Causal associations of antioxidants with Alzheimer's disease and cognitive function: a Mendelian randomisation study.

BACKGROUND: Circulating antioxidants are associated with a lower risk of Alzheimer's disease (AD) in observational studies, suggesting potential target areas for intervention. However, whether the associations are causal remains unclear. Here, we studied the causality between antioxidants and AD or cognitive function using two-sample Mendelian randomisation (MR). METHODS: Single nucleotide polymorphisms strongly (p<5×10-8) associated with antioxidants (vitamin A, vitamin C, zinc, selenium, ß-carotene and urate) and outcomes (AD, cognitive performance and reaction time) were obtained from the largest and most recent genome-wide association studies (GWAS). MR inverse variance weighting (IVW) and MR pleiotropy residual sum and outlier test (MR-PRESSO) were used for data analysis. RESULTS: Higher genetically determined selenium level was associated with 5% higher risk of AD (OR 1.047, 95% CI 1.005 to 1.091, p=0.028) using IVW. Higher genetically determined urate level was associated with worse cognitive performance (ß=-0.026, 95% CI -0.044 to -0.008, p=0.005) using MR-PRESSO. No association between the other antioxidants and AD, cognitive performance and reaction time was found. Similar results were found in the sensitivity analyses. CONCLUSION: Our results suggest that lifelong exposure to higher selenium may be associated with a higher risk of AD, and higher urate levels could be associated with worse cognitive performance. Further analyses using larger GWAS of antioxidants are warranted to confirm these observations. Our results suggest that caution is needed in the interpretation of traditional observational evidence on the neuroprotective effects of antioxidants.

Causal associations between polyunsaturated fatty acids and kidney function: A bidirectional Mendelian randomization study.

BACKGROUND: PUFAs were suggested to be beneficial for kidney function in observational studies. However, whether these associations are causal remains unclear. OBJECTIVES: This study explores the causality between PUFAs and chronic kidney disease (CKD) or estimated glomerular filtration rate (eGFR) using bidirectional 2-sample Mendelian randomization (MR). METHODS: Single nucleotide polymorphisms associated with PUFAs and kidney function were obtained from the largest and most recent genome-wide association studies with sample sizes of 13,544, 13,506, 13,499, 13,527, and 13,549 for omega-3 fatty acids, omega-6 fatty acids, DHA, LA, and other PUFAs than 18:2 (otPUFA), and 480,698 and 1,201,909 for CKD and eGFR, respectively. MR inverse-variance weighted (IVW) and pleiotropy residual sum and outlier test (MR-PRESSO) were used for data analysis, supplemented with a weighted median estimator, MR-Egger regression, and multivariable MR, giving ß or OR and their 95% CIs. RESULTS: There was suggestive evidence that higher omega-6 fatty acids were associated with increased eGFR using MR-PRESSO [ß: 0.005 log(mL/min/1.73 m2) per SD increase in omega-6 fatty acids; 95% CI: 0.002, 0.008; P = 0.008]. Higher LA level was also associated with higher eGFR [ß: 0.005 log(mL/min/1.73 m2) per SD increase in LA; 95% CI: 0.003, 0.007; P = 0.0007] using MR-PRESSO. Neither association of the other PUFAs, i.e., omega-3 fatty acids, DHA, and otPUFA, with CKD or eGFR nor the association of CKD and eGFR with PUFAs was found. Similar results were found in sensitivity analyses. CONCLUSIONS: Our results suggest that higher omega-6 fatty acids and LA may increase eGFR levels. Although the estimated effects were relatively small, the results provide public health and research relevance, indicating the need for further longitudinal cohorts or randomized controlled trials on omega-6 fatty acids in improving kidney function.

Plasma polyunsaturated fatty acid concentrations and sleep apnea risk: A two-sample Mendelian randomization study.

Background: Previous observational studies have found that lower levels of circulating polyunsaturated fatty acids (PUFAs) were associated with a higher risk of sleep apnea (SA). However, the causality of the association remains unclear. Materials and methods: We used the two-sample Mendelian randomization (MR) study to assess the causal association of omega-3 and omega-6 fatty acids with SA. Single-nucleotide polymorphisms (SNPs) predicting the plasma level of PUFAs at the suggestive genome-wide significance level (p < 5 × 10-6) were selected as instrumental variables (IVs) from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) (n = ∼8,000) Consortium. For outcomes, the summary-level statistics of SA were obtained from the latest genome-wide association study (GWAS), which combined five cohorts with a total number of 25,008 SA cases and 172,050 snoring cases (total = 523,366). Results: We found no association of α-linolenic acid (ALA) [odds ratio (OR) = 1.09 per% changed, 95% confidence interval (CI) 0.67-1.78], eicosapentaenoic acid (EPA) (OR = 0.94, 95% CI 0.88-1.01), docosapentaenoic acid (DPA) (OR = 0.95, 95% CI 0.88-1.02), and docosahexaenoic acid (DHA) (OR = 0.99, 95% CI 0.96-1.02) with the risk of SA using inverse-variance weighted (IVW) method. Moreover, for omega-6 PUFAs, no association between linoleic acid (LA) (OR = 0.98, 95% CI 0.96-1.01), arachidonic acid (AA) (1.00, 95% CI 0.99-1.01), and adrenic acid (AdrA) (0.93, 95% CI 0.71-1.21) with the risk of SA was found. Similarly, no associations of PUFAs with SA were found in single-locus MR analysis. Conclusion: In the current study, we first found that there is no genetic evidence to support the causal role of omega-3 and omega-6 PUFAs in the risk of SA. From a public health perspective, our findings refute the notion that consumption of foods rich in PUFAs or the use of PUFAs supplementation can reduce the risk of SA.

Mortality in relation to changes in physical activity in middle-aged to older Chinese: An 8-year follow-up of the Guangzhou Biobank Cohort Study.

BACKGROUND: Physical activity (PA) is generally encouraged. Studies from developed countries in the West have shown that maintenance of adequate PA or increasing PA are associated with lower mortality risk. It is unclear whether these associations apply to an older Chinese population. Hence, we examined the changes in PA prospectively among a middle-aged and older Chinese population over an average of 4 years and explored their subsequent mortality risks. METHODS: Metabolic equivalent scores of PA among participants in the Guangzhou Biobank Cohort Study were calculated. Participants were divided into 3 groups related to PA level, and changes in PA were classified into 9 categories. Information on vital status and causes of death from March 2008 to December 2012 (the first repeated examination) until December 31, 2017, was obtained via record linkage with the Death Registry. RESULTS: Of 18,104 participants aged 61.21 ± 6.85 years (mean ± SD), 1461 deaths occurred within 141,417 person-years. Compared to participants who maintained moderate PA, those who decreased PA from moderate or high levels to a low level had increased risks for all-cause mortality (hazard ratio (HR) = 1.47, 95% confidence interval (95%CI): 1.11-1.96). Participants who maintained a high level of PA (HR = 0.83, 95%CI: 0.70-0.98) or increased PA from low to high levels (HR = 0.71, 95%CI: 0.52-0.97) showed lower all-cause mortality risks. Those who maintained low PA levels showed a higher all-cause mortality risk, whereas those who increased their PA levels showed a non-significantly lower risk. Similar results were found for cardiovascular disease risk. CONCLUSION: Even at an older age, maintaining a high PA level or increasing PA from low to high levels results in lower mortality risks, suggesting that substantial health benefits might be achieved by maintaining or increasing engagement in adequate levels of PA. The increased risk of maintaining a low PA level or decreasing PA to a low level warrants the attention of public health officials and clinicians.