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Mendelian randomization analysis reveals a causal effect of Streptococcus salivarius on diabetic retinopathy through regulating host fasting glucose.

ABSTRACT: Diabetic retinopathy (DR) is one of leading causes of vision loss in adults with increasing prevalence worldwide. Increasing evidence has emphasized the importance of gut microbiome in the aetiology and development of DR. However, the causal relationship between gut microbes and DR remains largely unknown. To investigate the causal associations of DR with gut microbes and DR risk factors, we employed two-sample Mendelian Randomization (MR) analyses to estimate the causal effects of 207 gut microbes on DR outcomes. Inputs for MR included Genome-wide Association Study (GWAS) summary statistics of 207 taxa of gut microbes (the Dutch Microbiome Project) and 21 risk factors for DR. The GWAS summary statistics data of DR was from the FinnGen Research Project. Data analysis was performed in May 2023. We identified eight bacterial taxa that exhibited significant causal associations with DR (FDR < 0.05). Among them, genus Collinsella and species Collinsella aerofaciens were associated with increased risk of DR, while the species Bacteroides faecis, Burkholderiales bacterium_1_1_47, Ruminococcus torques, Streptococcus salivarius, genus Burkholderiales_noname and family Burkholderiales_noname showed protective effects against DR. Notably, we found that the causal effect of species Streptococcus salivarius on DR was mediated through the level of host fasting glucose, a well-established risk factor for DR. Our results reveal that specific gut microbes may be causally linked to DR via mediating host metabolic risk factors, highlighting potential novel therapeutic or preventive targets for DR.

SUBMITTER: Li J

PROVIDER: S-EPMC10951888 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Mendelian randomization analysis reveals a causal effect of Streptococcus salivarius on diabetic retinopathy through regulating host fasting glucose.

Li Jingjing J Zheng Gongwei G Jiang Dingping D Deng Chunyu C Zhang Yaru Y Ma Yunlong Y Su Jianzhong J

Journal of cellular and molecular medicine 20240401 7

Diabetic retinopathy (DR) is one of leading causes of vision loss in adults with increasing prevalence worldwide. Increasing evidence has emphasized the importance of gut microbiome in the aetiology and development of DR. However, the causal relationship between gut microbes and DR remains largely unknown. To investigate the causal associations of DR with gut microbes and DR risk factors, we employed two-sample Mendelian Randomization (MR) analyses to estimate the causal effects of 207 gut micro ...[more]

PMID: 38506069

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Project description:BackgroundResearch indicates that there may be an association between plasma lipidome levels and the incidence of diabetic retinopathy (DR) in patients. However, the potential causality of this relationship is yet to be determined. To investigate this matter further, we employed a two-sample Mendelian randomization (MR) analysis to comprehensively assess the causality between lipidome levels and DR.MethodsSummary statistics for lipid levels and DR were obtained from the Genome-Wide Association Studies (GWAS) Catalog database and the FinnGen Consortium, respectively. We conducted a two-sample MR analysis, and statistical analysis were performed using the inverse variance weighted (IVW) with the addition of the MR-Egger, weighted median (WM), constrained maximum likelihood and model averaging (cML-MA) to test for causal associations between lipid levels and DR. Heterogeneity was checked using Cochran's Q statistic. The MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) global test and the MR-Egger regression were used to detect horizontal pleiotropy. The robustness of our findings was assessed using leave-one-out and funnel plots. To further assess the reliability of the results, linkage disequilibrium score regressions, colocalization analysis and reverse MR analysis were also performed.ResultsAnalysis of the pooled MR results and after correction for the false discovery rate (FDR) revealed that five lipid levels were associated with DR risk. Phosphatidylcholine (16:0_16:0) levels [OR = 0.869 (0.810 to 0.933), Pfdr = 0.006], phosphatidylcholine (16:0_20:2) levels [OR = 0.893 (0.834 to 0.956), Pfdr = 0.043] and phosphatidylethanolamine (18:0_20:4) levels [OR = 0.906 (0.863 to 0.951), Pfdr = 0.006] were protective against DR, whereas sphingomyelin (d36:1) levels [OR = 1.120 (1.061 to 1.183), Pfdr = 0.006], and sphingomyelin (d40:1) levels [OR = 1.081 (1.031 to 1.134), Pfdr = 0.043] were associated with a greater risk of DR. Further sensitivity analysis did not reveal heterogeneity or horizontal pleiotropy.ConclusionIn summary, genetic evidence suggests a causal relationship between the levels of specific lipid levels and DR. These findings may provide valuable insights into the causal relationships between lipid levels and DR, potentially informing future prevention and treatment strategies.

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: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:BackgroundPrevious research has indicated a vital association between hypertension, intraocular pressure (IOP), and diabetic retinopathy (DR); however, the relationship has not been elucidated. In this study, we aim to investigate the causal association of hypertension, IOP, and DR.MethodsThe genome-wide association study (GWAS) IDs for DR, hypertension, and IOP were identified from the Integrative Epidemiology Unit (IEU) Open GWAS database. There were 33,519,037 single-nucleotide polymorphisms (SNPs) and a sample size of 1,030,836 for DR. There were 16,380,466 SNPs and 218,754 participants in the hypertension experiment. There were 9,851,867 SNPs and a sample size of 97,465 for IOP. Univariable, multivariable, and bidirectional Mendelian randomization (MR) studies were conducted to estimate the risk of hypertension and IOP in DR. Moreover, causality was examined using the inverse variance weighted method, and MR results were verified by numerous sensitivity analyses.ResultsA total of 62 SNPs at the genome-wide significance level were selected as instrumental variables (IVs) for hypertension-DR. The results of univariable MR analysis suggested a causal relationship between hypertension and DR and regarded hypertension as a risk factor for DR [p = 0.006, odds ratio (OR) = 1.080]. A total of 95 SNPs at the genome-wide significance level were selected as IVs for IOP-DR. Similarly, IOP was causally associated with DR and was a risk factor for DR (p = 0.029, OR = 1.090). The results of reverse MR analysis showed that DR was a risk factor for hypertension (p = 1.27×10-10, OR = 1.119), but there was no causal relationship between DR and IOP (p > 0.05). The results of multivariate MR analysis revealed that hypertension and IOP were risk factors for DR, which exhibited higher risk scores (p = 0.001, OR = 1.121 and p = 0.030, OR = 1.124, respectively) than those in univariable MR analysis. Therefore, hypertension remained a risk factor for DR after excluding the interference of IOP, and IOP was still a risk factor for DR after excluding the interference of hypertension.ConclusionThis study validated the potential causal relationship between hypertension, IOP, and DR using MR analysis, providing a reference for the targeted prevention of DR.

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Mendelian randomization analysis reveals a causal effect of Streptococcus salivarius on diabetic retinopathy through regulating host fasting glucose.

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Mendelian randomization analysis reveals a causal effect of Streptococcus salivarius on diabetic retinopathy through regulating host fasting glucose.

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