Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, United States of America.
Department of Medicine, Yale University School of Medicine, New Haven, CT, United States of America.
PLoS One. 2020 Nov 9;15(11):e0239752. doi: 10.1371/journal.pone.0239752. eCollection 2020.
Therapeutic inhibition of PCSK9 protects against coronary artery disease (CAD) and ischemic stroke (IS). The impact on other diseases remains less well characterized.
We created a genetic risk score (GRS) for PCSK9 using four single nucleotide polymorphisms (SNPs) at or near the PCSK9 locus known to impact lower LDL-Cholesterol (LDL-C): rs11583680, rs11591147, rs2479409, and rs11206510. We then used our GRS to calculate weighted odds ratios reflecting the impact of a genetically determined 10 mg/dL decrease in LDL-C on several pre-specified phenotypes including CAD, IS, peripheral artery disease (PAD), abdominal aortic aneurysm (AAA), type 2 diabetes, dementia, chronic obstructive pulmonary disease, and cancer. Finally, we used our weighted GRS to perform a phenome-wide association study.
Genetic and electronic health record data that passed quality control was available in 312,097 individuals, (227,490 White participants, 58,907 Black participants, and 25,700 Hispanic participants). PCSK9 mediated reduction in LDL-C was associated with a reduced risk of CAD and AAA in trans-ethnic meta-analysis (CAD OR 0.83 [95% CI 0.80-0.87], p = 6.0 x 10-21; AAA OR 0.76 [95% CI 0.68-0.86], p = 2.9 x 10-06). Significant protective effects were noted for PAD in White individuals (OR 0.83 [95% CI 0.71-0.97], p = 2.3 x 10-04) but not in other genetic ancestries. Genetically reduced PCSK9 function associated with a reduced risk of dementia in trans-ethnic meta-analysis (OR 0.86 [95% CI 0.78-0.93], p = 5.0 x 10-04).
Genetically reduced PCSK9 function results in a reduction in risk of several important extra-coronary atherosclerotic phenotypes in addition to known effects on CAD and IS, including PAD and AAA. We also highlight a novel reduction in risk of dementia, supporting a well-recognized vascular component to cognitive impairment and an opportunity for therapeutic repositioning.
PCSK9 的治疗性抑制可预防冠状动脉疾病 (CAD) 和缺血性中风 (IS)。但其对其他疾病的影响尚不清楚。
我们使用四个位于 PCSK9 基因座附近或位于该基因座的单核苷酸多态性 (SNP) 来创建 PCSK9 的遗传风险评分 (GRS)，这些 SNP 已知可降低 LDL 胆固醇 (LDL-C)：rs11583680、rs11591147、rs2479409 和 rs11206510。然后，我们使用 GRS 计算加权优势比，反映基因决定的 LDL-C 降低 10mg/dL 对几种预先指定的表型的影响，包括 CAD、IS、外周动脉疾病 (PAD)、腹主动脉瘤 (AAA)、2 型糖尿病、痴呆、慢性阻塞性肺疾病和癌症。最后，我们使用加权 GRS 进行表型全基因组关联研究。
在 312097 名个体中，存在经过质量控制的遗传和电子健康记录数据（227490 名白人参与者、58907 名黑人参与者和 25700 名西班牙裔参与者）。跨种族荟萃分析显示，PCSK9 介导的 LDL-C 降低与 CAD 和 AAA 的风险降低相关（CAD OR 0.83 [95%CI 0.80-0.87]，p = 6.0 x 10-21；AAA OR 0.76 [95%CI 0.68-0.86]，p = 2.9 x 10-06）。在白人个体中观察到 PAD 的显著保护作用（OR 0.83 [95%CI 0.71-0.97]，p = 2.3 x 10-04），但在其他遗传背景中则没有。跨种族荟萃分析显示，PCSK9 功能的遗传降低与痴呆风险降低相关（OR 0.86 [95%CI 0.78-0.93]，p = 5.0 x 10-04）。
PCSK9 功能的遗传降低除了对 CAD 和 IS 有已知影响外，还导致几种重要的冠状动脉外动脉粥样硬化表型的风险降低，包括 PAD 和 AAA。我们还强调了痴呆风险降低的新发现，这支持了认知障碍与血管因素的公认关系，也为治疗定位提供了机会。
