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 quantiï¬ed 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.
Subject(s)
Polymorphism, Single Nucleotide , Vitamin D/analogs & derivatives , Adult , Aged , China , Cholestanetriol 26-Monooxygenase/genetics , Cytochrome P450 Family 2/genetics , Female , Genotype , Humans , Male , Mendelian Randomization Analysis , Metabolome , Middle Aged , Oxidoreductases Acting on CH-CH Group Donors/genetics , Vitamin D/bloodABSTRACT
BACKGROUND: Little prospective evidence exists about risk factors and prognosis of acute pancreatitis in China. We examined the associations of certain metabolic and lifestyle factors with risk of acute pancreatitis in Chinese adults. METHODS AND FINDINGS: The prospective China Kadoorie Biobank (CKB) recruited 512,891 adults aged 30 to 79 years from 5 urban and 5 rural areas between 25 June 2004 and 15 July 2008. During 9.2 years of follow-up (to 1 January 2015), 1,079 cases of acute pancreatitis were recorded. Cox regression was used to estimate adjusted hazard ratios (HRs) for acute pancreatitis associated with various metabolic and lifestyle factors among all or male (for smoking and alcohol drinking) participants. Overall, the mean waist circumference (WC) was 82.1 cm (SD 9.8) cm in men and 79.0 cm (SD 9.5) cm in women, 6% had diabetes, and 6% had gallbladder disease at baseline. WC was positively associated with risk of acute pancreatitis, with an adjusted HR of 1.35 (95% CI 1.27-1.43; p < 0.001) per 1-SD-higher WC. Individuals with diabetes or gallbladder disease had HRs of 1.34 (1.07-1.69; p = 0.01) and 2.42 (2.03-2.88; p < 0.001), respectively. Physical activity was inversely associated with risk of acute pancreatitis, with each 4 metabolic equivalent of task (MET) hours per day (MET-h/day) higher physical activity associated with an adjusted HR of 0.95 (0.91-0.99; p = 0.03). Compared with those without any metabolic risk factors (i.e., obesity, diabetes, gallbladder disease, and physical inactivity), the HRs of acute pancreatitis for those with 1, 2, or ≥3 risk factors were 1.61 (1.47-1.76), 2.36 (2.01-2.78), and 3.41 (2.46-4.72), respectively (p < 0.001). Among men, heavy alcohol drinkers (≥420 g/week) had an HR of 1.52 (1.11-2.09; p = 0.04, compared with abstainers), and current regular smokers had an HR of 1.45 (1.28-1.64; p = 0.02, compared with never smokers). Following a diagnosis of acute pancreatitis, there were higher risks of pancreatic cancer (HR = 8.26 [3.42-19.98]; p < 0.001; 13 pancreatic cancer cases) and death (1.53 [1.17-2.01]; p = 0.002; 89 deaths). Other diseases of the pancreas had similar risk factor profiles and prognosis to acute pancreatitis. The main study limitations are ascertainment of pancreatitis using hospital records and residual confounding. CONCLUSIONS: In this relatively lean Chinese population, several modifiable metabolic and lifestyle factors were associated with higher risks of acute pancreatitis, and individuals with acute pancreatitis had higher risks of pancreatic cancer and death.
