DIAbetes Genetics Replication And Meta-analysis Research Articles

SGLT2 Inhibition, Choline Metabolites, and Cardiometabolic Diseases: A Mediation Mendelian Randomization Study.

To investigate the causal role of choline metabolites mediating sodium-glucose cotransporter 2 (SGLT2) inhibition in coronary artery disease (CAD) and type 2 diabetes (T2D) using Mendelian randomization (MR). A two-sample two-step MR was used to determine 1) causal effects of SGLT2 inhibition on CAD and T2D; 2) causal effects of three choline metabolites, total choline, phosphatidylcholine, and glycine, on CAD and T2D; and 3) mediation effects of these metabolites. Genetic proxies for SGLT2 inhibition were identified as variants in the SLC5A2 gene that were associated with both levels of gene expression and hemoglobin A1c. Summary statistics for metabolites were from UK Biobank, CAD from CARDIoGRAMplusC4D (Coronary ARtery DIsease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) consortium, and T2D from DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) and the FinnGen study. SGLT2 inhibition (per 1 SD, 6.75 mmol/mol [1.09%] lowering of HbA1c) was associated with lower risk of T2D and CAD (odds ratio [OR] 0.25 [95% CI 0.12, 0.54], and 0.51 [0.28, 0.94], respectively) and positively with total choline (β 0.39 [95% CI 0.06, 0.72]), phosphatidylcholine (0.40 [0.13, 0.67]), and glycine (0.34 [0.05, 0.63]). Total choline (OR 0.78 [95% CI 0.68, 0.89]) and phosphatidylcholine (OR 0.81 [0.72, 0.91]) were associated with T2D but not with CAD, while glycine was associated with CAD (0.94 [0.91, 0.98]) but not with T2D. Mediation analysis showed evidence of indirect effect of SGLT2 inhibition on T2D through total choline (0.91 [0.83, 0.99]) and phosphatidylcholine (0.93 [0.87, 0.99]) with a mediated proportion of 8% and 5% of the total effect, respectively, and on CAD through glycine (0.98 [0.96, 1.00]) with a mediated proportion of 2%. The results were well validated in at least one independent data set. Our study identified the causal roles of SGLT2 inhibition in choline metabolites. SGLT2 inhibition may influence T2D and CAD through different choline metabolites.

