Dataset Information

Correlation between diabetic retinopathy and diabetic nephropathy: a two-sample Mendelian randomization study.

ABSTRACT:

Rationale & objective

A causal relationship concerning diabetic retinopathy (DR) and diabetic nephropathy (DN) has been studied in many epidemiological observational studies. We conducted a two-sample mendelian randomization study from the perspective of genetics to assess these associations.

Methods

20 independent single nucleotide polymorphisms (SNPs) associated with diabetic retinopathy were selected from the FinnGen consortium. Summary-level data for diabetic nephropathy were obtained from the publicly available genome-wide association studies (GWAS) database, FinnGen and CKDGen consortium. Inverse variance weighted (IVW) was selected as the primary analysis. MR-Egger, weighted median (WM), simple mode and weighted mode were used as complementary methods to examine causality. Additionally, sensitivity analyses including Cochran's Q test, MR-Egger, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO), and leave-one-out analyses were conducted to guarantee the accuracy and robustness of our MR analysis.

Results

Our current study demonstrated positive associations of genetically predicted diabetic retinopathy with diabetic nephropathy (OR=1.32; P=3.72E-11), type 1 diabetes with renal complications (OR=1.96; P= 7.11E-11), and type 2 diabetes with renal complications (OR=1.26, P=3.58E-04). Further subtype analysis and multivariate mendelian randomization (MVMR) also reached the same conclusion. A significant casualty with DN was demonstrated both in non-proliferative DR (OR=1.07, P=0.000396) and proliferative DR (OR=1.67, P=3.699068E-14). All the findings were robust across several sensitivity analyses.

Conclusion

Consistent with previous clinical studies, our findings revealed a positive correlation between DR and DN, providing genetic evidence for the non-invasive nature of DR in predicting DN.

SUBMITTER: Fang J

PROVIDER: S-EPMC10646564 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Correlation between diabetic retinopathy and diabetic nephropathy: a two-sample Mendelian randomization study.

Fang Jiaxi J Luo Chuxuan C Zhang Di D He Qiang Q Liu Lin L

Frontiers in endocrinology 20231101

<h4>Rationale & objective</h4>A causal relationship concerning diabetic retinopathy (DR) and diabetic nephropathy (DN) has been studied in many epidemiological observational studies. We conducted a two-sample mendelian randomization study from the perspective of genetics to assess these associations.<h4>Methods</h4>20 independent single nucleotide polymorphisms (SNPs) associated with diabetic retinopathy were selected from the FinnGen consortium. Summary-level data for diabetic nephropathy were ...[more]

PMID: 38027162

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Project description:ObjectiveThe association between myopia and diabetic retinopathy (DR) is unclear, with inconsistent results reported, and whether the association represents causality remains unknown. This study aimed to investigate the causal associations of genetically determined myopia with DR, and further explore specific mechanisms.MethodsWe conducted two-sample mendelian randomization (MR) analyses of any myopia and high myopia on six DR phenotypes, including any DR, background DR, severe background DR, proliferative DR (PDR), diabetic maculopathy and unspecific DR in the primary study. Mechanism exploration of spherical equivalent refraction (SER), corneal curvature (CC) and axial length (AL) on any DR was carried out subsequently. Single-nucleotide polymorphisms (SNPs), used as genetic instruments, were derived from UK Biobank, Genetic Epidemiology Research on Adult Health and Aging cohort (GERA) and FinnGen. The inverse variance weighted (IVW) method was mainly used to assess the causality, and was complemented with sensitivity analyses and causality direction analyses.ResultsUsing SNPs that have excluded possible confounders, we discovered suggestive and positive causal associations of any myopia with any DR (IVW: odds ratio [OR] = 1.133, 95% confidence interval [95%CI]: 1.070-1.201, P = 1.91×10-5) and PDR (IVW: OR = 1.182, 95% CI: 1.088-1.285, P = 8.31×10-5). Similar but more significant associations were found of high myopia with any DR and PDR (IVW: OR = 1.107, 95%CI: 1.051-1.166, P = 1.39×10-4; OR = 1.163, 95%CI: 1.088-1.244, P = 8.76×10-6, respectively). Further mechanism analyses found only AL, rather than SER or CC, was strongly and significantly associated with any DR. These associations were robust in sensitivity analyses and causality direction analyses.ConclusionsWe found significant and positive causal associations of any myopia and high myopia with the risk of DR and PDR, which might be related with AL, indicating the significance of myopia control for preventing DR development and progression.

