scholarly journals Low Plasma Adiponectin in Risk of Type 2 Diabetes: Observational Analysis and One- and Two-Sample Mendelian Randomization Analyses in 756,219 Individuals

Diabetes ◽  
2021 ◽  
pp. db210131
Author(s):  
Maria B. Nielsen ◽  
Yunus Çolak ◽  
Marianne Benn ◽  
Børge G. Nordestgaard
Keyword(s):  
Type 2 Diabetes ◽  
Mendelian Randomization ◽  
Plasma Adiponectin ◽  
Observational Analysis

Low plasma adiponectin in risk of type 2 diabetes: Observational and Mendelian randomization analyses

2021 ◽  
Vol 331 ◽  
pp. e45-e46
Author(s):  
M.B. Nielsen ◽  
B.G. Nordestgaard ◽  
M. Benn ◽  
Y. Colak
Keyword(s):  
Type 2 Diabetes ◽  
Mendelian Randomization ◽  
Plasma Adiponectin

scholarly journals Low plasma adiponectin in risk of type 2 diabetes: observational analysis and one- and two-sample Mendelian randomization analyses in 756,219 individuals

2021 ◽  
Author(s):  
Maria B. Nielsen ◽  
Yunus Çolak ◽  
Marianne Benn ◽  
Børge G. Nordestgaard
Keyword(s):  
Type 2 Diabetes ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Lower Plasma ◽  
Plasma Adiponectin ◽  
Hazard Ratios ◽  
Increased Risk ◽  
Median Plasma ◽  
Risk Ratios

<p>We tested the hypothesis that low plasma adiponectin is observationally and genetic, causally associated with increased risk of type 2 diabetes. Observational analyses are prone to confounding and reverse causation, while genetic Mendelian randomization analyses are much less influenced by these biases. We examined 30,045 Copenhagen individuals observationally (1,751 type 2 diabetes; plasma adiponectin), 96,903 Copenhagen individuals using <a>one-sample Mendelian randomization </a>(5,012 type 2 diabetes; five genetic variants), and 659,316 Europeans (ADIPOGen, GERA, DIAGRAM, UK Biobank) using two-sample Mendelian randomization (62,892 type 2 diabetes; ten genetic variants). Observationally, and compared to individuals with median plasma adiponectin of 28.9µg/mL(4th quartile), multivariable adjusted hazard ratios for type 2 diabetes were 1.42(95% CI:1.18-1.72) for 19.2µg/mL(3rd quartile), 2.21(1.84-2.66) for 13.9µg/mL(2nd quartile), and 4.05(3.38-4.86) for 9.2µg/mL(1st quartile). Corresponding cumulative incidences for type 2 diabetes at age 70 were 3%, 7%, 11%, and 20%, respectively.<b> </b>A 1µg/mL lower plasma adiponectin conferred a hazard ratio for type 2 diabetes of 1.07(1.06-1.09), while genetic, causal risk ratios per 1 unit log-transformed lower plasma adiponectin were 1.13(0.83-1.53) in one-sample Mendelian randomization and 1.26(1.01-1.57) in two-sample Mendelian randomization. <a>In conclusion, </a>low plasma adiponectin is associated with increased risk of type 2 diabetes, an association that could represent a causal relationship.</p>

scholarly journals Low plasma adiponectin in risk of type 2 diabetes: observational analysis and one- and two-sample Mendelian randomization analyses in 756,219 individuals

2021 ◽  
Author(s):  
Maria B. Nielsen ◽  
Yunus Çolak ◽  
Marianne Benn ◽  
Børge G. Nordestgaard
Keyword(s):  
Type 2 Diabetes ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Lower Plasma ◽  
Plasma Adiponectin ◽  
Hazard Ratios ◽  
Increased Risk ◽  
Median Plasma ◽  
Risk Ratios