190-LB: Vaspin—A Novel Predictor of Type 2 Diabetes Risk

Vaspin (visceral adipose tissue-derived serpinA12) is an adipokine suspected to be involved in type 2 diabetes (T2D) pathogenesis, linking obesity and T2D. We sought to assess epidemiological and genetic associations of vaspin with T2D and related variables. We assessed the relationship of body-mass index (BMI) and waist-hip ratio (WHR) and plasma vaspin concentration, along with the relationship between plasma vaspin and adiposity-related variables and T2D in (i) a case-cohort within the Prospective Urban and Rural Epidemiology (PURE) prospective multi-country study (N=10,052) , and (ii) the Outcome Reduction with Initial Glargine Intervention (ORIGIN) Trial (N=7,840) of participants with dysglycemia. We next investigated the predictive value of vaspin for T2D risk. All models adjusted for age, sex, and ethnicity. Using two-sample Mendelian randomization (MR) , we analyzed if genetically higher vaspin is causal for T2D. The MR analysis used 34 independent genetic variants (linkage disequilibrium r2<0.1) associated with vaspin concentration in PURE (N=3,513) , estimating their effect on BMI-adjusted T2D risk in the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis) consortium (N=898,130) . In PURE, a 1 unit increase in BMI and WHR was associated with a 0.01 SD (95% CI 0.01 - 0.02; P = 2.04x10−15) and 0.45 SD (95% CI, 0.21 - 0.70; P = 2.87 × 10−4) increase in plasma vaspin respectively. A 1 SD increase in plasma vaspin was associated with higher triglycerides (0.09 mmol/L; 95% CI, 0.07 - 0.12, P = 4.08x10−13) . Directionally-consistent associations were observed in ORIGIN. A 1 SD increase in plasma vaspin was associated with a 19% increase in incident T2D risk in PURE (HR, 1.19; 95% CI, 1.12 - 1.26; P = 6.36x10−8) and a 16% increase in prevalent T2D in ORIGIN (OR, 1.16; 95% CI, 1.07 - 1.25; P = 2.17x10−4) . Sensitivity analyses showed vaspin's specificity for T2D. Genetically-higher vaspin was associated with increased BMI-adjusted T2D risk (OR, 1.02; 95% CI, 1.00 - 1.03; P = 5.46x10−3) . Our data suggests that vaspin is a predictor for T2D risk, a modest causal factor for T2D development, and might represent a potential T2D therapeutic target. Disclosure H. Wang: None. M. Chong: None. N. Perrot: None. J. Feiner: None. S. Hess: Employee; Sanofi. S. Yusuf: None. H. C. Gerstein: Advisory Panel; Abbott, Eli Lilly and Company, Hanmi Pharm. Co., Ltd., Novo Nordisk, Pfizer Inc., Sanofi, Viatris Inc., Consultant; Kowa Company, Ltd., Other Relationship; DKSH, Eli Lilly and Company, Sanofi, Zuellig Pharma Holdings Pte. Ltd., Research Support; AstraZeneca, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi. G. Pare: Advisory Panel; Amgen Inc., Bayer AG, Sanofi, Research Support; Bayer AG. M. Pigeyre: n/a. Funding PURE biomarker study was sponsored by Bayer and CIHR. Origin (NCT00069784) and the biomarker-substudy in Origin were sponsored by Sanofi and CIHR.

Causal Association Between Periodontitis and Type 2 Diabetes: A Bidirectional Two-Sample Mendelian Randomization Analysis.

Background: Previous observational studies have reported a bidirectional association between periodontitis and type 2 diabetes, but the causality of these relationships remains unestablished. We clarified the bidirectional causal association through two-sample Mendelian randomization (MR). Methods: We obtained summary-level data for periodontitis and type 2 diabetes from several published large-scale genome-wide association studies (GWAS) of individuals of European ancestry. For the casual effect of periodontitis on type 2 diabetes, we used five independent single-nucleotide polymorphisms (SNPs) specific to periodontitis from three GWAS. The summary statistics for the associations of exposure-related SNPs with type 2 diabetes were drawn from the GWAS in the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) consortium and the FinnGen consortium R5 release, respectively. For the reversed causal inference, 132 and 49 SNPs associated with type 2 diabetes from the DIAGRAM consortium and the FinnGen consortium R5 release were included, and the summary-level statistics were obtained from the Gene-Lifestyle Interactions in Dental Endpoints consortium. Multiple approaches of MR were carried out. Results: Periodontitis was not causally related with the risk of type 2 diabetes (all p > 0.05). No causal effect of type 2 diabetes on periodontitis was found (all p > 0.05). Estimates were consistent across multiple MR analyses. Conclusion: This study based on genetic data does not support a bidirectional causal association between periodontitis and type 2 diabetes.

Obesity and Kidney Function: A Two-Sample Mendelian Randomization Study.

