Genetic Association between Lipid-Regulating Drug Targets and Diabetic Retinopathy: A Drug Target Mendelian Randomization Study.

Genetic proxy of lipid-lowering drugs and calcific aortic valve stenosis: A Mendelian randomization study

Purpose Diabetic retinopathy (DR) is a common microvascular complication of diabetes. Previous observation studies identified the association between Galectins (Gal) and the risk of DR, but the causal relationship between Gal and the risk of DR is still unclear. This study aimed to explore the causal associations between circulating galectins (Gal) family levels and the risk of diabetic retinopathy (DR) and its phenotypes including proliferative DR (PDR), background DR (BDR), and severe non-proliferative background DR (SNPDR) using two-sample Mendelian randomization (MR) analysis. Methods The single nucleotide polymorphism (SNP) as instrumental variables (IVs) were identified from previous genome-wide association studies (GWAS). Qualified SNPs associated with Gals were selected via strict screening process. The causal association between Gal family levels and the risk of DR was analyzed using MR analysis. The main MR method was Inverse variance weighted (IVW). Causal estimates before and after outlier removal were presented as odds ratio (OR) with 95% confidence interval (CI). Results The results of IVW indicated that Gal-4 levels were causally related to elevated risk of DR (OR = 1.068, 95%CI: 1.006–1.133), and PDR (OR = 1.084, 95%CI: 1.004–1.169). Gal-3 had causal effect on the risk of SNPDR (OR = 1.455, 95%CI: 1.103–1.919). Gal-3 binding protein was causally associated with higher risk of SNPDR (OR = 1.295, 95%CI: 1.014–1.654). In addition, Gal-9 had causal association with decreased risk of SNPDR (OR = 0.669, 95%CI: 0.491–0.911). Leave-one-out analysis depicted that no individual SNP could affect the causal associations of Gal-4 with DR and PDR, Gal-3, Gal-3 binding protein and Gal-9 with SNPDR. Conclusion Gal-4 levels were causally related to elevated risk of DR, and PDR. Gal-3 and Gal-3 binding protein had causal effect on increased risk of SNPDR while Gal-9 had causal effect on decreased risk of SNPDR.

We addressed fundamental questions about the influence of metabolites on the development of Diabetic retinopathy (DR), and explored the related pathological mechanism. Genome-wide association study (GWAS) database data for metabolites and DR were used to perform Mendelian randomization (MR) studies. The inverse variance weighting (IVW) was chosen as the primary analysis method. Sensitivity analysis was conducted using MR-PRESSO, leave-one-out and Cochran’s Q test. Confounding factors were eliminated to ensure robustness. We also conducted metabolic pathway analysis. In vivo experimental validation was conducted using Sprague Dawley rats. The serum metabolites of the DR group rats and normal group rats were examined to evaluate the MR results. The screen identified eighteen metabolites associated with DR risk, twelve of which were known components. Seven metabolites were positively correlated with DR risk, while five could reduce it. Eight metabolites associated with proliferative DR (PDR) risk were identified, four of which are known components. Three of these were positively associated with PDR risk and one metabolite reduced PDR risk. Additionally, two possible metabolic pathways involved in the biological mechanism of DR were identified. The ELISA results showed that the serum levels of isoleucine and 4-HPA were significantly increased in DR rats, while the level of inosine was decreased. This study offers novel insights into the biological mechanisms underlying DR. Metabolites that are causally linked to DR may serve as promising biomarkers and therapeutic targets.

Gut microbiota (GM) homeostasis in the human body is closely associated with health, which can be used as a regulator for preventing the onset and progression of disease. Diabetic microvascular complications bring about not only a huge economic burden to society, but also miserable mental and physical pain. Thus, alteration of the GM may be a method to delay diabetic microvascular complications. A two-sample Mendelian randomization (MR) analysis was conducted to reveal the causal inference between GM and three core diabetic microvascular complications, namely, diabetic kidney disease (DKD), diabetic retinopathy (DR), and diabetic neuropathy (DNP). First, genome-wide association study (GWAS) summary statistics for GM from the MiBioGen consortium and three main diabetic microvascular complications acquired from the FinnGen research project were assessed. Second, a forward MR analysis was conducted to assess the causality of GM on the risk of DKD, DR, and DNP. Third, a series of sensitivity studies, such as heterogeneity tests, pleiotropy evaluations, and leave-one-out analyses, were further conducted to assess the accuracy of MR analysis. Finally, Steiger tests and reverse MR analyses were performed to appraise the possibility of reverse causation. A total of 2,092 single-nucleotide polymorphisms related to 196 bacterial traits were selected as instrumental variables. This two-sample MR analysis provided strongly reasonable evidence that 28 genetically predicted abundance of specific GM that played non-negligible roles in the occurrence of DKD, DR, and DNP complications were causally associated with 23 GM, the odds ratio of which generally ranged from 0.9 to 1.1. Further sensitivity analysis indicated low heterogeneity, low pleiotropy, and high reliability of the causal estimates. The study raised the possibility that GM may be a potential target to prevent and delay the progression of diabetic microvascular complications. Further experiments of GM therapy on diabetic microvascular complications are warranted to clarify their effects and specific mechanisms.

