MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK.
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 2PN, UK.
Hum Mol Genet. 2022 Nov 28;31(23):4034-4054. doi: 10.1093/hmg/ddac153.
Despite early interest, the evidence linking fatty acids to cardiovascular diseases (CVDs) remains controversial. We used Mendelian randomization to explore the involvement of polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids biosynthesis in the etiology of several CVD endpoints in up to 1 153 768 European (maximum 123 668 cases) and 212 453 East Asian (maximum 29 319 cases) ancestry individuals. As instruments, we selected single nucleotide polymorphisms mapping to genes with well-known roles in PUFA (i.e. FADS1/2 and ELOVL2) and MUFA (i.e. SCD) biosynthesis. Our findings suggest that higher PUFA biosynthesis rate (proxied by rs174576 near FADS1/2) is related to higher odds of multiple CVDs, particularly ischemic stroke, peripheral artery disease and venous thromboembolism, whereas higher MUFA biosynthesis rate (proxied by rs603424 near SCD) is related to lower odds of coronary artery disease among Europeans. Results were unclear for East Asians as most effect estimates were imprecise. By triangulating multiple approaches (i.e. uni-/multi-variable Mendelian randomization, a phenome-wide scan, genetic colocalization and within-sibling analyses), our results are compatible with higher low-density lipoprotein (LDL) cholesterol (and possibly glucose) being a downstream effect of higher PUFA biosynthesis rate. Our findings indicate that PUFA and MUFA biosynthesis are involved in the etiology of CVDs and suggest LDL cholesterol as a potential mediating trait between PUFA biosynthesis and CVDs risk.
尽管早期有研究对此感兴趣，但脂肪酸与心血管疾病（CVD）之间的关联仍存在争议。我们使用孟德尔随机化方法，在多达 115.3768 名欧洲人（最大 123668 例）和 212453 名东亚人（最大 29319 例）中，探讨了多不饱和（PUFA）和单不饱和（MUFA）脂肪酸生物合成与多种 CVD 终点之间的关系。我们选择了单核苷酸多态性作为工具，这些多态性映射到在 PUFA（即 FADS1/2 和 ELOVL2）和 MUFA（即 SCD）生物合成中具有已知作用的基因上。我们的研究结果表明，较高的 PUFA 生物合成率（由 FADS1/2 附近的 rs174576 代表）与多种 CVD 的发病风险增加相关，尤其是缺血性中风、外周动脉疾病和静脉血栓栓塞，而较高的 MUFA 生物合成率（由 SCD 附近的 rs603424 代表）与欧洲人冠心病发病风险降低相关。由于大多数效应估计值不精确，东亚人的结果不明确。通过多种方法（即单变量/多变量孟德尔随机化、全基因组扫描、遗传共定位和同胞内分析）的三角测量，我们的结果与较高的低密度脂蛋白（LDL）胆固醇（可能还有葡萄糖）是较高的 PUFA 生物合成率的下游效应相一致。我们的研究结果表明，PUFA 和 MUFA 生物合成参与了 CVD 的发病机制，并提示 LDL 胆固醇可能是 PUFA 生物合成与 CVD 风险之间的潜在中介特征。