Obesity and type 2 diabetes (T2D) are correlated risk factors for chronic kidney disease (CKD). Using summary data from GIANT (Genetic Investigation of Anthropometric Traits), DIAGRAM (DIAbetes Genetics Replication And Meta-analysis), and CKDGen (CKD Genetics), we examined causality and directionality of the association between obesity and kidney function. Bidirectional 2-sample Mendelian randomization (MR) estimated the total causal effects of body mass index (BMI) and waist-to-hip ratio (WHR) on kidney function, and vice versa. Effects of adverse obesity and T2D were examined by stratifying BMI variants by their association with WHR and T2D. Multivariable MR estimated the direct causal effects of BMI and WHR on kidney function. The inverse variance weighted random-effects MR for Europeans was the main analysis, accompanied by several sensitivity MR analyses. One standard deviation (SD ≈ 4.8 kg/m2) genetically higher BMI was associated with decreased estimated glomerular filtration rate (eGFR) [β=-0.032 (95% confidence intervals: -0.036, -0.027) log[eGFR], P = 1 × 10-43], increased blood urea nitrogen (BUN) [β = 0.010 (0.005, 0.015) log[BUN], P = 3 × 10-6], increased urinary albumin-to-creatinine ratio [β = 0.199 (0.067, 0.332) log[urinary albumin-to-creatinine ratio (UACR)], P = 0.003] in individuals with diabetes, and increased risk of microalbuminuria [odds ratios (OR) = 1.15 [1.04-1.28], P = 0.009] and CKD [1.13 (1.07-1.19), P = 3 × 10-6]. Corresponding estimates for WHR and for trans-ethnic populations were overall similar. The associations were driven by adverse obesity, and for microalbuminuria additionally by T2D. While genetically high BMI, unlike WHR, was directly associated with eGFR, BUN, and CKD, the pathway to albuminuria was likely through T2D. Genetically predicted kidney function was not associated with BMI or WHR. Genetically high BMI is associated with impaired kidney function, driven by adverse obesity, and for albuminuria additionally by T2D.

The role of circulating galectin-1 in type 2 diabetes and chronic kidney disease: evidence from cross-sectional, longitudinal and Mendelian randomisation analyses

Aims/hypothesisGalectin-1 modulates inflammation and angiogenesis, and cross-sectional studies indicate that galectin-1 may be a uniting factor between obesity, type 2 diabetes and kidney function. We examined whether circulating galectin-1 can predict incidence of chronic kidney disease (CKD) and type 2 diabetes in a middle-aged population, and if Mendelian randomisation (MR) can provide evidence for causal direction of effects.MethodsParticipants (n = 4022; 58.6% women) in the Malmö Diet and Cancer Study–Cardiovascular Cohort enrolled between 1991 and 1994 (mean age 57.6 years) were examined. eGFR was calculated at baseline and after a mean follow-up of 16.6 ± 1.5 years. Diabetes status was ascertained through registry linkage (mean follow-up of 18.4 ± 6.1 years). The associations of baseline galectin-1 with incident CKD and type 2 diabetes were assessed with Cox regression, adjusting for established risk factors. In addition, a genome-wide association study on galectin-1 was performed to identify genetic instruments for two-sample MR analyses utilising the genetic associations obtained from the Chronic Kidney Disease Genetics (CKDGen) Consortium (41,395 cases and 439,303 controls) and the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (74,124 cases and 824,006 controls). One genome-wide significant locus in the galectin-1 gene region was identified (sentinel SNP rs7285699; p = 2.4 × 10−11). The association between galectin-1 and eGFR was also examined in individuals with newly diagnosed diabetes from the All New Diabetics In Scania (ANDIS) cohort.ResultsGalectin-1 was strongly associated with lower eGFR at baseline (p = 2.3 × 10−89) but not with incident CKD. However, galectin-1 was associated with increased risk of type 2 diabetes (per SD increase, HR 1.12; 95% CI 1.02, 1.24). Two-sample MR analyses could not ascertain a causal effect of galectin-1 on CKD (OR 0.92; 95% CI 0.82, 1.02) or type 2 diabetes (OR 1.05; 95% CI 0.98, 1.14) in a general population. However, in individuals with type 2 diabetes from ANDIS who belonged to the severe insulin-resistant diabetes subgroup and were at high risk of diabetic nephropathy, genetically elevated galectin-1 was significantly associated with higher eGFR (p = 5.7 × 10−3).Conclusions/interpretationGalectin-1 is strongly associated with lower kidney function in cross-sectional analyses, and two-sample MR analyses suggest a causal protective effect on kidney function among individuals with type 2 diabetes at high risk of diabetic nephropathy. Future studies are needed to explore the mechanisms by which galectin-1 affects kidney function and whether it could be a useful target among individuals with type 2 diabetes for renal improvement.Graphical abstract

Genome-wide association study of pancreatic fat: The Multiethnic Cohort Adiposity Phenotype Study.