Background Most ocular diseases are associated with lipid metabolism, but the exact mechanisms are unclear. Statins, PCSK9 inhibitors and NPC1L1 inhibitors are common lipid-modulating agents. The aim of this study was to explore the causal relationship between common lipid-lowering drugs and ocular diseases through Mendelian randomization analysis. Methods In this study, we used the summary-data-based Mendelian randomization (SMR) method and inverse-variance-weighted Mendelian randomization (IVW-MR). Low-density lipoprotein cholesterol (LDL-C) was used as a biomarker. We then obtained instrumental variables (IVs) from the Global Lipids Genetics Consortium (GLGC) (n = 173082) and UK Biobank (n = 440546). The 3-Hydroxy-9-methylglutaryl-coenzyme A reductase (HMGCR) expression quantitative trait loci (eQTL) was obtained from a cohort study containing 31,684 blood samples. Summary data for ocular diseases were obtained from the Integrative Epidemiology Unit (IEU) database. Results IVW-MR showed that statins increased the risk of allergic conjunctivitis (OR = 1.96, 95% CI: 1.30–2.95, P = 0.001) and diabetic retinopathy (OR = 2.58, 95% CI: 1.67–3.99, P < 0.001). PCSK9 inhibitors reduced the risk of allergic conjunctivitis (OR = 0.67, 95% CI: 0.47–0.95, P = 0.02) but increased the risk of glaucoma (OR = 1.23, 95% CI: 1.06–1.43, P = 0.006). The SMR approach showed that inhibition of HMGCR significantly elevated the risk of allergic conjunctivitis (OR = 1.28, 95% CI: 1.11–1.45, P < 0.001) and diabetic retinopathy (OR = 1.56, 95% CI: 1.33–1.84, P < 0.001). Conclusion The study found that statin elevated the risk of allergic conjunctivitis and diabetic retinopathy. PCSK9 inhibitors reduced the risk of allergic conjunctivitis but elevated the risk of glaucoma. But more mechanisms remain to be further explored.

IntroductionLipid metabolism is pivotal in diabetic retinopathy (DR) development. Nevertheless, the relationship between lipid-lowering drugs and the risk of DR remains a topic of debate. This study employed Mendelian randomization (MR) to investigate the potential effects of pharmacological lipid-lowering targets on DR and to clarify the causal association between blood lipid characteristics and DR.Material and methodsThe data comprised genetic variations related to lipid traits and genetic variations associated with lipid-lowering drug targets obtained from the Global Lipid Consortium. Total DR, non-proliferative DR (NPDR), and proliferative DR (PDR) were sourced from the Finnish R9 database. Lipid-lowering drug targets were tested using inverse variance-weighted MR (IVW-MR) and statistics-based MR (SMR). Colocalization and mediation analysis were conducted to validate the results and explore potential mediating factors.ResultsA reduced risk of total DR and NPDR was associated with genetically improved 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) (OR = 0.62; 95% CI: 0.46–0.83; p = 1.30 × 10–2; OR = 0.49; 95% CI: 0.34–0.70; p = 9.70 × 10–4). Strong colocalization (PP.H4 = 0.85) was observed between whole blood tissue HMGCR expression and a significant MR relationship with total DR (OR = 0.66; ‌95% CI: 0.52–0.85; p = 7.31 × 10–4). Furthermore, body mass index (BMI) and glycated hemoglobin (HbA1c) are critical factors that mediate the impact of HMGCR and apolipoprotein B (APOB) on DR risk.ConclusionsThis Mendelian randomization study suggests that abnormalities in triglyceride (TG) levels serve as a pathogenic element in DR. Of the nine lipid-lowering drug targets assessed, HMGCR and APOB have emerged as potential promising targets for managing NPDR. These findings underscore the importance of controlling both BMI and HbA1c levels to optimize outcomes in diabetic patients at risk for DR. The therapeutic mechanisms of HMGCR and APOB in DR go beyond lipid lowering alone, and a multimodal lipid-lowering strategy should be selected early and comprehensively to address the patient’s medical conditions.