Project description:ObjectiveTo explore the causal relationship between cystatin C levels and different stages of diabetic retinopathy through Mendelian randomization (MR).MethodsThe MRC Integrative Epidemiology Unit provided the Genome-wide association studies (GWAS) data related to cystatin C (exposure). GWAS data for outcomes [DR, proliferative diabetic retinopathy (PDR), severe non-proliferative background diabetic retinopathy (SNPBDR)] were sourced from the FinnGen. Adopted Inverse Variance Weighting (IVW), MR-Egger regression MR-PRESSO, Weighted Median, Constrained Maximum Likelihood and Model Averaging (cML-MA), Weighted model, Radial MR, and MR-Lasso to estimate the causal relationship between cystatin C and diabetic retinopathy. We conducted multivariable MR analysis to evaluate the independent causal effects of cystatin C levels on diabetic retinopathy.ResultsBased on the IVW method, we observed a causal relationship between cystatin C and diabetic retinopathy [odds ratio (OR)random effect = 1.137, 95% confidence interval (CI): 1.035-1.250]/PDR (ORrandom effect = 1.123, 95%CI: 1.004-1.255)/SNPBDR (ORfixed effect = 2.002, 95%CI: 1.343-2.986). Consistent findings were obtained through the cML-MA method. Cochran's Q test suggested the presence of heterogeneity between the cystatin C level and instrumental variables in relation to diabetic retinopathy and proliferative diabetic retinopathy, respectively. After adjusting for outliers using MR-PRESSO and Radial MR, it was observed that the statistical significance of the association between cystatin C level and diabetic retinopathy persists. Reverse MR analysis indicated that genetically related SNPBDR may influence the cystatin C level. In multivariable MR analysis, there were indications suggesting a causal relationship of cystatin C with the risk of DR/PDR/SNPBDR adjusting for confounders.ConclusionsThis study utilizes Mendelian randomization analyses to establish a causal relationship between cystatin C and diabetic retinopathy, and reveals the impact of cystatin C on the risk of diabetic retinopathy, thus providing new evidence for clinical intervention of diabetic retinopathy.

Project description:ObjectivesTo assess the association between thyroid dysfunction and diabetic retinopathy (DR), a two-sample bidirectional Mendelian randomization (MR) study utilizing the Genome-wide Association Study (GWAS) database was conducted to investigate the causal relationship between these two variables.MethodsIn this study, GWAS of 48,328,151 single nucleotide polymorphisms(SNP) in the European population from the IEU open GWAS database were utilized as genetic tools for investigating thyroid dysfunction. The total sample size for the study on hyperthyroidism was 460,499 (case group: 3557; control group: 456,942). The total sample size for hypothyroidism was 410,141 (case group: 30,155; control group: 37,986). In addition, the data on DR were extracted from the FinnGen Biobank, comprising a total sample size of 319,046 individuals (10,413 cases and 308,633 controls). For the forward MR analysis, hyperthyroidism and hypothyroidism were considered as exposures with DR as the outcome. Reverse MR analysis was conducted using DR as exposure and hyperthyroidism and hypothyroidism as outcomes.MethodsThe main analytical approach employed inverse variance weighting(IVW), supplemented by MR-Egger, Weighted mode method, weighted median, and Simple mode. Cochran's Q test, MR-PRESSO, MR-Egger and leave-one-out analysis were used to evaluate the sensitivity and pleiotropy.ResultsTwo-sample bidirectional MR analysis revealed a significant association between the presence of hyperthyroidism and hypothyroidism and an increased risk of DR in the forward MR analysis (IVW: OR = 1.29, 95% [CI] = 1.12-1.49, P < 0.001; OR = 1.17, 95% CI = 1.10-1.25, P < 0.001). In the reverse MR analysis, DR was found to be associated with an elevated risk of developing hyperthyroidism and hypothyroidism (IVW: OR = 1.56, 95% CI 1.38-1.76, P < 0.001; OR = 1.41, 95% CI 1.25-1.59, P < 0.001). Furthermore, most supplementary MR methods also demonstrated statistically significant differences and exhibited effect sizes consistent with those obtained from IVW. The sensitivity analysis confirmed the relative reliability of our causal findings.ConclusionsOur findings provide genetic evidence supporting a bidirectional causal relationship between thyroid function and DR.