Several studies have found associations between higher pancreatic fat content and adverse health outcomes, such as diabetes and the metabolic syndrome, but investigations into the genetic contributions to pancreatic fat are limited. This genome-wide association study, comprised of 804 participants with MRI-assessed pancreatic fat measurements, was conducted in the ethnically diverse Multiethnic Cohort-Adiposity Phenotype Study (MEC-APS). Two genetic variants reaching genome-wide significance, rs73449607 on chromosome 13q21.2 (Beta = -0.67, P = 4.50x10-8) and rs7996760 on chromosome 6q14 (Beta = -0.90, P = 4.91x10-8) were associated with percent pancreatic fat on the log scale. Rs73449607 was most common in the African American population (13%) and rs79967607 was most common in the European American population (6%). Rs73449607 was also associated with lower risk of type 2 diabetes (OR = 0.95, 95% CI = 0.89–1.00, P = 0.047) in the Population Architecture Genomics and Epidemiology (PAGE) Study and the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM), which included substantial numbers of non-European ancestry participants (53,102 cases and 193,679 controls). Rs73449607 is located in an intergenic region between GSX1 and PLUTO, and rs79967607 is in intron 1 of EPM2A. PLUTO, a lncRNA, regulates transcription of an adjacent gene, PDX1, that controls beta-cell function in the mature pancreas, and EPM2A encodes the protein laforin, which plays a critical role in regulating glycogen production. If validated, these variants may suggest a genetic component for pancreatic fat and a common etiologic link between pancreatic fat and type 2 diabetes.

The potential shared role of inflammation in insulin resistance and schizophrenia: A bidirectional two-sample mendelian randomization study.

Insulin resistance predisposes to cardiometabolic disorders, which are commonly comorbid with schizophrenia and are key contributors to the significant excess mortality in schizophrenia. Mechanisms for the comorbidity remain unclear, but observational studies have implicated inflammation in both schizophrenia and cardiometabolic disorders separately. We aimed to examine whether there is genetic evidence that insulin resistance and 7 related cardiometabolic traits may be causally associated with schizophrenia, and whether evidence supports inflammation as a common mechanism for cardiometabolic disorders and schizophrenia. We used summary data from genome-wide association studies of mostly European adults from large consortia (Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) featuring up to 108,557 participants; Diabetes Genetics Replication And Meta-analysis (DIAGRAM) featuring up to 435,387 participants; Global Lipids Genetics Consortium (GLGC) featuring up to 173,082 participants; Genetic Investigation of Anthropometric Traits (GIANT) featuring up to 339,224 participants; Psychiatric Genomics Consortium (PGC) featuring up to 105,318 participants; and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium featuring up to 204,402 participants). We conducted two-sample uni- and multivariable mendelian randomization (MR) analysis to test whether (i) 10 cardiometabolic traits (fasting insulin, high-density lipoprotein and triglycerides representing an insulin resistance phenotype, and 7 related cardiometabolic traits: low-density lipoprotein, fasting plasma glucose, glycated haemoglobin, leptin, body mass index, glucose tolerance, and type 2 diabetes) could be causally associated with schizophrenia; and (ii) inflammation could be a shared mechanism for these phenotypes. We conducted a detailed set of sensitivity analyses to test the assumptions for a valid MR analysis. We did not find statistically significant evidence in support of a causal relationship between cardiometabolic traits and schizophrenia, or vice versa. However, we report that a genetically predicted inflammation-related insulin resistance phenotype (raised fasting insulin (raised fasting insulin (Wald ratio OR = 2.95, 95% C.I, 1.38-6.34, Holm-Bonferroni corrected p-value (p) = 0.035) and lower high-density lipoprotein (Wald ratio OR = 0.55, 95% C.I., 0.36-0.84; p = 0.035)) was associated with schizophrenia. Evidence for these associations attenuated to the null in multivariable MR analyses after adjusting for C-reactive protein, an archetypal inflammatory marker: (fasting insulin Wald ratio OR = 1.02, 95% C.I, 0.37-2.78, p = 0.975), high-density lipoprotein (Wald ratio OR = 1.00, 95% C.I., 0.85-1.16; p = 0.849), suggesting that the associations could be fully explained by inflammation. One potential limitation of the study is that the full range of gene products from the genetic variants we used as proxies for the exposures is unknown, and so we are unable to comment on potential biological mechanisms of association other than inflammation, which may also be relevant. Our findings support a role for inflammation as a common cause for insulin resistance and schizophrenia, which may at least partly explain why the traits commonly co-occur in clinical practice. Inflammation and immune pathways may represent novel therapeutic targets for the prevention or treatment of schizophrenia and comorbid insulin resistance. Future work is needed to understand how inflammation may contribute to the risk of schizophrenia and insulin resistance.