Associations of genetically determined lipid traits and lipid-modifying agents with the risk of diabetic retinopathy: A Mendelian randomization study

Association between myopia and diabetic retinopathy: A two-sample mendelian randomization study

Background: Previous Mendelian randomization (MR) studies showed an association between hypothyroidism and cataract and between high-normal free thyroxine (FT4) and late age-related macular degeneration (AMD), but not between FT4, thyroid stimulating hormone (TSH), or hyperthyroidism and diabetic retinopathy or cataract. These studies included a limited number of genetic variants for thyroid function and did not investigate autoimmune thyroid disease (AITD) or glaucoma, include bidirectional and multivariable MR (MVMR), and examine sex differences or potential mediation effects of diabetes. We aimed to address this knowledge gap. Methods: We examined the causality and directionality of the associations of AITD, and FT4 and TSH within the reference range with common age-related eye diseases (diabetic retinopathy, cataract, early and late AMD, and primary open-angle glaucoma). We conducted a bidirectional two-sample MR study utilizing publicly available genome-wide association study (GWAS) summary statistics from international consortia (ThyroidOmics, International AMD Genetics Consortium, deCODE, UK Biobank, FinnGen, and DIAGRAM). Bidirectional MR tested directionality, whereas MVMR estimated independent causal effects. Furthermore, we investigated type 1 diabetes (T1D) and type 2 diabetes (T2D) as potential mediators. Results: Genetic predisposition to AITD was associated with increased risk of diabetic retinopathy (p = 3 × 10-4), cataract (p = 3 × 10-3), and T1D (p = 1 × 10-3), but less likely T2D (p = 0.01). MVMR showed attenuated estimates for diabetic retinopathy and cataract when adjusting for T1D, but not T2D. We found pairwise bidirectional associations between AITD, T1D, and diabetic retinopathy. Genetic predisposition to both T1D and T2D increased the risk of diabetic retinopathy and cataract (p < 4 × 10-4). Moreover, genetically predicted higher FT4 within the reference range was associated with an increased risk of late AMD (p = 0.01), particularly in women (p = 7 × 10-3). However, we neither found any association between FT4 and early AMD nor between TSH and early and late AMD. No other associations were observed. Conclusions: Genetic predisposition to AITD is associated with risk of diabetic retinopathy and cataract, mostly mediated through increased T1D risk. Reciprocal associations between AITD, diabetic retinopathy, and T1D imply a shared autoimmune origin. The role of FT4 in AMD and potential sex discrepancies needs further investigation.

Although serum bilirubin levels have been linked to diabetic retinopathy (DR), their causal role remains uncertain. We aimed to assess the relationship between bilirubin levels and diabetic retinopathy (DR) using both observational analyses and Mendelian randomization (MR) to infer causality. The relationship between bilirubin levels and the risk of DR was analyzed using a cross-sectional study design and MR analysis, respectively. Data for the observational study were obtained from the 1999–2018 National Health and Nutrition Examination Survey (NHANES). Logistic regression was used to evaluate the association between bilirubin levels and DR. For MR, genetic instrumental variables (single-nucleotide polymorphisms, SNPs) associated with bilirubin levels and DR were obtained from the IEU Open genome-wide association studies (GWAS) project. The results of the inverse variance weighting (IVW) analysis were the primary results of the MR analysis. Odds ratio (OR) and 95% confidence interval (CI) were used to report results. A total of 8,274 diabetic patients from NHANES were included, of whom 1,242 (13.57%) had DR. Diabetic patients with serum total bilirubin > 10.3 µmol/L (vs. ≤ 10.3 µmol/L) had a lower prevalence of DR (OR = 0.77, 95% CI: 0.62–0.96). This association was observed in males (OR = 0.62, 95% CI: 0.47–0.81), individuals with chronic kidney disease (CKD) (OR = 0.72, 95% CI: 0.56–0.94), those with body mass index (BMI) ≥ 25 kg/m² (OR = 0.79, 95% CI: 0.63–1.00, P = 0.049), and those aged ≥ 65 years (OR = 0.76, 95% CI: 0.59–0.99, P = 0.043). MR analysis showed that genetically higher serum total bilirubin levels were associated with reduced risk of proliferative DR (PDR) [IVW OR = 0.910 (95% CI: 0.831–0.997), P = 0.044], whereas genetically predicted bilirubin was not related to non-proliferative DR (NPDR) (P = 0.893) or any DR (P = 0.481). This study support a potential causal relationship between higher serum total bilirubin levels and lower risk of PDR.