Project description:ObjectiveEmerging evidence has provided compelling evidence linking gut microbiota (GM) and diabetic nephropathy (DN) via the "gut-kidney" axis. But the causal relationship between them hasn't been clarified yet. We perform a Two-Sample Mendelian randomization (MR) analysis to reveal the causal connection with GM and the development of DN, type 1 diabetes nephropathy (T1DN), type 2 diabetes nephropathy (T2DN), type 1 diabetes mellitus (T1DM), and type 2 diabetes mellitus (T2DM).MethodsWe used summary data from MiBioGen on 211 GM taxa in 18340 participants. Generalized MR analysis methods were conducted to estimate their causality on risk of DN, T1DN, T2DN, T1DM and T2DM from FinnGen. To ensure the reliability of the findings, a comprehensive set of sensitivity analyses were conducted to confirm the resilience and consistency of the results.ResultsIt was showed that Class Verrucomicrobiae [odds ratio (OR) =1.5651, 95%CI:1.1810-2.0742,PFDR=0.0018], Order Verrucomicrobiales (OR=1.5651, 95%CI: 1.1810-2.0742, PFDR=0.0018) and Family Verrucomicrobiaceae (OR=1.3956, 95%CI:1.0336-1.8844, PFDR=0.0296) had significant risk of DN. Our analysis found significant associations between GM and T2DN, including Class Verrucomimicrobiae (OR=1.8227, 95% CI: 1.2414-2.6763, PFDR=0.0139), Order Verrucomimicrobiae (OR=1.5651, 95% CI: 1.8227-2.6764, PFDR=0.0024), Rhodospirillales (OR=1.8226, 95% CI: 1.2412-2.6763, PFDR=0.0026), and Family Verrucomicroniaceae (OR=1.8226, 95% CI: 1.2412-2.6763, PFDR=0.0083). The Eubacteriumprotogenes (OR=0.4076, 95% CI: 0.2415-0.6882, PFDR=0.0021) exhibited a protection against T1DN. Sensitivity analyses confirmed that there was no significant heterogeneity and pleiotropy.ConclusionsAt the gene prediction level, we identified the specific GM that is causally linked to DN in both T1DM and T2DM patients. Moreover, we identified distinct microbial changes in T1DN that differed from those seen in T2DN, offering valuable insights into GM signatures associated with subtype of nephropathy.

Project description:Diabetic retinopathy (DR) is the most frequent microvascular complication of diabetes mellitus, however, its underlying biological mechanisms remain poorly understood. We examined single nucleotide polymorphisms linked to 486 blood metabolites through extensive genome-wide association studies conducted on individuals of European ancestry. The FinnGen Biobank database served as a reference to define DR. Two-sample MR analysis was conducted to reveal the association between the levels of genetically predicted circulating metabolites and the susceptibility to DR. To validate the robustness of the obtained findings, sensitivity analyses with weighted median, weighted mode, and MR-Egger were conducted. 1-oleoylglycerophosphoethanolamine (odds ratio [OR] (OR per one standard deviation [SD] increase) = 0.414; 95% confidence interval [CI] 0.292-0.587; P = 7.613E-07, PFDR = 6.849E-06), pyroglutamine (OR per one SD increase = 0.414; 95% confidence interval [CI] 0.292-0.587; P = 8.31E-04, PFDR = 0.007), phenyllactate (PLA) (OR per one SD increase = 0.591; 95% confidence interval [CI] 0.418-0.836; P = 0.003, PFDR = 0.026), metoprolol acid metabolite (OR per one SD increase = 0.978; 95% confidence interval [CI] 0.962-0.993; P = 0.005, PFDR = 0.042), 10-undecenoate (OR per one SD increase = 0.788; 95% confidence interval [CI] 0.667-0.932; P = 0.005, PFDR = 0.049), erythritol (OR per one SD increase = 0.691; 95% confidence interval [CI] 0.513-0.932; P = 0.015, PFDR = 0.034), 1-stearoylglycerophosphoethanolamine (OR per one SD increase = 0.636; 95% confidence interval [CI] 0.431-0.937; P = 0.022, PFDR = 0.099), 1-arachidonoylglycerophosphoethanolamine (OR per one SD increase = 0.636; 95% confidence interval [CI] 0.431-0.937; P = 0.030, PFDR = 0.099) showed a significant causal relationship with DR and could have protective effects. stachydrine (OR per one SD increase = 1.146; 95% confidence interval [CI] 1.066-1.233; P = 2.270E-04, PFDR = 0.002), butyrylcarnitine (OR per one SD increase = 1.117; 95% confidence interval [CI] 1.023-1.219; P = 0.014, PFDR = 0.062), 5-oxoproline (OR per one SD increase = 1.569; 95% confidence interval [CI] 1.056-2.335; P = 0.026, PFDR = 0.082), and kynurenine (OR = 1.623; 95% CI 1.042-2.526; P = 0.041, PFDR = 0.097) were significantly associated with an increased risk of DR. This study identified metabolites have the potential to be considered prospective compounds for investigating the underlying mechanisms of DR and for selecting appropriate drug targets.