Genetic discovery and risk characterization in type 2 diabetes across diverse populations.

SummaryGenomic discovery and characterization of risk loci for type 2 diabetes (T2D) have been conducted primarily in individuals of European ancestry. We conducted a multiethnic genome-wide association study of T2D among 53,102 cases and 193,679 control subjects from African, Hispanic, Asian, Native Hawaiian, and European population groups in the Population Architecture Genomics and Epidemiology (PAGE) and Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortia. In individuals of African ancestry, we discovered a risk variant in the TGFB1 gene (rs11466334, risk allele frequency (RAF) = 6.8%, odds ratio [OR] = 1.27, p = 2.06 × 10−8), which replicated in independent studies of African ancestry (p = 6.26 × 10−23). We identified a multiethnic risk variant in the BACE2 gene (rs13052926, RAF = 14.1%, OR = 1.08, p = 5.75 × 10−9), which also replicated in independent studies (p = 3.45 × 10−4). We also observed a significant difference in the performance of a multiethnic genetic risk score (GRS) across population groups (pheterogeneity = 3.85 × 10−20). Comparing individuals in the top GRS risk category (40%–60%), the OR was highest in Asians (OR = 3.08) and European (OR = 2.94) ancestry populations, followed by Hispanic (OR = 2.39), Native Hawaiian (OR = 2.02), and African ancestry (OR = 1.57) populations. These findings underscore the importance of genetic discovery and risk characterization in diverse populations and the urgent need to further increase representation of non-European ancestry individuals in genetics research to improve genetic-based risk prediction across populations.

Nonconserved Long Intergenic Noncoding RNAs Associate With Complex Cardiometabolic Disease Traits.

Transcriptome profiling of human tissues has revealed thousands of long intergenic noncoding RNAs (lincRNAs) at loci identified through large-scale genome-wide studies for complex cardiometabolic traits. This raises the question of whether genetic variation at nonconserved lincRNAs has any systematic association with complex disease, and if so, how different this pattern is from conserved lincRNAs. We evaluated whether the associations between nonconserved lincRNAs and 8 complex cardiometabolic traits resemble or differ from the pattern of association for conserved lincRNAs. Approach and Results: Our investigation of over 7000 lincRNA annotations from GENCODE Release 33-GRCh38.p13 for complex trait genetic associations leveraged several large, established meta-analyses genome-wide association study summary data resources, including GIANT (Genetic Investigation of Anthropometric Traits), UK Biobank, GLGC (Global Lipids Genetics Consortium), Cardiogram (Coronary Artery Disease Genome Wide Replication and Meta-Analysis), and DIAGRAM (Diabetes Genetics Replication and Meta-Analysis)/DIAMANTE (Diabetes Meta-Analysis of Trans-Ethnic Association Studies). These analyses revealed that (1) nonconserved lincRNAs associate with a range of cardiometabolic traits at a rate that is generally consistent with conserved lincRNAs; (2) these findings persist across different definitions of conservation; and (3) overall across all cardiometabolic traits, approximately one-third of genome-wide association study-associated lincRNAs are nonconserved, and this increases to about two-thirds using a more stringent definition of conservation. These findings suggest that the traditional notion of conservation driving prioritization for functional and translational follow-up of complex cardiometabolic genomic discoveries may need to be revised in the context of the abundance of nonconserved long noncoding RNAs in the human genome and their apparent predilection to associate with complex cardiometabolic traits.

