Association of the endothelial nitric oxide synthase (eNOS) 4a/b polymorphism with the risk of incident diabetic retinopathy in patients with type 2 diabetes mellitus: a systematic review and updated meta-analysis

To conduct a systematic review and updated meta-analysis on the potential association between endothelial nitric oxide synthase (eNOS) 4a/b polymorphism and the risk of developing diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM) and to identify possible clinical biomarkers for early screening of DR. A meta-analysis based on case-control or cross-sectional studies was conducted to examine the correlation between eNOS 4a/b polymorphism and DR. Pooled odds ratio (OR) and 95% confidence interval (CI) were used to estimate the association strength. We included 19 studies, covering 7838 subjects. An association was observed in Caucasians (allelic model: OR = 1.273, 95% CI: 1.006–1.610, p = .045; recessive model: OR = 0.575, 95% CI: 0.371–0.892, p = .014; dominant model: OR = 1.268, 95% CI: 1.052–1.528, p = .013; homozygote model: OR = 1.833, 95% CI: 1.176–2.856, p = .007). Moreover, population-based studies have indicated an association between eNOS 4a/b polymorphism and DR susceptibility. The present study showed that intron 4a allele of eNOS 4a/b is a risk factor for DR in Caucasians with T2DM. Thus, eNOS 4a/b may be used as a biomarker for the early screening and diagnosis of DR in Caucasian T2DM patients.Key messagesEndothelial nitric oxide synthase 4a/b gene polymorphism is not associated with the risk of developing diabetic retinopathy in the overall population, Asians, or Chinese Han patients with type 2 diabetes. However, 4a is a risk factor for the development of diabetic retinopathy in Caucasians.Endothelial nitric oxide synthase 4a/b gene polymorphism is not associated with the type of diabetic retinopathy. Endothelial nitric oxide synthase 4a/b gene polymorphism is not associated with the risk of developing diabetic retinopathy in the overall population, Asians, or Chinese Han patients with type 2 diabetes. However, 4a is a risk factor for the development of diabetic retinopathy in Caucasians. Endothelial nitric oxide synthase 4a/b gene polymorphism is not associated with the type of diabetic retinopathy.</p

S1 File -

BackgroundObservational studies suggest physical activity (PA) enhances intelligence, while sedentary behavior (SB) poses a risk. However, causality remains unclear.MethodsWe extracted genetic instruments from large genome-wide association studies summary data and employed an inverse-variance weighted (IVW) approach within a random-effects model as the primary method of Mendelian randomization (MR) analysis to estimate the overall effect of various physical activity statuses on intelligence. To assess IVW stability and MR sensitivity, we also utilized supplementary methods including weighted median, MR-Egger, and MR-PRESSO. Furthermore, multivariable MR analysis was conducted to examine the independent effects of each physical activity trait on intelligence.ResultsThe MR primary results indicated that LST was negatively associated with intelligence (β = -0.133, 95%CI: -0.177 to -0.090, p = 1.34×10–9), while SBW (β = 0.261, 95% CI: 0.059 to 0.463, p = 0.011) may have a positive effect on intelligence; however, MVPA and SC did not show significant effects on intelligence. Inverse causality analyses demonstrated intelligence significantly influenced all physical activity states.ConclusionsOur study highlights a bidirectional causal relationship between physical activity states and intelligence.</div

Overview of the study design in this bidirectional MR study.

A. Eight MR analysis to investigate the bidirectional association between PAS and intelligence. B. The three key assumptions of MR analysis. C. Sketch of the study design. MR: Mendelian randomization. PAS: Physical activity status; LST: Leisure screen time; MVPA: Moderate-to-vigorous intensity physical activity during leisure time; SC: Sedentary commuting; SBW: Sedentary behavior at work; SNP: Single nucleotide polymorphism.</p

DataSheet_1_Smoking and BMI mediate the causal effect of education on lower back pain: observational and Mendelian randomization analyses.docx

