Background: The microbiota composition is now considered as one of the main modifiable risk factors for health. No controlled study has been performed on the association between microbiota composition and renal function. We applied Mendelian randomization (MR) to estimate the casual impact of eight microbiota genera on renal function and the risk of chronic kidney disease (CKD). Methods: MR was implemented by using summary-level data from the largest-ever genome-wide association studies (GWAS) conducted on microbiota genera, CKD and renal function parameters. The inverse-variance weighted method (IVW), weighted median (WM)-based method, MR-Egger, MR-Robust Adjusted Profile Score (RAPS), MR-Pleiotropy RESidual Sum and Outlier (PRESSO) were applied. A sensitivity analysis was conducted using the leave-one-out method. Results: The Anaerostipes genus was associated with higher estimated glomerular filtration rate (eGFR) in the overall population (IVW: β = 0.003, p = 0.021) and non-diabetes mellitus (DM) subgroup (IVW: β = 0.003, p = 0.033), while it had a non-significant association with the risk of CKD and eGFR in DM patients. Subjects with higher abundance of Desulfovibrio spp. had a significantly lower level of eGFR (IVW: β = −0.001, p = 0.035); the same results were observed in non-DM (IVW: β = −0.001, p = 0.007) subjects. Acidaminococcus, Bacteroides, Bifidobacterium, Faecalibacterium, Lactobacillus and Megamonas had no significant association with eGFR in the overall population, DM and non-DM subgroups (IVW: p > 0.105 for all groups); they also presented no significant association with the risk of CKD (IVW: p > 0.201 for all groups). Analyses of MR-PRESSO did not highlight any outlier. The pleiotropy test, with very negligible intercept and insignificant p-value, also indicated no chance of pleiotropy for all estimations. The leave-one-out method demonstrated that the observed links were not driven by single single-nucleotide polymorphism. Conclusions: Our results suggest an adverse association of Desulfovibrio spp. and a beneficial association of Anaerostipes spp. with eGFR. Further studies using multiple robust instruments are needed to confirm these results.

Background/Aim: Several observational studies evaluated the links between serum monounsaturated fatty acids (MUFAs) and cardiovascular events with controversial results. In the present study, Mendelian randomization (MR) analysis was applied to obtain unconfounded estimates of the causal associations of genetically determined serum MUFAs with coronary heart disease (CHD), myocardial infarction (MI), cardioembolic stroke (CS), and ischemic stroke (IS). Methods: Four MUFAs were studied (i.e., 10-heptadecenoate, myristoleic, oleic, and palmitoleic acid). Data from the largest genome-wide association studies on MUFAs, CHD, MI, and stroke were analyzed. Inverse variance weighted method (IVW), weighted median (WM)-based method, MR-Egger, as well as MR-pleiotropy residual sum and outlier were applied. To rule out the impact of single-nucleotide polymorphism (SNP), the leave-one-out method was also performed. Results: Genetically higher-serum 10-heptadecenoate levels did not affect the risk of CHD (IVW = Beta: −0.304, p = 0.185), MI (IVW = Beta: −0.505, p = 0.066), CS (IVW = Beta: −0.056, p = 0.945), and IS (IVW = Beta: −0.121, p = 0.767). Similarly, no significant associations were observed for myristoleic acid (CHD: IVW = Beta: 0.008; MI: IVW = Beta: 0.041; CS: IVW = Beta: 0.881; IS: IVW = Beta: 0.162), oleic acid (CHD: IVW = Beta: −0.2417; MI: IVW = Beta: −0.119; CS: IVW = Beta: 1.059; IS: IVW = Beta: 0.008491), and palmitoleic acid (CHD: IVW = Beta: −0.06957; MI: IVW = Beta: −0.01255; CS: IVW = Beta: 1.042; IS: IVW = Beta: −0.1862). A low likelihood of heterogeneity and pleiotropy was reported, and the observed associations were not driven by single SNPs. Conclusions: In the present MR analysis, serum MUFA levels were not associated with the risk of CHD, MI, CS, and IS. Further research, evaluating more MUFAs, is required to elucidate the links between MUFAs and CVD to contribute to health policy decisions in reducing CVD risk.

IntroductionThe relationship between inflammatory and anti-inflammato�ry markers and telomere length (TL), a biological index of aging, is still poor�ly understood. By applying a 2-sample Mendelian randomization (MR), we investigated the causal associations between adiponectin, bilirubin, C-reac�tive protein (CRP), leptin, and serum uric acid (SUA) with TL.Material and methodsMR was implemented by using summary-level data from the largest ever genome-wide association studies (GWAS) conducted on our interested exposure and TL. Inverse variance weighted method (IVW), weighted median (WM)-based method, MR-Egger, MR-Robust Adjusted Pro�file Score (RAPS), and MR-Pleiotropy RESidual Sum and Outlier (PRESSO) were applied. Sensitivity analysis was conducted using the leave-one-out method.ResultsWith regard to adiponectin, CRP, leptin, and SUA levels, we found no effect on TL for all 4 types of tests (all p > 0.108). Results of the MR-Egger (p = 0.892) and IVW (p = 0.124) showed that bilirubin had no effect on telomere maintenance, whereas the results of the WM (p = 0.030) and RAPS (p = 0.022) were negative, with higher bilirubin concentrations linked to shorter TL. There was a low likelihood of heterogeneity for all the estima�tions, except for bilirubin (IVW p = 0.026, MR Egger p = 0.018). MR-PRESSO highlighted no outlier. For all the estimations, we observed negligible inter�cepts that were indicative of low likelihood of the pleiotropy (all p > 0.161). The results of leave-one-out method demonstrated that the links are not driven because of single nucleotide polymorphisms (SNPs).ConclusionsOur results highlight that neither the anti-inflammatory nor pro-inflammatory markers tested have any significant causal effect on TL. The casual role of bilirubin on TL still needs to be investigated.