Project description:BackgroundThe causal effect of obesity on diabetic retinopathy (DR) remains controversial. The aim of this study was to assess the causal association of generalized obesity evaluated by body mass index (BMI) and abdominal obesity evaluated by waist or hip circumference with DR, background DR, and proliferative DR using a two-sample Mendelian randomization (MR) analysis.MethodsGenetic variants associated with obesity at the genome-wide significance (P<5×10-8) level were derived using GWAS summary statistics from the UK Biobank (UKB) with a sample size of 461 460 individuals for BMI, 462 166 individuals for waist circumference, and 462 117 individuals for hip circumference. We obtained genetic predictors of DR (14 584 cases and 202 082 controls), background DR (2026 cases and 204 208 controls), and proliferative DR (8681 cases and 204 208 controls) from FinnGen. Univariable and multivariable Mendelian randomization analyses were conducted. Inverse variance weighted (IVW) was the main method used to analyze causality, accompanied by several sensitivity MR analyses.ResultsGenetically predicted increased BMI [OR=1.239; 95% CI=(1.134, 1.353);P=1.94×10-06], waist circumference [OR=1.402; 95% CI=(1.242, 1.584); P=5.12×10-08], and hip circumference [OR=1.107; 95% CI=(1.003, 1.221); P=0.042] were associated with increased risk of DR. BMI [OR=1.625; 95% CI=(1.285, 2.057); P=5.24×10-05], waist circumference [OR=2.085; 95% CI=(1.54, 2.823); P=2.01×10-06], and hip circumference [OR=1.394; 95% CI=(1.085, 1.791); P=0.009] were correlated with the risk of background DR. MR analysis also supported a causal association between BMI [OR=1.401; 95% CI=(1.247, 1.575); P=1.46×10-08], waist circumference [OR=1.696; 95% CI=(1.455, 1.977); P=1.47×10-11], and hip circumference [OR=1.221; 95% CI=(1.076, 1.385); P=0.002] and proliferative DR. The association of obesity with DR continued to be significant after adjustment for type 2 diabetes.ConclusionThis study using two-sample MR analysis indicated that generalized obesity and abdominal obesity might increase the risk of any DR. These results suggested that controlling obesity may be effective in DR development.

Project description:ObjectivePrevious observational studies have indicated associations between various immune cells and diabetic nephropathy (DN). However, the causality remains unclear. We aimed to further evaluate the causal association between immune cells and DN using bidirectional two-sample Mendelian randomization (MR) analysis.MethodThe DN data were retrieved from the IEU OpenGWAS Project database, while the data for 731 immune cells were sourced from GWAS summary statistics by Orru ̀ et al. The investigation into the causal relationship between immune cells and DN employed the inverse variance weighted (IVW), weighted median (WME), and MR-Egger methods. The stability and reliability of the findings underwent evaluation through Cochran's Q test, MR-Egger intercept's P-value, MR-PRESSO, and Leave-One-Out (LOO) method.ResultThe IVW estimates suggested a positive causal effect of CD25 on IgD-CD38dim B cell, CD25 on naive-mature B cell, CD127 on granulocyte, SSC-A on HLA DR + Natural Killer, HLA DR on plasmacytoid Dendritic Cell, and HLA DR on Dendritic Cell on DN. Conversely, the abundance of Myeloid Dendritic Cell, CD62L- Dendritic Cell %Dendritic Cell, CD86+ myeloid Dendritic Cell %Dendritic Cell, CD14- CD16-, CX3CR1 on CD14- CD16-, and SSC-A on CD4+ T cell had negative causal effects on DN. However, after correcting the P value for significant causality results using the FDR method, it was concluded that only Myeloid Dendritic Cells had a causal relationship with DN (FDR-p = 0.041), while the other immune cells showed no significant association with DN, so their relationship was suggestive. The results were stable with no observed horizontal pleiotropy and heterogeneity. Reverse MR analysis indicated no causal relationship between DN and the increased risk of positively identified immune cells.ConclusionThis study provides an initial insight into the genetic perspective of the causal relationship between immune cells and DN. It establishes a crucial theoretical foundation for future endeavors in precision medicine and individualized treatment.

Dataset Information

Correlation between diabetic retinopathy and diabetic nephropathy: a two-sample Mendelian randomization study.

Rationale & objective

Methods

Results

Conclusion

Publications

Correlation between diabetic retinopathy and diabetic nephropathy: a two-sample Mendelian randomization study.

Similar Datasets

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