Background Diabetic retinopathy (DR) is a major cause of vision loss, linked to hyperglycemia, oxidative stress, and inflammation. Despite advancements in DR treatments, approximately 40% of patients do not respond effectively, underscoring the need for novel, noninvasive biomarkers to predict DR risk and progression. This study investigates causal relationships between specific biomarkers, dietary factors, and DR development using Mendelian randomization (MR) and cross-sectional data.Methods We conducted a two-phase analysis combining MR and cross-sectional methods. First, MR analysis examined causal associations between 35 biomarkers, 226 dietary factors, and DR progression using data from the UK Biobank and Genome-Wide Association Study (GWAS) datasets. Second, a cross-sectional study with National Health and Nutrition Examination Survey (NHANES) and a clinical cohort from Tianjin Medical University Eye Hospital validated findings and explored biomarkers’ predictive capabilities through a nomogram-based prediction model.Results MR analysis identified eight biomarkers (e.g., glycosylated hemoglobin [HbA1c], high-density lipoprotein cholesterol [HDL-C]) with significant causal links to DR. Inflammatory markers and metabolic factors, such as high glucose and HDL-C levels, were strongly associated with DR risk and progression. Specific dietary factors, like cheese intake, exhibited protective roles, while alcohol intake increased DR risk. Validation within NHANES and Tianjin cohorts supported these causal associations.Conclusion This study elucidates causal relationships between biomarkers, dietary habits, and DR progression, emphasizing the potential for personalized dietary interventions to prevent or manage DR. Findings support the use of HDL-C, HbA1c, and dietary factors as biomarkers or therapeutics in DR, though further studies are needed for broader applicability.

ObjectiveTo investigate the causal link between ametropia and diabetic retinopathy, as well as to offer genetic support for the association between these two conditions.MethodsThis study employed a methodology involving the utilisation of genome-wide association studies data that are publicly accessible. Specifically, single nucleotide polymorphisms (SNPs) that exhibit a strong association with ametropia were employed as instrumental variables, and a two-sample Mendelian randomization (MR) approach was employed to examine the causal relationship between different types of ametropia and diabetic retinopathy. The main findings were derived from the utilisation of inverse variance weighted (IVW), while supplementary results were obtained through the utilisation of MR Egger, weighted median, simple mode and weighted mode. Additionally, a sensitivity analysis was conducted using the ‘leave-one-out’ method. Cochran’s Q statistics were also used to quantify the heterogeneity of SNPs.Results38 SNPs were finally included. The results of the IVW analysis indicate that myopia may exert an inhibitory effect on the development of diabetic retinopathy (OR=0.596, 95% CI (0.371, 0.957), p<0.05). Conversely, hypermetropia (OR=8.882, 95% CI (0.389×10-3, 2.06×105), p>0.05) and astigmatism (OR=1.004, 95% CI (0.888, 1.135), p>0.05) do not exhibit a causal relationship with the risk of diabetic retinopathy.ConclusionThis two-sample Mendelian randomization study provides evidence that myopia may impede diabetic retinopathy occurrence, while hypermetropia and astigmatism show no significant causal effects. However, our analysis treats refractive errors as independent entities, which may not reflect their clinical interdependence. Further investigations are warranted to elucidate myopia’s protective mechanisms.

Our study aims to investigate the causal effects of life course adiposity on diabetic microvascular complications. Life course adiposity was considered as the exposure, including adult body mass index (BMI), childhood BMI, and birth weight, and diabetic microvascular complications were considered as the outcome, including diabetic kidney disease (DKD), diabetic retinopathy (DR), and diabetic neuropathy (DN). We utilized large-scale genome-wide association study datasets of European ancestry to conduct univariable Mendelian randomization and multivariable Mendelian randomization analyses to estimate the independent causal effects of life course adiposity on diabetic microvascular complications. Univariable Mendelian randomization analyses revealed a causal effect of high adiposity in adults and children on an increased risk of DKD, DR, and DN. Similarly, there was a causal effect of low birth weight on an increased risk of DKD and DR, but no causal relationship was found between birth weight and DN. In multivariable Mendelian randomization analyses, the causal effect of adult BMI on DN became nonsignificant, while it remained significant for both DKD and DR (DKD: inverse-variance weighted (IVW) odds ratio (OR) = 1.142, 95% confidence interval (CI) 1.029–1.829, P = .012; DR: IVW OR = 1.108, 95% CI 1.022–1.200, P = .012). Birth weight continued to demonstrate an independent causal effect on both DKD and DR (DKD: IVW OR = 0.583, 95% CI 0.430–0.790, P < .001; DR: IVW OR = 0.614, 95% CI 0.486–0.777, P < .001). Genetically predicted life course adiposity demonstrates a causal relationship with diabetic microvascular complications. Low birth weight and high adult BMI independently increase the risk of developing DKD and DR.

