Causal association of blood lipids with all-cause and cause-specific mortality risk: a Mendelian randomization study.

Dyslipidemia has long been implicated in elevating mortality risk; yet, the precise associations between lipid traits and mortality remained undisclosed. Our study aimed to explore the causal effects of lipid traits on both all-cause and cause-specific mortality. One-sample Mendelian randomization (MR) with linear and nonlinear assumptions was conducted in a cohort of 407,951 European participants from the UK Biobank. Six lipid traits, consisting of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and lipoprotein(a), were included to investigate the causal associations with mortality. Two-sample MR was performed to replicate the association between each lipid trait and all-cause mortality. Univariable MR results showed that genetically predicted higher ApoA1 was significantly associated with a decreased all-cause mortality risk (HR[95% CI]:0.93 [0.89-0.97], P value = 0.001), which was validated by the two-sample MR analysis. Higher lipoprotein(a) was associated with an increased risk of all-cause mortality (1.03 [1.01-1.04], P value = 0.002). Multivariable MR confirmed the direct causal effects of ApoA1 and lipoprotein(a) on all-cause mortality. Meanwhile, nonlinear MR found no evidence for nonlinearity between lipids and all-cause mortality. Our examination into cause-specific mortality revealed a suggestive inverse association between ApoA1 and cancer mortality, a significant positive association between lipoprotein(a) and cardiovascular disease mortality, and a suggestive positive association between lipoprotein(a) and digestive disease mortality. High LDL-C was associated with an increased risk of cardiovascular disease mortality but a decreased risk of neurodegenerative disease mortality. The findings suggest that implementing interventions to raise ApoA1 and decrease lipoprotein(a) levels may improve overall health outcomes and mitigate cancer and digestive disease mortality.

Investigating linear and nonlinear associations of LDL cholesterol with incident chronic kidney disease, atherosclerotic cardiovascular disease and all-cause mortality: A prospective and Mendelian randomization study.

BACKGROUND AND AIMS: Observational studies suggest potential nonlinear associations of low-density lipoprotein cholesterol (LDL-C) with cardio-renal diseases and mortality, but the causal nature of these associations is unclear. We aimed to determine the shape of causal relationships of LDL-C with incident chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD) and all-cause mortality, and to evaluate the absolute risk of adverse outcomes contributed by LDL-C itself. METHODS: Observational analysis and one-sample Mendelian randomization (MR) with linear and nonlinear assumptions were performed using the UK Biobank of >0.3 million participants with no reported prescription of lipid-lowering drugs. Two-sample MR on summary-level data from the Global Lipid Genetics Consortium (N = 296,680) and the CKDGen (N = 625,219) was employed to replicate the relationship for kidney traits. The 10-year probabilities of the outcomes was estimated by integrating the MR and Cox models. RESULTS: Observationally, participants with low LDL-C were significantly associated with a decreased risk of ASCVD, but an increased risk of CKD and all-cause mortality. Univariable MR showed an inverse total effect of LDL-C on incident CKD (HR [95% CI]:0.84 [0.73-0.96]; p = 0.011), a positive effect on ASCVD (1.41 [1.29-1.53]; p<0.001), and no significant causal effect on all-cause mortality. Multivariable MR, controlling for high-density lipoprotein cholesterol (HDL-C) and triglycerides, identified a positive direct effect on ASCVD (1.32 [1.18-1.47]; p<0.001), but not on CKD and all-cause mortality. These results indicated that genetically predicted low LDL-C had an inverse indirect effect on CKD mediated by HDL-C and triglycerides, which was validated by a two-sample MR analysis using summary-level data from the Global Lipid Genetics Consortium (N = 296,680) and the CKDGen consortium (N = 625,219). Suggestive evidence of a nonlinear causal association between LDL-C and CKD was found. The 10-year probability curve showed that LDL-C concentrations below 3.5 mmol/L were associated with an increased risk of CKD. CONCLUSIONS: In the general population, lower LDL-C was causally associated with lower risk of ASCVD, but appeared to have a trade-off for an increased risk of CKD, with not much effect on all-cause mortality. LDL-C concentration below 3.5 mmol/L may increase the risk of CKD.

Effects of metabolic factors in mediating the relationship between Type 2 diabetes and depression in East Asian populations: A two-step, two-sample Mendelian randomization study.

BACKGROUND: Observational studies suggested a close link between type 2 diabetes (T2D), metabolic factors and depression, while the causal relationships remained poorly understood. OBJECTIVE: To determine the causality between T2D and depression, and to investigate the roles of metabolic factors in mediating the relationship between T2D and depression in East Asians. METHODS: Using summary statistics from the largest and most up-to-date genome-wide association studies of depression (12,588 cases and 85,914 controls) and T2D (36,614 cases and 155,150 controls) among East Asians, two-step and two-sample MR analyses were performed to estimate the causal mediation effects of metabolic factors including lipid profiles, blood pressure (BP) and fasting insulin (FI) on the relationship between T2D and depression. RESULTS: Genetically predicted T2D was significantly associated with depression (OR [95 % CI]:1.06 [1.01, 1.11], P = 0.043), but not vice versa. T2D was causally associated with lower levels of HDL-C and higher levels of LDL-C, triglycerides (TG), BP and FI. Furthermore, the causal effects of T2D on depression were significantly mediated by LDL-C (ß [95 % CI]: -0.003 [-0.005, -0.001], P = 0.007), and suggestively mediated by TG (0.001 [0.001, 0.003], P = 0.049) and FI (0.006 [0.001, 0.012], P = 0.049). LIMITATIONS: First, depression was defined by several methods, like symptom questionnaires or self-completed surveys. Second, two-sample MR approach is unable to detect the non-linear causal relationships. Third, independent data sets were not available for replication of our findings. CONCLUSION: T2D was causally associated with the risk of depression, and LDL-C, TG, and FI were potential causal mediators of the effect of T2D on depression. Understanding the causality among T2D, metabolic factors and depression is crucial for identifying potential targets for early intervention.

