pressure With Lifetime Risk of Cardiovascular Disease
JAMA ( IF 63.1 ) Pub Date : 2019-10-08 , DOI: 10.1001/jama.2019.14120
Brian A Ference _{1,

2} , Deepak L Bhatt ₃ , Alberico L Catapano ₄ , Chris J Packard ₅ , Ian Graham ₆ , Stephen Kaptoge ₂ , Thatcher B Ference ₁ , Qi Guo _{1,

2} , Ulrich Laufs ₇ , Christian T Ruff ₈ , Arjen Cupido _{1,

9} , G Kees Hovingh ₉ , John Danesh ₂ , Michael V Holmes ₁₀ , George Davey Smith ₁₁ , Kausik K Ray ₁₂ , Stephen J Nicholls ₁₃ , Marc S Sabatine ₈

Affiliation

Centre for Naturally Randomized Trials, University of Cambridge, Cambridge, United Kingdom.
MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
Brigham and Women's Hospital Heart and Vascular Center, Harvard Medical School, Boston, Massachusetts.
Department of Pharmacological and Biomolecular Sciences, University of Milan, Multimedica IRCCS, Milano, Italy.
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
School of Medicine, Trinity College, Dublin, Ireland.
Department of Cardiology, University of Leipzig, Leipzig, Germany.
Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
MRC Population Health Research Unit, Clinical Trial Service Unit, and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
School of Public Health, Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, London, United Kingdom.
Monash University, Melbourne, Australia.

Importance The relationship between exposure to lower low-density lipoprotein cholesterol (LDL-C) and lower systolic blood pressure (SBP) with the risk of cardiovascular disease has not been reliably quantified. Objective To assess the association of lifetime exposure to the combination of both lower LDL-C and lower SBP with the lifetime risk of cardiovascular disease. Design, Setting, and Participants Among 438 952 participants enrolled in the UK Biobank between 2006 and 2010 and followed up through 2018, genetic LDL-C and SBP scores were used as instruments to divide participants into groups with lifetime exposure to lower LDL-C, lower SBP, or both. Differences in plasma LDL-C, SBP, and cardiovascular event rates between the groups were compared to estimate associations with lifetime risk of cardiovascular disease. Exposures Differences in plasma LDL-C and SBP compared with participants with both genetic scores below the median. Genetic risk scores higher than the median were associated with lower LDL-C and lower SBP. Main Outcomes and Measures Odds ratio (OR) for major coronary events, defined as coronary death, nonfatal myocardial infarction, or coronary revascularization. Results The mean age of the 438 952 participants was 65.2 years (range, 40.4-80.0 years), 54.1% were women, and 24 980 experienced a first major coronary event. Compared with the reference group, participants with LDL-C genetic scores higher than the median had 14.7-mg/dL lower LDL-C levels and an OR of 0.73 for major coronary events (95% CI, 0.70-0.75; P < .001). Participants with SBP genetic scores higher than the median had 2.9-mm Hg lower SBP and an OR of 0.82 for major coronary events (95% CI, 0.79-0.85, P < .001). Participants in the group with both genetic scores higher than the median had 13.9-mg/dL lower LDL-C, 3.1-mm Hg lower SBP, and an OR of 0.61 for major coronary events (95% CI, 0.59-0.64; P < .001). In a 4 × 4 factorial analysis, exposure to increasing genetic risk scores and lower LDL-C levels and SBP was associated with dose-dependent lower risks of major coronary events. In a meta-regression analysis, combined exposure to 38.67-mg/dL lower LDL-C and 10-mm Hg lower SBP was associated with an OR of 0.22 for major coronary events (95% CI, 0.17-0.26; P < .001), and 0.32 for cardiovascular death (95% CI, 0.25-0.40; P < .001). Conclusions and Relevance Lifelong genetic exposure to lower levels of low-density lipoprotein cholesterol and lower systolic blood pressure was associated with lower cardiovascular risk. However, these findings cannot be assumed to represent the magnitude of benefit achievable from treatment of these risk factors.

中文翻译：

与较低的低密度脂蛋白和较低的收缩压联合暴露相关的遗传变异与心血管疾病的终生风险之间的关联

重要性暴露于较低的低密度脂蛋白胆固醇 (LDL-C) 和较低的收缩压 (SBP) 与心血管疾病风险之间的关系尚未得到可靠量化。目的评估终生暴露于较低 LDL-C 和较低 SBP 的组合与终生心血管疾病风险之间的关系。设计、设置和参与者在 2006 年至 2010 年间登记在英国生物银行并随访至 2018 年的 438,952 名参与者中，遗传 LDL-C 和 SBP 评分被用作工具，将参与者分为终生暴露于较低 LDL-C 的组，降低收缩压，或两者兼而有之。比较各组之间血浆 LDL-C、SBP 和心血管事件发生率的差异，以估计与心血管疾病终生风险的关联。暴露与基因评分均低于中位数的参与者相比，血浆 LDL-C 和 SBP 存在差异。高于中位数的遗传风险评分与较低的 LDL-C 和较低的 SBP 相关。主要结果和措施主要冠状动脉事件的比值比 (OR)，定义为冠状动脉死亡、非致命性心肌梗死或冠状动脉血运重建。结果 438 952 名参与者的平均年龄为 65.2 岁（范围为 40.4-80.0 岁），其中 54.1% 为女性，其中 24 980 人经历了首次重大冠状动脉事件。与参考组相比，LDL-C 遗传评分高于中位数的参与者的 LDL-C 水平降低了 14.7 mg/dL，主要冠状动脉事件的 OR 为 0.73（95% CI，0.70-0.75；P < . 001）。 SBP 遗传评分高于中位数的参与者的 SBP 降低了 2.9 mm Hg，主要冠状动脉事件的 OR 为 0.82（95% CI，0.79-0.85，P < .001）。两项遗传评分均高于中位数的组参与者的 LDL-C 降低了 13.9 mg/dL，SBP 降低了 3.1 mm Hg，主要冠状动脉事件的 OR 为 0.61（95% CI，0.59-0.64；P % 3C .001)。在 4 × 4 因子分析中，暴露于增加的遗传风险评分以及较低的 LDL-C 水平和 SBP 与主要冠心病事件风险的剂量依赖性降低相关。在荟萃回归分析中，结合暴露于 38.67 mg/dL 较低的 LDL-C 和 10 mm Hg 较低的 SBP 与主要冠状动脉事件的 OR 为 0.22 相关（95% CI，0.17-0.26；P < . 001），心血管死亡为 0.32（95% CI，0.25-0.40；P < .001）。结论和相关性终身遗传暴露于较低水平的低密度脂蛋白胆固醇和较低的收缩压与较低的心血管风险相关。然而，不能假设这些发现代表了治疗这些危险因素可实现的获益程度。

更新日期：2019-10-08

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