Causal association between mTOR-dependent EIF-4E and EIF-4A circulating protein levels and type 2 diabetes: a Mendelian randomization study

The mammalian Target of Rapamycin complex 1 (mTORC1) nutrient-sensing pathway is a central regulator of cell growth and metabolism and is dysregulated in diabetes. The eukaryotic translation initiation factor 4E (EIF-4E) protein, a key regulator of gene translation and protein function, is controlled by mTORC1 and EIF-4E Binding Proteins (EIF4EBPs). Both EIF4EBPs and ribosomal protein S6K kinase (RP-S6K) are downstream effectors regulated by mTORC1 but converge to regulate two independent pathways. We investigated whether the risk of type 2 diabetes varied with genetically predicted EIF-4E, EIF-4A, EIF-4G, EIF4EBP, and RP-S6K circulating levels using Mendelian Randomization. We estimated the causal role of EIF-4F complex, EIF4EBP, and S6K in the circulation on type 2 diabetes, based on independent single nucleotide polymorphisms strongly associated (p = 5 × 10–6) with EIF-4E (16 SNPs), EIF-4A (11 SNPs), EIF-4G (6 SNPs), EIF4EBP2 (12 SNPs), and RP-S6K (16 SNPs). The exposure data were obtained from the INTERVAL study. We applied these SNPs for each exposure to publically available genetic associations with diabetes from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) case (n = 26,676) and control (n = 132,532) study (mean age 57.4 years). We meta-analyzed SNP-specific Wald-estimates using inverse variance weighting with multiplicative random effects and conducted sensitivity analysis. Mendelian Randomization (MR-Base) R package was used in the analysis. The PhenoScanner curated database was used to identify disease associations with SNP gene variants. EIF-4E is associated with a lowered risk of type 2 diabetes with an odds ratio (OR) 0.94, 95% confidence interval (0.88, 0.99, p = 0.03) with similar estimates from the weighted median and MR-Egger. Similarly, EIF-4A was associated with lower risk of type 2 diabetes with odds ratio (OR) 0.90, 95% confidence interval (0.85, 0.97, p = 0.0003). Sensitivity analysis using MR-Egger and weighed median analysis does not indicate that there is a pleiotropic effect. This unbiased Mendelian Randomization estimate is consistent with a protective causal association of EIF-4E and EIF-4A on type 2 diabetes. EIF-4E and EIF-4A may be targeted for intervention by repurposing existing therapeutics to reduce the risk of type 2 diabetes.

Desaturase Activity and the Risk of Type 2 Diabetes and Coronary Artery Disease: A Mendelian Randomization Study.