<p>We tested the hypothesis that low plasma adiponectin is observationally and genetic, causally associated with increased risk of type 2 diabetes. Observational analyses are prone to confounding and reverse causation, while genetic Mendelian randomization analyses are much less influenced by these biases. We examined 30,045 Copenhagen individuals observationally (1,751 type 2 diabetes; plasma adiponectin), 96,903 Copenhagen individuals using <a>one-sample Mendelian randomization </a>(5,012 type 2 diabetes; five genetic variants), and 659,316 Europeans (ADIPOGen, GERA, DIAGRAM, UK Biobank) using two-sample Mendelian randomization (62,892 type 2 diabetes; ten genetic variants). Observationally, and compared to individuals with median plasma adiponectin of 28.9µg/mL(4th quartile), multivariable adjusted hazard ratios for type 2 diabetes were 1.42(95% CI:1.18-1.72) for 19.2µg/mL(3rd quartile), 2.21(1.84-2.66) for 13.9µg/mL(2nd quartile), and 4.05(3.38-4.86) for 9.2µg/mL(1st quartile). Corresponding cumulative incidences for type 2 diabetes at age 70 were 3%, 7%, 11%, and 20%, respectively.<b> </b>A 1µg/mL lower plasma adiponectin conferred a hazard ratio for type 2 diabetes of 1.07(1.06-1.09), while genetic, causal risk ratios per 1 unit log-transformed lower plasma adiponectin were 1.13(0.83-1.53) in one-sample Mendelian randomization and 1.26(1.01-1.57) in two-sample Mendelian randomization. <a>In conclusion, </a>low plasma adiponectin is associated with increased risk of type 2 diabetes, an association that could represent a causal relationship.</p>

scholarly journals A comprehensive evaluation of methods for Mendelian randomization using realistic simulations and an analysis of 38 biomarkers for risk of type 2 diabetes

2021 ◽  
Author(s):  
Guanghao Qi ◽  
Nilanjan Chatterjee
Keyword(s):  
Type 2 Diabetes ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Real Data ◽  
Causal Effects ◽  
Type I ◽  
Genome Wide Association Studies ◽  
Simulation Studies ◽  
Sample Sizes

Abstract Background Previous studies have often evaluated methods for Mendelian randomization (MR) analysis based on simulations that do not adequately reflect the data-generating mechanisms in genome-wide association studies (GWAS) and there are often discrepancies in the performance of MR methods in simulations and real data sets. Methods We use a simulation framework that generates data on full GWAS for two traits under a realistic model for effect-size distribution coherent with the heritability, co-heritability and polygenicity typically observed for complex traits. We further use recent data generated from GWAS of 38 biomarkers in the UK Biobank and performed down sampling to investigate trends in estimates of causal effects of these biomarkers on the risk of type 2 diabetes (T2D). Results Simulation studies show that weighted mode and MRMix are the only two methods that maintain the correct type I error rate in a diverse set of scenarios. Between the two methods, MRMix tends to be more powerful for larger GWAS whereas the opposite is true for smaller sample sizes. Among the other methods, random-effect IVW (inverse-variance weighted method), MR-Robust and MR-RAPS (robust adjust profile score) tend to perform best in maintaining a low mean-squared error when the InSIDE assumption is satisfied, but can produce large bias when InSIDE is violated. In real-data analysis, some biomarkers showed major heterogeneity in estimates of their causal effects on the risk of T2D across the different methods and estimates from many methods trended in one direction with increasing sample size with patterns similar to those observed in simulation studies. Conclusion The relative performance of different MR methods depends heavily on the sample sizes of the underlying GWAS, the proportion of valid instruments and the validity of the InSIDE assumption. Down-sampling analysis can be used in large GWAS for the possible detection of bias in the MR methods.

scholarly journals Association of serum 25-hydroxyvitamin D with metabolic syndrome and type 2 diabetes: a one sample Mendelian randomization study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jing Xiao ◽  
Jingyi Lv ◽  
Shiyu Wang ◽  
Yang Zhou ◽  
Lunwen Chen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Mendelian Randomization ◽  
Middle Aged ◽  
Hydroxyvitamin D ◽  
25 Hydroxyvitamin D ◽  
Randomization Analysis

