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Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study.

ABSTRACT: Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.

SUBMITTER: Sobrin L

PROVIDER: S-EPMC5697951 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study.

Sobrin Lucia L Chong Yong He YH Fan Qiao Q Gan Alfred A Stanwyck Lynn K LK Kaidonis Georgia G Craig Jamie E JE Kim Jihye J Liao Wen-Ling WL Huang Yu-Chuen YC Lee Wen-Jane WJ Hung Yi-Jen YJ Guo Xiuqing X Hai Yang Y Ipp Eli E Pollack Samuela S Hancock Heather H Price Alkes A Penman Alan A Mitchell Paul P Liew Gerald G Smith Albert V AV Gudnason Vilmundur V Tan Gavin G Klein Barbara E K BEK Kuo Jane J Li Xiaohui X Christiansen Mark W MW Psaty Bruce M BM Sandow Kevin K Jensen Richard A RA Klein Ronald R Cotch Mary Frances MF Wang Jie Jin JJ Jia Yucheng Y Chen Ching J CJ Chen Yii-Der Ida YI Rotter Jerome I JI Tsai Fuu-Jen FJ Hanis Craig L CL Burdon Kathryn P KP Wong Tien Yin TY Cheng Ching-Yu CY

Diabetes 20170926 12

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (<i>N</i> = 2,969 case and 4,096 control subjects) and severe DR (<i>N</i> = 1,277 case and 3,980 control subjects). Previously identified lipid-associated ...[more]

PMID: 28951389

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Project description:The causal effects of plasma lipid levels and the risk of retinal vascular occlusion (RVO) have not been clearly identified, especially for high-density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C). Here, we try to identify these causal risk factors using a two-sample Mendelian randomization (MR) analysis. Single nucleotide polymorphisms (SNPs) were chosen as instrumental variables (IVs). We obtained genetic variants associated with lipid exposure at the genome-wide significance (P<5×10−8) level from a meta-analysis of GWAS from the Global Lipids Genetics Consortium (GLGC) based on 188,577 individuals of mostly European ancestry for MR analyses. Meanwhile, we used lipid GWAS from UK Biobank (UKB) with a sample size of 115,078 individuals as a supplement. We obtained genetic predictors of RVO from a FinnGen biobank study. We conducted both univariable and multivariable MR (MVMR) analyses to identify the causal effects of RVO. Although inverse variance weighted (IVW) was the primary method used for MR analyses, MR–Egger and weighted-median methods were used as supplements to IVW. We determined the heterogeneity of IVs using Cochrane’s Q test and I2, and used the MR–Egger intercept and MR-PRESSO Global test to detect horizontal pleiotropy. A leave-one-out sensitivity analysis was conducted by removing a single variant from the analysis. Genetically predicted increased HDL-C level was associated with decreased risk of RVO from GLGC [OR=0.806; 95% CI=(0.659, 0.986); P=0.036], which was consistent with UKB results [OR=0.766; 95% CI=(0.635, 0.925); P=0.005]. MVMR analysis for plasma lipids [adjusted OR=0.639; 95% CI=(0.411, 0.992); P=0.046] or diabetes [adjusted OR=0.81; 95% CI=(0.67, 0.979); P=0.029] suggested that low HDL-C may be an independent risk factor for RVO. However, there was no evidence to support a causal association between LDL-C {GLGC [adjusted OR=1.015; 95% CI=(0.408, 2.523); P=0.975], UKB [OR=1.115; 95% CI=(0.884, 1.407); P=0.359]}, total cholesterol {GLGC [adjusted OR=0.904; 95% CI=(0.307, 2.659); P=0.854], UKB [OR=1.047; 95% CI=(0.816, 1.344); P=0.716]} or triglycerides {GLGC [OR=1.103; 95% CI=(0.883, 1.378); P=0.385], UKB [OR=1.003; 95% CI=(0.827, 1.217); P=0.098]} and RVO. Using two-sample MR analysis, our study suggested that dyslipidemia was a risk factor for RVO. Furthermore, our results indicated that a low HDL-C level may be an independent risk factor for RVO, suggesting that controlling HDL-C level may be effective in RVO development.

Project description:Background: Positive associations between inflammatory biomarkers and the risk of heart failure (HF) have been reported in conventional observational studies. However, the causal effects of inflammatory biomarkers on HF have not been fully elucidated. We conducted a Mendelian randomization (MR) study to examine the possible etiological roles of inflammatory biomarkers in HF. Methods: Summary statistical data for the associations between single nucleotide polymorphisms (SNPs) and C-reactive protein (CRP), fibrinogen, and components of the interleukin-1 (IL-1)-interleukin-6 (IL-6) inflammatory signaling pathway, namely, interleukin-1β (IL-1β), IL-1 receptor antagonist (IL-1ra), IL-6, and soluble IL-6 receptor (sIL-6r), were obtained from genome-wide association studies (GWASs) for individuals of European descent. The GWAS dataset of 977,323 participants of European ancestry, which included 47,309 HF cases and 930,014 controls, was collected to identify genetic variants underlying HF. A two-sample Mendelian randomization framework was implemented to examine the causality of the association between these inflammatory biomarkers and HF. Results: Our MR analyses found that genetically determined CRP and fibrinogen were not causally associated with HF risk (odds ratio [OR] = 0.93, 95% confidence interval [CI] = 0.84-1.02, p = 0.15; OR = 0.94, 95% CI = 0.55-1.58, p = 0.80, respectively). These findings remained consistent using different Mendelian randomization methods and in sensitivity analyses. For the IL-1-IL-6 pathway, causal estimates for IL-6 (OR = 0.86, 95% CI 0.81-0.91, p < 0.001), but not for IL-1β, IL-1ra, or sIL-6r, were significant. However, the association between genetically determined IL-6 and HF risk became non-significant after excluding SNPs with potential pleiotropy (OR = 0.89, 95% CI = 0.77-1.03, p = 0.12). Conclusion: Our study did not identify convincing evidence to support that CRP and fibrinogen, together with their upstream IL-1-IL-6 signaling pathway, were causally associated with HF risk.

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Dataset Information

Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study.

Publications

Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study.

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