Zhenhuang Zhuang1, Canqing Yu1, Yu Guo2, Zheng Bian2, Ling Yang3, Iona Y Millwood3, Robin G Walters3, Yiping Chen3, Qinai Xu4, Mingyuan Zou5, Junshi Chen6, Zhengming Chen3, Jun Lv1,7,8, Tao Huang1,7, Liming Li1. 1. Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing 100191, China. 2. Chinese Academy of Medical Sciences, Beijing 100730, China. 3. Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX1 3QR, UK. 4. NCDs Prevention and Control Department, Nangang CDC, Harbin 150000, China. 5. Heilongjiang CDC, Harbin 150030, China. 6. China National Center for Food Safety Risk Assessment, Beijing 100022, China. 7. Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, China. 8. Peking University Institute of Environmental Medicine, Beijing 100191, China.
Abstract
CONTEXT: Observational studies have suggested that higher circulating 25-hydroxyvitamin D [25(OH)D] levels are associated with favorable serum lipids and related metabolites. However, whether such observations reflect causality remains unclear. OBJECTIVE: We aimed to investigate the causal effect of elevated 25(OH)D with a detailed systemic metabolite profile in Chinese adults. METHODS: A total of 225 lipid and other metabolites were quantified in 4662 individuals in the China Kadoorie Biobank. Instrumental variable analyses were performed to test the causal associations of plasma 25(OH)D with lipids and metabolites. RESULTS: Higher plasma 25(OH)D was related to favorable lipid profiles in observational analyses. The genetic risk score was robustly correlated with observed 25(OH)D (beta[SE] = 3.54 [0.32]; P < 1 × 10-5, F-statistic = 122.3) and explained 8.4% of the variation in 25(OH)D in the Chinese population. For all individual metabolites, the causal estimates were not significant at the threshold P < 5 × 10-4 (multiple testing corrected). However, a Mendelian randomization (MR) estimate showed that per 1-SD increase in genetically determined 25(OH)D was suggestive of association with decreased levels of cholesterol, lipoprotein particles, and phospholipids within very small very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) (P ≤ 0.05, nominal significance). For amino acids, fatty acids, ketone bodies, glycoprotein acetyls, fatty acids, and other traits, we did not observe any significant causal association. CONCLUSIONS: The MR analysis of metabolic data based a population-based cohort suggested a potential causal association of plasma 25(OH)D with cholesterol, lipoprotein particle, phospholipid concentrations, and total lipids within very small VLDL and IDL. Our findings highlight a long-term effect of 25(OH)D levels in maintaining healthy lipid metabolism.
CONTEXT: Observational studies have suggested that higher circulating 25-hydroxyvitamin D [25(OH)D] levels are associated with favorable serum lipids and related metabolites. However, whether such observations reflect causality remains unclear. OBJECTIVE: We aimed to investigate the causal effect of elevated 25(OH)D with a detailed systemic metabolite profile in Chinese adults. METHODS: A total of 225 lipid and other metabolites were quantified in 4662 individuals in the China Kadoorie Biobank. Instrumental variable analyses were performed to test the causal associations of plasma 25(OH)D with lipids and metabolites. RESULTS: Higher plasma 25(OH)D was related to favorable lipid profiles in observational analyses. The genetic risk score was robustly correlated with observed 25(OH)D (beta[SE] = 3.54 [0.32]; P < 1 × 10-5, F-statistic = 122.3) and explained 8.4% of the variation in 25(OH)D in the Chinese population. For all individual metabolites, the causal estimates were not significant at the threshold P < 5 × 10-4 (multiple testing corrected). However, a Mendelian randomization (MR) estimate showed that per 1-SD increase in genetically determined 25(OH)D was suggestive of association with decreased levels of cholesterol, lipoprotein particles, and phospholipids within very small very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) (P ≤ 0.05, nominal significance). For amino acids, fatty acids, ketone bodies, glycoprotein acetyls, fatty acids, and other traits, we did not observe any significant causal association. CONCLUSIONS: The MR analysis of metabolic data based a population-based cohort suggested a potential causal association of plasma 25(OH)D with cholesterol, lipoprotein particle, phospholipid concentrations, and total lipids within very small VLDL and IDL. Our findings highlight a long-term effect of 25(OH)D levels in maintaining healthy lipid metabolism.
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