Dataset Information

Exposing the Causal Effect of C-Reactive Protein on the Risk of Type 2 Diabetes Mellitus: A Mendelian Randomization Study.

ABSTRACT: As a biomarker of inflammation, C-reactive protein (CRP) has attracted much attention due to its role in the incidence of type 2 diabetes mellitus (T2DM). Prospective studies have observed a positive correlation between the level of serum CRP and the incidence of T2DM. Recently, studies have reported that drugs for curing T2DM can also decrease the level of serum CRP. However, it is not yet clear whether high CRP levels cause T2DM. To evaluate this, we conducted a Mendelian randomization (MR) analysis using genetic variations as instrumental variables (IVs). Significantly associated single nucleotide polymorphisms (SNPs) of CRP were obtained from a genome-wide study and a replication study. Therein, 17,967 participants were utilized for the genome-wide association study (GWAS), and another 14,747 participants were utilized for the replication of identifying SNPs associated with CRP levels. The associations between SNPs and T2DM were from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium. After removing SNPs in linkage disequilibrium (LD) and T2DM-related SNPs, the four remaining CRP-related SNPs were deemed as IVs. To evaluate the pooled influence of these IVs on the risk of developing T2DM through CRP, the penalized robust inverse-variance weighted (IVW) method was carried out. The combined result (OR 1.114048; 95% CI 1.058656 to 1.172338; P = 0.024) showed that high levels of CRP significantly increase the risk of T2DM. In the subsequent analysis of the relationship between CRP and type 1 diabetes mellitus (T1DM), the pooled result (OR 1.017145; 95% CI 0.9066489 to 1.14225; P = 0.909) supported that CRP levels cannot determine the risk of developing T1DM.

SUBMITTER: Cheng L

PROVIDER: S-EPMC6306438 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Exposing the Causal Effect of C-Reactive Protein on the Risk of Type 2 Diabetes Mellitus: A Mendelian Randomization Study.

Cheng Liang L Zhuang He H Yang Shuo S Jiang Huijie H Wang Song S Zhang Jun J

Frontiers in genetics 20181220

As a biomarker of inflammation, C-reactive protein (CRP) has attracted much attention due to its role in the incidence of type 2 diabetes mellitus (T2DM). Prospective studies have observed a positive correlation between the level of serum CRP and the incidence of T2DM. Recently, studies have reported that drugs for curing T2DM can also decrease the level of serum CRP. However, it is not yet clear whether high CRP levels cause T2DM. To evaluate this, we conducted a Mendelian randomization (MR) an ...[more]

PMID: 30619477

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Project description:BackgroundThe presence of type 1 diabetes mellitus (T1DM) has been demonstrated to pose an increased risk for developing cardiovascular diseases (CVDs). However, the causal relationships between T1DM and CVDs remain unclear due to the uncontrolled confounding factors and reverse causation bias of the observational studies.MethodsSummary statistics of T1DM and seven CVDs from the largest available genome-wide association studies (GWAS) of European ancestry and FinnGen biobank were extracted for the primary MR analysis, and the analysis was replicated using UK biobank (UKBB) for validation. Three complementary methods: inverse variance weighted (IVW), weighted median, and MR-Egger were used for the MR estimates. The potential pleiotropic effects were assessed by MR-Egger intercept and MR-PRESSO global test. Additionally, multivariable MR (MVMR) analysis was performed to examine whether T1DM has independent effects on CVDs with adjustment of potential confounding factors. Moreover, a two-step MR approach was used to assess the potential mediating effects of these factors on the causal effects between T1DM and CVDs.ResultsCausal effects of T1DM on peripheral atherosclerosis (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 1.02-1.10; p = 0.002)] and coronary atherosclerosis (OR = 1.03, 95% CI: 1.01-1.05; p = 0.001) were found. The results were less likely to be biased by the horizontal pleiotropic effects (both p values of MR-Egger intercept and MR-PRESSO Global test > 0.05). In the following MVMR analysis, we found the causal effects of T1DM on peripheral atherosclerosis and coronary atherosclerosis remain significant after adjusting for a series of potential confounding factors. Moreover, we found that hypertension partly mediated the causal effects of T1DM on peripheral atherosclerosis (proportion of mediation effect in total effect: 11.47%, 95% CI: 3.23-19.71%) and coronary atherosclerosis (16.84%, 95% CI: 5.35-28.33%). We didn't find significant causal relationships between T1DM and other CVDs, including heart failure (HF), coronary artery disease (CAD), atrial fibrillation (AF), myocardial infarction (MI) and stroke. For the reverse MR from CVD to T1DM, no significant causal relationships were identified.ConclusionThis MR study provided evidence supporting the causal effect of T1DM on peripheral atherosclerosis and coronary atherosclerosis, with hypertension partly mediating this effect.