Abstract Background Vitamin D deficiency has been associated with type 2 diabetes (T2D) and metabolic syndrome (MS) and its components. However, it is unclear whether a low concentration of vitamin D is the cause or consequence of these health conditions. Thus, this study aimed to evaluate the association of vitamin D concentrations and its genetic risk scores (GRSs) with MS and its component diseases, such as T2D, in middle-aged and elderly participants from rural eastern China. Methods A subset of 2393 middle-aged and elderly individuals were selected from 70,458 participants of the Nantong Chronic Diseases Study of 2017–2018 in China. We used two 25-hydroxyvitamin D (25[OH]D) synthesis single-nucleotide polymorphisms (SNPs) (DHCR7-rs12785878 and CYP2R1-rs10741657) and two 25(OH) D metabolism SNPs (GC-rs2282679 and CYP24A1-rs6013897) for creating GRSs, which were used as instrumental variables to assess the effect of genetically lowered 25(OH) D concentrations on MS and T2D based on the Wald ratio. F statistics were used to validate that the four SNPs genetically determined 25(OH) D concentrations. Results Compared to vitamin D sufficient individuals, individuals with vitamin D insufficiency had an odds ratio (OR [95% confidence interval {CI}]) of MS of 1.30 (1.06–1.61) and of T2D of 1.32 (1.08–1.64), individuals with vitamin D deficiency had an ORs (95% CI) of MS of 1.50 (1.24–1.79) and of T2D of 1.47 (1.12–1.80), and those with vitamin D severe deficiency had an ORs (95% CI) of MS of 1.52 (1.29–1.85) and of T2D of 1.54 (1.27–1.85). Mendelian randomization analysis showed a 25-nmol/L decrease in genetically instrumented serum 25(OH) D concentrations using the two synthesis SNPs (DHCR7 and CYP2R1 genes) associated with the risk of T2D and abnormal diastolic blood pressure (DBP) with ORs of 1.10 (95%CI: 1.02–1.45) for T2D and 1.14 (95%CI: 1.03–1.43) for DBP. Conclusions This one sample Mendelian randomization analysis shows genetic evidence for a causal role of lower 25(OH) D concentrations in promoting of T2D and abnormal DBP in middle-aged and elderly participants from rural China.

scholarly journals Association of leukocyte telomere length with chronic kidney disease in East Asians with type 2 diabetes: A Mendelian randomization study

2021 ◽  
Author(s):  
Resham L Gurung ◽  
Rajkumar Dorajoo ◽  
Yiamunaa M ◽  
Ling Wang ◽  
Sylvia Liu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Telomere Length ◽  
Mendelian Randomization ◽  
Random Effect ◽  
Leukocyte Telomere Length ◽  
Increased Risk ◽  
Genetically Determined

Abstract Background Chronic kidney disease (CKD) is common among type 2 diabetes (T2D) and increases the risk of kidney failure and cardiovascular diseases. Shorter leukocyte telomere length is associated with CKD in patients with T2D. We previously reported single nucleotide polymorphisms (SNPs) associated with leukocyte telomere length in Asian population. In this study, we elucidated the association of these SNPs with CKD in patients with T2D using Mendelian randomization (MR) approach. Methods The cross-sectional association of 16 leukocyte telomere length SNPs with CKD, defined as an estimated glomerular filtration rate of less than 60 ml/min/1.73m2 was assessed among 4,768 (1,628 cases, 3,140 controls) participants in the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes and Diabetic Nephropathy cohorts. MR analysis was performed using the random-effect inverse-variance weighted (IVW) method, the weighted median, MR-Egger and Radial MR adjusted for age and sex-stratified by cohorts and ethnicity (Chinese and Malays), then meta-analysed. Results Genetically determined shorter leukocyte telomere length was associated with increased risk of CKD in patients with T2D (meta-IVW adjusted odds ratio = 1.51 [95% confidence interval, 1.12 - 2.12; P = 0.007; Phet= 0.547]). Similar results were obtained following sensitivity analysis. MR-Egger analysis (intercept) suggested no evidence of horizontal pleiotropy (β  =  0.010, P = 0.751). Conclusions Our findings suggest that genetically determined leukocyte telomere length is associated with CKD in patients with T2D. Further studies are warranted to elucidate the causal role of telomere length in CKD progression.

scholarly journals Gallstone disease, diabetes, calcium, triglycerides, smoking and alcohol consumption and pancreatitis risk: Mendelian randomization study

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Shuai Yuan ◽  
Edward L. Giovannucci ◽  
Susanna C. Larsson
Keyword(s):  
Type 2 Diabetes ◽  
Chronic Pancreatitis ◽  
Alcohol Consumption ◽  
Mendelian Randomization ◽  
Gallstone Disease ◽  
Smoking Initiation ◽  
Disease Type ◽  
Uk Biobank ◽  
Increased Risk