IntroductionThe impact of low-density lipoprotein cholesterol (LDL-C) on the risk of different types of strokes is unclear. Therefore, we systematically evaluated the impact of LDL-C levels (cohort studies) and lipid lowering drugs (LLAs, randomized controlled trials) on the different types of stroke.Material and methodsPubMed, SCOPUS, Web of Science and Google Scholar were searched up to 1st December 2019.ResultsParticipants at highest category of LDL-C had a lower risk for of hemorrhagic stroke (RR: 0.91, 95%CI 0.85-0.98, I2:0%) compared with the lowest category of LDL-C. Subjects with the highest category of LDL-C had a higher risk of ischemic stroke (RR: 1.11, 95%CI 1.07-1.14, I2:0%) compared to the lowest LDL-C category. LLAs decreased the risk of all types of strokes for those who achieved LDL-C<1.8 mmol/L (<70 mg/dL; RR=0.88, 95% CI 0.80-0.96, absolute risk reduction [ARR]: 0.7 %, number needed to treat (NNT): 143, I2:53%, n=13). Statin therapy decreased the risk of all strokes (RR=0.88, 95% CI 0.80-0.97, ARR: 0.6 %, NNT: 167, I2:56%). With regard to ischemic stroke only, LLAs decreased the risk of ischemic stroke for those who achieved LDL-C <1.8 mmol/L (<70 mg/dL; RR=0.75, 95%CI:0.67-0.83, ARR: 1.3%, NNT: 77, I2:0%); the same was observed for statins (RR= 0.76, 95%CI:0.69-0.84, ARR: 1.3%, NNT: 77, I2:32%). TSA indicated that both benefit boundaries and optimal sample size was reached.ConclusionsOur study sheds light on the debatable association between low LDL-C and different type of strokes. This information can help determine the optimal LDL-C range for stroke prevention, and help plan future LLAs studies.

Background Omega-6 polyunsaturated fatty acids (PUFAs) represent almost 15% of the total energy intake in the Western countries. Their effects on several cardiovascular (CV) risk factors are still controversial. Purpose We performed a systematic review and meta-analysis of randomized control trials (RCTs) as well as a Mendelian randomization (MR) analysis to evaluate the links (or possible causality) between supplementation or serum levels of omega-6 PUFA, CV disease (CVD) and cardiometabolic risk factors. Methods Selected databases were searched until 31 August 2019 to identify prospective studies investigating the effects of omega-6 PUFAs supplementation on CVD events/mortality. Random-effects model meta-analysis was performed for quantitative data synthesis. Trial sequential analysis (TSA) was used to evaluate the optimal sample size to detect a 20% reduction in outcomes after administration of omega-6 PUFAs. Inverse variance weighted method (IVW), weighted median-based method, MR-Egger and MR-Pleiotropy RESidual Sum and Outlier (PRESSO) were applied for MR. Results In the meta-analysis of 9 studies with 4,433 participants we showed that omega-6 PUFAs supplementation was not associated with CVD event risk - RR 0.94 (95% CI: 0.77–1.15, heterogeneity p=0.031; I2=66.2%, n=4 studies). The pooled estimate (RR) of the effect of omega-6 PUFAs supplementation on CVD death was 1.06 (95% C:I 0.73–1.55, heterogeneity p=0.011; I2=66.2%, n=6 studies), on CHD events 0.84 (95% CI: 0.61–1.16, heterogeneity p=0.001; I2=79.4%), on MI 0.87 (95% CI: 0.74–1.01, heterogeneity p=0.381; I2=2.3%) (Figure), and on stroke 1.36 (95% CI: 0.45–4.07, heterogeneity p=0.082; I2=55.3%). In MR analysis we showed that individuals with genetically higher serum adrenic acid (AA; 22:4, n-6) levels had a greater risk of CHD events (IVW=Beta: 0.526, p=0.007), MI (IVW=Beta: 0.606, p=0.017) and stroke (IVW=Beta: 1.694, p=0.009), as well as higher levels of FBG (IVW=Beta: 0.417, p=1.0x10–3), LDL-C (IVW=Beta: 0.806, p=4.9x10–5), HDL-C (IVW=Beta: −0.820, p=4.3x10–17), whereas lower levels of TG (IVW=Beta: −1.064, p=1.2x10–12) and TC (IVW=Beta: −1.064, p=1.2x10–12). Conclusions In the pooled analysis different omega-6 PUFAs supplementation did not affect the risk of MI, stroke and CHD event/mortality or the serum concentration of cardiometabolic parameters (data not presented), however in MR analysis, higher AA levels significantly associated with the risk of CHD, MI and stroke, as well as with elevated levels of FBG, LDL-C and HDL-C and reduced levels of TC and TG. There is probably lack of class effect for omega-6 PUFAs, therefore further studies are needed to assess the effects of omega-6 PUFAs on cardiometabolic outcomes. Funding Acknowledgement Type of funding source: None