载脂蛋白 B 或前蛋白转化酶枯草溶菌素 9 中罕见蛋白截断 DNA 变异与低密度脂蛋白胆固醇水平及冠心病风险的关联。

Association of Rare Protein-Truncating DNA Variants in APOB or PCSK9 With Low-density Lipoprotein Cholesterol Level and Risk of Coronary Heart Disease.

机构信息

Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston.

Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

出版信息

JAMA Cardiol. 2023 Mar 1;8(3):258-267. doi: 10.1001/jamacardio.2022.5271.

DOI:10.1001/jamacardio.2022.5271

PMID:36723951

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9996405/

Abstract

IMPORTANCE

Protein-truncating variants (PTVs) in apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with significantly lower low-density lipoprotein (LDL) cholesterol concentrations. The association of these PTVs with coronary heart disease (CHD) warrants further characterization in large, multiracial prospective cohort studies.

OBJECTIVE

To evaluate the association of PTVs in APOB and PCSK9 with LDL cholesterol concentrations and CHD risk.

DESIGN, SETTING, AND PARTICIPANTS: This studied included participants from 5 National Heart, Lung, and Blood Institute (NHLBI) studies and the UK Biobank. NHLBI study participants aged 5 to 84 years were recruited between 1971 and 2002 across the US and underwent whole-genome sequencing. UK Biobank participants aged 40 to 69 years were recruited between 2006 and 2010 in the UK and underwent whole-exome sequencing. Data were analyzed from June 2021 to October 2022.

EXPOSURES

PTVs in APOB and PCSK9.

MAIN OUTCOMES AND MEASURES

Estimated untreated LDL cholesterol levels and CHD.

RESULTS

Among 19 073 NHLBI participants (10 598 [55.6%] female; mean [SD] age, 52 [17] years), 139 (0.7%) carried an APOB or PCSK9 PTV, which was associated with 49 mg/dL (95% CI, 43-56) lower estimated untreated LDL cholesterol level. Over a median (IQR) follow-up of 21.5 (13.9-29.4) years, incident CHD was observed in 12 of 139 carriers (8.6%) vs 3029 of 18 934 noncarriers (16.0%), corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.28-0.89; P = .02). Among 190 464 UK Biobank participants (104 831 [55.0%] female; mean [SD] age, 57 [8] years), 662 (0.4%) carried a PTV, which was associated with 45 mg/dL (95% CI, 42-47) lower estimated untreated LDL cholesterol level. Estimated CHD risk by age 75 years was 3.7% (95% CI, 2.0-5.3) in carriers vs 7.0% (95% CI, 6.9-7.2) in noncarriers, corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.32-0.81; P = .004).

CONCLUSIONS AND RELEVANCE

Among 209 537 individuals in this study, 0.4% carried an APOB or PCSK9 PTV that was associated with less exposure to LDL cholesterol and a 49% lower risk of CHD.

摘要

重要提示

载脂蛋白 B（APOB）和前蛋白转化酶枯草溶菌素/柯萨奇蛋白酶 9（PCSK9）中的蛋白截断变异（PTV）与低密度脂蛋白（LDL）胆固醇浓度显著降低有关。这些 PTV 与冠心病（CHD）的关联需要在大型、多种族前瞻性队列研究中进一步描述。

目的

评估 APOB 和 PCSK9 中的 PTV 与 LDL 胆固醇浓度和 CHD 风险的关联。

设计、地点和参与者：这项研究包括来自美国国立心肺血液研究所（NHLBI）的 5 项研究和英国生物银行的参与者。NHLBI 研究的参与者年龄在 5 至 84 岁之间，于 1971 年至 2002 年在美国各地招募，并接受了全基因组测序。英国生物银行的参与者年龄在 40 至 69 岁之间，于 2006 年至 2010 年在英国招募，并接受了全外显子组测序。数据分析于 2021 年 6 月至 2022 年 10 月进行。

暴露情况

APOB 和 PCSK9 中的 PTV。

主要结果和测量指标

未治疗的 LDL 胆固醇水平和 CHD。

结果

在 19073 名 NHLBI 参与者中（1398 名[55.6%]为女性；平均[SD]年龄为 52[17]岁），有 139 人（0.7%）携带 APOB 或 PCSK9 PTV，这与未经治疗的 LDL 胆固醇水平降低 49mg/dL（95%CI，43-56）有关。在中位（IQR）随访 21.5（13.9-29.4）年后，139 名携带者中有 12 人（8.6%）发生了 CHD 事件，而 18934 名非携带者中有 3029 人（16.0%）发生了 CHD 事件，相应的调整后风险比为 0.51（95%CI，0.28-0.89；P=0.02）。在 190464 名英国生物银行参与者中（104831 名[55.0%]为女性；平均[SD]年龄为 57[8]岁），有 662 人（0.4%）携带 PTV，这与未经治疗的 LDL 胆固醇水平降低 45mg/dL（95%CI，42-47）有关。75 岁时的估计 CHD 风险在携带者中为 3.7%（95%CI，2.0-5.3），在非携带者中为 7.0%（95%CI，6.9-7.2），相应的调整后风险比为 0.51（95%CI，0.32-0.81；P=0.004）。