Linear and non-linear Mendelian randomization analyses of sex-specific associations between sleep duration and hyperuricemia.

Background: Observational studies have suggested a potential non-linear association between sleep duration and hyperuricemia. However, the causal nature and sex-specific differences are poorly understood. We aimed to determine the shape of sex-specific causal associations between sleep duration and hyperuricemia in the UK Biobank. Methods: Logistic regression was used to investigate the observational association between self-reported sleep duration and hyperuricemia among 387,980 white British participants (mean age: 56.9 years and 46.0% males). Linear and non-linear Mendelian Randomization (MR) analyses were performed to assess the causal association between continuous sleep duration and hyperuricemia. The causal effects of genetically predicted short (<7 h) and long (>8 h) sleep durations on hyperuricemia were further estimated, respectively. Results: Traditional observational analysis suggested U- and J-shaped associations between sleep duration and hyperuricemia in females and males, respectively. Linear MR did not support the causal effect of sleep duration on hyperuricemia. Non-linear MR demonstrated an approximately U-shaped causal association between continuous sleep duration and hyperuricemia in overall participants and females, but not in males. Genetically predicted short sleep duration was significantly associated with hyperuricemia in females (OR [95% CI]: 1.21 [1.08-1.36]; P = 0.001), but not in males (1.08 [0.98-1.18]; P = 0.137). By contrast, genetically predicted long sleep duration was not significantly associated with the risk of hyperuricemia in either females or males. Conclusion: Genetically predicted short sleep duration is a potential causal risk factor for hyperuricemia for females but has little effect on males. Long sleep duration does not appear to be causally associated with hyperuricemia.

Nighttime sleep duration, restlessness and risk of multimorbidity - A longitudinal study among middle-aged and older adults in China.

PURPOSE: To assess the associations of nighttime sleep duration and restlessness with the risk of multimorbidity in Chinese middle-aged and older adults. METHODS: We used the 2011 and 2015 surveys of the China Health and Retirement Longitudinal Study (CHARLS). Sleep duration was grouped into ≤ 5, (5-6], (6-8], (8-9], and > 9 h/night. Restlessness days in the past week were categorized into < 1, 1-2, 3-4, and 5-7 days/week. Multimorbidity was defined as the co-existence of two or more of 14 chronic conditions (hypertension, dyslipidemia, diabetes mellitus, cancer, chronic lung disease, liver disease, heart problems, stroke, kidney disease, digestive disease, psychiatric problems, memory-related disease, arthritis, and asthma). Log-binomial regression models were used to estimate the associations. RESULTS: A total of 6,037 participants free of multimorbidity at baseline were included. During four-years of follow-up, 2,203 (36.5%) participants developed multimorbidity. Compared to participants who slept 6-8 h/night, those with short sleep duration ≤ 5 h/night and 5-6 h/night were associated with 33.3% (95% CI: 14.8%-54.7%) and 24.2% (95% CI: 5.9%-45.6%) increased risk of multimorbidity, respectively. Long sleep duration was not significantly associated with incident multimorbidity. Compared to those who rarely or never had a restless sleep in the past week, participants with 5-7 days of restless sleep had increased risk of multimorbidity (RR: 1.750, 95% CI: 1.476-2.076). Similar findings were confirmed in subgroups by age, gender, and baseline chronic condition status. CONCLUSIONS: Short nighttime sleep duration and restlessness were associated with increased risk of multimorbidity in China.

The association of nighttime sleep duration and quality with chronic kidney disease in middle-aged and older Chinese: a cohort study.

OBJECTIVE: This cohort study aimed to assess the associations between sleep duration and quality with the risk of incident chronic kidney disease (CKD) in middle-aged and older Chinese. METHODS: We used the 2011 and 2015 surveys of the China Health and Retirement Longitudinal Study (CHARLS). Nighttime sleep duration was categorized into five groups: ≤4, (4-6], (6-8], (8-10], and >10 h/night. Sleep quality was assessed by restless days in the past week (<1, 1-2, 3-4, and 5-7 days/week). Multivariate logistic regression was used to assess the association between sleep duration and quality with incident CKD. RESULTS: A total of 11,339 participants free of CKD at baseline were included in this study. After four years follow-up, the incidence of CKD was 7.8%. There was a "U-shaped" association between sleep duration and risk of CKD. Compared to 6-8 h of nighttime sleep duration, those who slept ≤4 h/night (RR: 1.639, 95% CI: 1.287-2.087) or >10 h/night (RR: 2.342, 95% CI: 1.007-5.451) had increased risk of developing CKD after adjustment for confounders. Participants with 5-7 restless days per week had significantly increased risk of CKD (adjusted RR: 1.686, 95% CI: 1.352-2.102), compared to those who rarely or never had a restless sleep. CONCLUSIONS: Extreme nighttime sleep duration and poor sleep quality were associated with increased risk of CKD in middle-aged and older Chinese. Obtaining an optimal nighttime sleep duration and better sleep quality might reduce the risk of CKD.