Estimated Δ5-desaturase (D5D) and Δ6-desaturase (D6D) are key enzymes in metabolism of polyunsaturated fatty acids (PUFA) and have been associated with cardiometabolic risk; however, causality needs to be clarified. We applied two-sample Mendelian randomization (MR) approach using a representative sub-cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC)–Potsdam Study and public data from DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) and Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) genome-wide association studies (GWAS). Furthermore, we addressed confounding by linkage disequilibrium (LD) as all instruments from FADS1 (encoding D5D) are in LD with FADS2 (encoding D6D) variants. Our univariable MRs revealed risk-increasing total effects of both, D6D and D5D on type 2 diabetes (T2DM) risk; and risk-increasing total effect of D6D on risk of coronary artery disease (CAD). The multivariable MR approach could not unambiguously allocate a direct causal effect to either of the individual desaturases. Our results suggest that D6D is causally linked to cardiometabolic risk, which is likely due to downstream production of fatty acids and products resulting from high D6D activity. For D5D, we found indication for causal effects on T2DM and CAD, which could, however, still be confounded by LD.

ACE and Type 2 Diabetes Risk: A Mendelian Randomization Study.

To determine whether ACE inhibitors reduce the risk of type 2 diabetes using a Mendelian randomization (MR) approach. A two-sample MR analysis included 17 independent genetic variants associated with ACE serum concentration in 4,147 participants from the Outcome Reduction with Initial Glargine INtervention (ORIGIN) (clinical trial reg. no. NCT00069784) trial, and their effects on type 2 diabetes risk were estimated from 18 studies of the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium. A genetic risk score (GRS) underpinning lower ACE concentration was then tested for association with type 2 diabetes prevalence in 341,872 participants, including 16,320 with type 2 diabetes, from the UK Biobank. MR estimates were compared after standardization for blood pressure change, with the estimate obtained from a randomized controlled trial (RCT) meta-analysis of ACE inhibitors versus placebo (n = 31,200). Genetically lower ACE concentrations were associated with a lower risk of type 2 diabetes (odds ratio [OR] per SD 0.92 [95% CI 0.89-0.95]; P = 1.79 × 10-7). This result was replicated in the UK Biobank (OR per SD 0.97 [0.96-0.99]; P = 8.73 × 10-4). After standardization, the ACE GRS was associated with a larger decrease in type 2 diabetes risk per 2.4-mmHg lower mean arterial pressure (MAP) compared with that obtained from an RCT meta-analysis (OR per 2.4-mmHg lower MAP 0.19 [0.07-0.51] vs. 0.76 [0.60-0.97], respectively; P = 0.007 for difference). These results support the causal protective effect of ACE inhibitors on type 2 diabetes risk and may guide therapeutic decision making in clinical practice.

Association of genetic variants related to plasma fatty acids with type 2 diabetes mellitus and glycaemic traits: a Mendelian randomisation study

Aims/hypothesisEpidemiological data on the associations of circulating fatty acid levels with type 2 diabetes are inconsistent. We conducted a two-sample Mendelian randomisation study to explore the causal associations of plasma levels of ten fatty acids with type 2 diabetes and glycaemic traits.MethodsThirteen SNPs associated with circulating levels of ten individual fatty acids at the genome-wide significance level (p < 5 × 10−8) were selected as instrumental variables for the exposures. For the outcomes, summary-level data were obtained from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium for type 2 diabetes (898,130 individuals) and from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) for the glycaemic traits (up to 46,186 non-diabetic individuals). The inverse-variance weighted method was used for analyses.ResultsGenetic predisposition to higher plasma levels of eight of the ten fatty acids were statistically significantly associated with lower or higher odds of type 2 diabetes. The OR per one SD increment of each fatty acid was 0.93 (95% CI 0.90, 0.96; p = 2.21 × 10−5) for α-linolenic acid, 0.96 (95% CI 0.94, 0.98; p = 1.85 × 10−4) for linoleic acid, 0.86 (95% CI 0.81, 0.91; p = 6.68 × 10−7) for palmitoleic acid, 0.87 (95% CI 0.81, 0.93; p = 2.21 × 10−5) for oleic acid, 1.08 (95% CI 1.03, 1.12; p = 0.002) for eicosapentaenoic acid, 1.04 (95% CI 1.02, 1.07; p = 0.001) for docosapentaenoic acid, 1.03 (95% CI 1.02, 1.05; p = 2.51 × 10−5) for arachidonic acid and 1.09 (95% CI 1.03, 1.15; p = 0.003) for stearic acid. The same eight fatty acids were also associated with fasting glucose levels and HOMA-B. The associations, except that for palmitoleic acid, were driven by variants in FADS1/2.Conclusions/interpretationGenetic predisposition to higher circulating levels of eight out of ten fatty acids was associated with type 2 diabetes, fasting glucose and islet beta cell function. However, the associations, except that for palmitoleic acid, were driven by variants in FADS1/2, which encode enzymes with a key role in fatty acid metabolism.