This study aimed to investigate the causal effect of plasma proteins on diabetic retinopathy (DR) risk and identify potential drug targets for this disease. Two-sample Mendelian randomization was performed to explore potential drug targets for DR. A total of 734 proteins were selected as instrumental variables. The Steiger filtering test and colocalization analysis were conducted to determine the causal direction and genetic pleiotropy. Plasma proteins from the decode study were used to validate the findings. Eleven plasma proteins were associated with DR risk. Genetically predicted high levels of CCL3L1 (odds ratio [OR] = 0.582; 95% confidence interval [CI], 0.343-0.986; P = 0.044), PAM (OR = 0.782; 95% CI, 0.652-0.937; P = 0.008), GP1BA (OR = 0.793; 95% CI, 0.632-0.994; P = 0.044), GALNT16 (OR = 0.832; 95% CI, 0.727-0.952; P = 0.008), POGLUT1 (OR = 0.836; 95% CI = 0.703-0.995; P = 0.043), and DKK3 (OR = 0.859; 95% CI, 0.777-0.950; P = 0.003) have the protective effect on DR risk. Genetically predicted high levels of GFRA2 (OR = 1.104; 95% CI, 1.028-1.187; P = 0.007), PATE4 (OR = 1.405; 95% CI, 1.060-1.860; P = 0.018), GSTA1 (OR = 1.464; 95% CI, 1.163-1.842; P = 0.001), SIRPG (OR = 1.600, 95% CI, 1.244-2.057; P = 2.51E-04), and MAPK13 (OR = 1.731; 95% CI, 1.233-2.431; P = 0.002) were associated with an increased risk of DR. However, the colocalization analysis results suggested that SIRPG and GP1BA have a shared causal variant with DR. CCL3L1, PAM, GALNT16, POGLUT1, DKK3, GFRA2, PATE4, GSTA1, and MAPK13 were associated with DR risk and were identified as potential drug targets for DR. The present study has highlighted the role of CCL3L1, PAM, GALNT16, POGLUT1, DKK3, GFRA2, PATE4, GSTA1, and MAPK13 in the development of DR.

BackgroundThe aim of this study was to investigate whether a causal relationship exists between serum uric acid (SUA) and diabetic microvascular complications using a two-sample Mendelian randomization (MR) method.MethodsWe used the MR approach, utilizing genome-wide association study (GWAS) summary statistics, to estimate the causal effect of SUA on diabetic microvascular complications in European individuals. The summary statistical data of SUA were obtained from the open database (IEU OPEN GWAS PROJECT) (p < 5 × 10− 8), and data on diabetic microvascular complications (diabetic nephropathy, diabetic neuropathy, diabetic retinopathy) were obtained from the FinnGen consortium. F-statistics were calculated to assess the correlation between instrumental variables (IVs) and SUA, and single nucleotide polymorphisms (SNPs) associated with confounders or outcomes were excluded by consulting the PhenoScanner database. Inverse variance weighting (IVW) was used for primary estimation, and MR‒Egger, weighted median (WM), and Mendelian randomization pleiotropy residuals sum and outliers (MR-PRESSO) were used for additional assessment. Heterogeneity was assessed using the Cochran’s Q test, and polytropy was assessed using the MR‒Egger intercept.ResultsMR analysis revealed a causal relationship between a genetically predicted increase in SUA and diabetic nephropathy [OR = 1.32, 95%(CI) = 1.07–1.63, p = 0.008]. The results were consistent with those after MR-PRESSO [OR = 1.30, 95%(CI) = 1.07–1.58, p = 0.008]. There was a causal relationship between type 2 diabetes mellitus (T2DM) and renal complication IVW [OR = 1.27, 95%(CI) = 1.00–1.62, p = 0.049]. These results were consistent with those after MR-PRESSO [OR = 1.27, 95%(CI) = 1.00–1.62, p = 0.050]. There was no significant causal relationship between the genetically predicted increase in SUA and diabetic retinopathy [OR 1.09, 95%(CI) = 0.94–1.26, p = 0.249] or diabetic neuropathy [OR = 1.08, 95%(CI) = 0.84–1.40, p = 0.549].ConclusionsThis MR analysis suggests a causal relationship between genetically predicted uric acid increases and diabetic microvascular complications. A significant causal relationship exists between SUA and diabetic nephropathy but not between SUA and diabetic retinopathy or diabetic neuropathy.