Blood phytosterols in relation to cardiovascular diseases and mediating effects of blood lipids and hematological traits: a Mendelian randomization analysis

• Published in: Metabolism, clinical and experimental Vol. 146; p. 155611
• Main Authors: Zhao, Yimin, Zhuang, Zhenhuang, Li, Yueying, Xiao, Wendi, Song, Zimin, Huang, Ninghao, Wang, Wenxiu, Dong, Xue, Jia, Jinzhu, Huang, Tao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2023
• Subjects: Blood lipids; Cardiovascular disease; Median analysis; Mendelian randomization; Phytosterol; single nucleotide polymorphism; Cardiovascular disease; Mendelian randomization; inverse-variance weighted; Median analysis; low-density lipoprotein; N-terminal Niemann-Pick C1; MR pleiotropy residual sum and outlier; Phytosterol; genome-wide association study; adenosine triphosphate-binding cassette sub-family G members 5 and 8; Blood lipids; non-high-density lipoprotein cholesterol
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2023.155611

Short-term clinical trials have shown the cholesterol-lowering potentials of phytosterols, but their impacts on cardiovascular disease (CVD) remain controversial. This study used the Mendelian randomization (MR) to investigate the relationships between genetic predisposition to blood sitosterol concentration and 11 CVD endpoints, along with the potential mediating effects of blood lipids and hematological traits. Random-effect inverse-variance weighted method was used as the main analysis of MR. Genetic instruments of sitosterol (seven SNPs, F = 253, and R2 = 15.4 %) were derived from an Icelandic cohort. Summary-level data of the 11 CVDs were obtained from UK Biobank, FinnGen, and publicly available genome-wide association study results. Genetically predicted one unit increment in log-transformed blood total sitosterol was significantly associated with a higher risk of coronary atherosclerosis (OR: 1.52; 95 % CI: 1.41, 1.65; n = 667,551), myocardial infarction (OR: 1.40; 95 % CI: 1.25, 1.56; n = 596,436), all coronary heart disease (OR: 1.33; 95 % CI: 1.22, 1.46; n = 766,053), intracerebral hemorrhage (OR: 1.68; 95 % CI: 1.24, 2.27; n = 659,181), heart failure (OR: 1.16; 95 % CI: 1.08, 1.25; n = 1,195,531), and aortic aneurysm (OR: 1.74; 95 % CI: 1.42, 2.13; n = 665,714). Suggestive associations were observed for an increased risk of ischemic stroke (OR: 1.06; 95 % CI: 1.01, 1.12; n = 2,021,995) and peripheral artery disease (OR: 1.20; 95 % CI: 1.05, 1.37; n = 660,791). Notably, blood non-high-density lipoprotein cholesterol (nonHDL-C) and apolipoprotein B mediated about 38–47 %, 46–60 %, and 43–58 % of the associations between sitosterol and coronary atherosclerosis, myocardial infarction, and coronary heart disease, respectively. However, the associations between sitosterol and CVDs were less likely to depend on hematological traits. The study suggests that genetic predisposition to higher blood total sitosterol is linked to a greater risk of major CVDs. Moreover, blood nonHDL-C and apolipoprotein B might mediate a significant proportion of the associations between sitosterol and coronary diseases. [Display omitted] •The causal relationships between blood phytosterols and cardiovascular disease remain to be established.•We found that genetic predisposition to higher blood total sitosterol is linked to increased risks of coronary disease and heart failure.•The associations between sitosterol and coronary diseases were partly mediated by blood nonHDL-C