AbstractWe conducted a Mendelian randomization study to determine the potential causal associations of gallstone disease, diabetes, serum calcium, triglyceride levels, smoking and alcohol consumption with acute and chronic pancreatitis. Genetic variants associated with the exposures at p < 5 × 10−8 were selected from corresponding genome-wide association studies. Summary-level data for pancreatitis were obtained from the FinnGen consortium and UK Biobank. Univariable and multivariable Mendelian randomization analyses were performed and results from FinnGen and UK Biobank were combined using the fixed-effects meta-analysis method. Genetic predisposition to gallstone disease, type 2 diabetes and smoking initiation was associated with an increased risk of acute pancreatitis. The combined odds ratios (ORs) were 1.74 (95% confidence interval (CI), 1.57, 1.93) for gallstone disease, 1.14 (95% CI, 1.06, 1.21) for type 2 diabetes and 1.56 (95% CI, 1.32, 1.83) for smoking initiation. The association for type 2 diabetes attenuated after adjustment for gallstone disease. Genetic predisposition to gallstone disease and smoking initiation as well as higher genetically predicted serum calcium and triglyceride levels were associated with an increased risk of chronic pancreatitis. The combined ORs of chronic pancreatitis were 1.27 (95% CI, 1.08, 1.50) for gallstone disease, 1.86 (95% CI, 1.43, 2.43) for smoking initiation, 2.20 (95% CI, 1.30, 3.72) for calcium and 1.47 (95% CI, 1.23, 1.76) for triglycerides. This study provides evidence in support that gallstone disease, type 2 diabetes, smoking and elevated calcium and triglyceride levels are causally associated with the risk of acute or chronic pancreatitis.

scholarly journals Evaluation of glycemic traits in susceptibility to COVID-19 risk: a Mendelian randomization study

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Shiu Lun Au Yeung ◽  
Jie V Zhao ◽  
C Mary Schooling
Keyword(s):  
Type 2 Diabetes ◽  
Genetic Predisposition ◽  
Mendelian Randomization ◽  
Fasting Glucose ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Inverse Association ◽  
Wide Confidence Interval

Abstract Background Observational studies suggest poorer glycemic traits and type 2 diabetes associated with coronavirus disease 2019 (COVID-19) risk although these findings could be confounded by socioeconomic position. We conducted a two-sample Mendelian randomization to clarify their role in COVID-19 risk and specific COVID-19 phenotypes (hospitalized and severe cases). Method We identified genetic instruments for fasting glucose (n = 133,010), 2 h glucose (n = 42,854), glycated hemoglobin (n = 123,665), and type 2 diabetes (74,124 cases and 824,006 controls) from genome wide association studies and applied them to COVID-19 Host Genetics Initiative summary statistics (17,965 COVID-19 cases and 1,370,547 population controls). We used inverse variance weighting to obtain the causal estimates of glycemic traits and genetic predisposition to type 2 diabetes in COVID-19 risk. Sensitivity analyses included MR-Egger and weighted median method. Results We found genetic predisposition to type 2 diabetes was not associated with any COVID-19 phenotype (OR: 1.00 per unit increase in log odds of having diabetes, 95%CI 0.97 to 1.04 for overall COVID-19; OR: 1.02, 95%CI 0.95 to 1.09 for hospitalized COVID-19; and OR: 1.00, 95%CI 0.93 to 1.08 for severe COVID-19). There were no strong evidence for an association of glycemic traits in COVID-19 phenotypes, apart from a potential inverse association for fasting glucose albeit with wide confidence interval. Conclusion We provide some genetic evidence that poorer glycemic traits and predisposition to type 2 diabetes unlikely increase the risk of COVID-19. Although our study did not indicate glycemic traits increase severity of COVID-19, additional studies are needed to verify our findings.

scholarly journals Plasma adiponectin levels, ADIPOQ variants, and incidence of type 2 diabetes: A nested case-control study

2017 ◽  
Vol 127 ◽  
pp. 254-264 ◽  
Author(s):  
Atsushi Goto ◽  
Mitsuhiko Noda ◽  
Maki Goto ◽  
Kazuki Yasuda ◽  
Tetsuya Mizoue ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Case Control Study ◽  
Case Control ◽  
Plasma Adiponectin ◽  
Nested Case Control ◽  
Control Study
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