Project description:ObjectiveExtensive literature put forward the link between sleep and type 2 diabetes mellitus (T2DM), however, little is known about the underlying causality of the associations. Here we aim to assess the causal relationships between five major sleep-related traits and T2DM.Design setting and participantsTwo-sample Mendelian randomization (MR) was utilized to investigate the potential causal relations. Independent genetic variants associated with five sleep-related phenotypes-insomnia, sleep duration, short sleep duration, long sleep duration, and morningness-were chosen as instrumental variables to estimate the causal associations with T2DM. Summary statistics were acquired from the genome-wide association studies of UK Biobank and 23andMe (for sleep-related measures), the DIAbetes Genetics Replication And Meta-analysis and the FinnGen (for T2DM).Main methodsIndividual Cochran's Q statistic was applied to remove the pleiotropic instruments, global Q statistics and MR-Egger regression were adopted to test for the global heterogeneity and horizontal pleiotropy of the screened instruments, respectively. Two T2DM cohorts were selected to analyze their associations with sleep traits. A modified inverse variance weighted (IVW) estimate was performed to combine the ratio estimators from each instrument and acquire the causal estimate, alternative methods including IVW with first-order weights, simple and weighted median estimations, and MR-Egger regression were conducted as sensitivity analyses, to ensure the robustness and solidity of the findings.ResultsTwo-sample MR supported findings for an adverse effect of genetically predicted insomnia on T2DM risk (odds ratio [OR] = 1.14, 95% confidence interval [CI]: 1.09-1.19, p = 1.29E-08) at the Bonferroni-adjusted level of significance (p < 0.005). We further investigated the causal role of T2DM on insomnia but obtained a non-significant estimation. There was also little evidence for the causal effect of other sleep-related measures on T2DM. Results were largely consistent when leveraging two different T2DM cohorts, and were robust among various sensitivity analyses.ConclusionFindings provide significant evidence for an adverse effect of insomnia on T2DM risk. The study extends fundamental knowledge to further understanding of the pathophysiological mechanisms of T2DM, and points out the non-negligible role of insomnia on epidemiologic intervention and clinical therapeutics of T2DM.

Project description:Background and purposeThe relationship between type 2 diabetes mellitus (T2D) and cerebral small vessel disease (CSVD) is unclear. We aimed to examine the causal effect of T2D, fasting glucose levels, and higher insulin resistance on CSVD using Mendelian randomization.MethodsFive CSVD phenotypes were studied; 2 were clinical outcomes associated with CSVD (lacunar stroke: n=2191/27 297 and intracerebral hemorrhage [ICH]: n=2254/8195 [deep and lobar ICH]), whereas 3 were radiological markers of CSVD (white matter hyperintensities: n=8429; fractional anisotropy [FA]: n=8357; and mean diffusivity: n=8357). We applied 2 complementary analyses to evaluate the association of T2D with CSVD. First, we used summarized data from genome-wide association study to calculate the effects of T2D-related variants on CSVD with inverse-variance weighted and weighted median approaches. Second, we performed a genetic risk score approach to test the effects of T2D-associated variants on white matter hyperintensities, FA, and mean diffusivity using individual-level data in UK Biobank.ResultsT2D was associated with higher risk of lacunar stroke (odds ratio [OR], 1.15; 95% confidence interval [CI], 1.04-1.28; P=0.007) and lower mean FA (OR, 0.78; 95% CI, 0.66-0.92; P=0.004) but not white matter hyperintensities volume (OR, 1.01; 95% CI, 0.97-1.04; P=0.626), higher mean diffusivity (OR, 1.04; 95% CI, 0.89-1.23; P=0.612), ICH (OR, 1.07; 95% CI, 0.95-1.20; P=0.269), lobar ICH (OR, 1.07; 95% CI, 0.89-1.28; P=0.466), or deep ICH (OR, 1.16; 95% CI, 0.99-1.36; P=0.074). Weighted median and penalized median weighted analysis showed similar effect estimates of T2D on lacunar stroke and FA, but with wider CIs, meaning they were not significant. The genetic score on individual-level data was significantly associated with FA (OR, 0.63; 95% CI, 0.45-0.89; P=0.008) after adjusting for potential confounders.ConclusionsOur Mendelian randomization study provides evidence to suggest that T2D may be causally associated with CSVD, in particular with lacunar stroke and FA.

Dataset Information

Exposing the Causal Effect of C-Reactive Protein on the Risk of Type 2 Diabetes Mellitus: A Mendelian Randomization Study.

Publications

Exposing the Causal Effect of C-Reactive Protein on the Risk of Type 2 Diabetes Mellitus: A Mendelian Randomization Study.

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