ObjectiveLow back pain (LBP) has been associated with education in previous observational studies, but the causality remains unclear. This study aims to assess the impact of education on LBP and to explore mediation by multiple lifestyle factors.DesignUnivariable Mendelian randomization (MR) was performed to examine the overall effect of education on LBP. Subsequently, multivariable MR was conducted to assess both the direct effect of education on LBP and the influence of potential mediators. Indirect effects were estimated using either the coefficient product method or the difference method, and the proportion of mediation was calculated by dividing the indirect effect by the total effect. The observational study utilized data from the NHANES database collected between 1999 and 2004, and included 15,580 participants aged 20 years and above.ResultsIncreasing education by 4.2 years leads to a 48% reduction in the risk of LBP (OR=0.52; 95% CI: 0.46 to 0.59). Compared to individuals with less than a high school education, those with education beyond high school have a 28% lower risk of LBP (OR=0.72; 95% CI: 0.63 to 0.83). In the MR study, smoking accounts for 12.8% (95% CI: 1.04% to 20.8%) of the total effect, while BMI accounts for 5.9% (95% CI: 2.99% to 8.55%). The combined mediation effect of smoking and BMI is 27.6% (95% CI: 23.99% to 32.7%). In the NHANES study, only smoking exhibits a mediating effect, accounting for 34.3% (95% CI: 21.07% to 41.65%) of the effect, while BMI does not demonstrate a mediating role.ConclusionsHigher levels of education provide a protective effect against the risk of LBP. Additionally, implementing interventions to reduce smoking and promote weight loss among individuals with lower levels of education can also decrease this risk.</p

Results of Mendelian randomization analysis of intelligence on PAS.

Results of Mendelian randomization analysis of intelligence on PAS.</p

Causal effects for PAS on intelligence.

Total effect represents the results of IVW analysis and the independent effect stands for that of multivariable MR analysis. PAS, Physical activity status; LST, Leisure screen time; MVPA, Moderate-to-vigorous intensity physical activity during leisure time; SC, Sedentary commuting; SBW, Sedentary behavior at work; IVW, Inverse variance weighted.</p

Flow chart of SNPs screening.

SNP: Single nucleotide polymorphism; PAS: Physical activity status; LST: Leisure screen time; MVPA: Moderate-to-vigorous intensity physical activity during leisure time; SC: Sedentary commuting; SBW: Sedentary behavior at work; LD: Linkage disequilibrium.</p

Results of Mendelian randomization analysis of PAS on intelligence.

Results of Mendelian randomization analysis of PAS on intelligence.</p

Causal effects for intelligence on PAS.

PAS, Physical activity status; LST, Leisure screen time; MVPA, Moderate-to-vigorous intensity physical activity during leisure time; SC, Sedentary commuting; SBW, Sedentary behavior at work; IVW, Inverse variance weighted; OR, Odds ratios.</p

S2 File -

BackgroundObservational studies suggest physical activity (PA) enhances intelligence, while sedentary behavior (SB) poses a risk. However, causality remains unclear.MethodsWe extracted genetic instruments from large genome-wide association studies summary data and employed an inverse-variance weighted (IVW) approach within a random-effects model as the primary method of Mendelian randomization (MR) analysis to estimate the overall effect of various physical activity statuses on intelligence. To assess IVW stability and MR sensitivity, we also utilized supplementary methods including weighted median, MR-Egger, and MR-PRESSO. Furthermore, multivariable MR analysis was conducted to examine the independent effects of each physical activity trait on intelligence.ResultsThe MR primary results indicated that LST was negatively associated with intelligence (β = -0.133, 95%CI: -0.177 to -0.090, p = 1.34×10–9), while SBW (β = 0.261, 95% CI: 0.059 to 0.463, p = 0.011) may have a positive effect on intelligence; however, MVPA and SC did not show significant effects on intelligence. Inverse causality analyses demonstrated intelligence significantly influenced all physical activity states.ConclusionsOur study highlights a bidirectional causal relationship between physical activity states and intelligence.</div