Negative Effects of Age at Menarche on Risk of Cardiometabolic Diseases in Adulthood: A Mendelian Randomization Study.

Observational studies have demonstrated that early menarche is associated with cardiometabolic diseases, but confounding factors make it difficult to infer causality. We used Mendelian randomization (MR) to examine whether age at menarche (AAM) is causally associated with type 2 diabetes (T2D), coronary artery disease (CAD) and cardiometabolic traits. A 2-sample MR analysis was conducted using genome-wide association study (GWAS) summary statistics from the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) consortium (n = 159 208) for T2D and the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics (CARDIoGRAMplusC4D) consortium (n = 184 305) for CAD. We used 122 instrumental variables (IVs) extracted from a published GWAS meta-analysis incorporating 182 416 women to determine the causal effect of AAM on cardiometabolic diseases, treating childhood and adult body mass index (BMI) as the confounders. Sensitivity analyses were also performed to detect the pleiotropy of the IVs. Employing the MR approach, we found that later AAM was associated with decreased risk of CAD (OR, 0.92 [95% CI, 0.88-0.96]; P = 2.06 × 10-4) in adults, as well as lower blood levels of log fasting insulin, log homeostatic model assessment of insulin resistance (HOMA-IR), log HOMA of β-cell function (HOMA-B), triglycerides, and diastolic blood pressure, but higher blood level of high-density lipoprotein. However, the associations were substantially attenuated after excluding BMI-related variants. MR analyses provide little evidence on the causal effect between AAM and T2D. Our findings showed that AAM did not appear to have a causal effect on the risk of cardiometabolic diseases in adult life, as their associations observed in epidemiological studies might be largely mediated through excessive adiposity. We propose adiposity might be a primary target in future intervention strategy.

P6502Association between diabetes mellitus and abdominal aortic aneurysm: a mendelian randomization study

Abstract Background It is generally acknowledged that those with diabetes mellitus (DM) have at least a 10-fold risk for cardiovascular disease (CVD). However, patients with DM have been shown with a lower incidence of abdominal aortic aneurysm (AAA) in epidemiological data. Related research has illustrated that the aortic may be protected in the hyperglycemic microenvironment while the causality of this relationship is still uncertain. Purpose Here, we undertake a two sample Mendelian randomization (MR) study to evaluate whether DM genetically influences the risk of AAA. Methods We analyzed the genetic summary data from the DIAGRAM (Diabetes Genetics Replication And Meta-analysis) consortium and MRC-IEU (Integrative Epidemiology Unit) consortium. Base on the result from GIAGRAM consortium (26488 DM cases and 83964 controls), 25 single nucleotide polymorphisms (SNPs) associated with DM as the instrumental variables in MR study. Then, for each of the 25 SNPs associated with DM, we retrieved their summary data from MRC-IEU Consortium (263 cases and 462747controls). Inverse-variance weighting (IVW) was conducted to obtain the associations of DM with AAA and several sensitivity analyses were also performed to assess the potential violation of MR assumptions. Results DM was not significantly associated with risk of AAA (odds ratio [OR], 1.ehz746.1092; 95% confidence interval [CI], 0.9998–1.0002; P, 0.9622). Weighted median (OR, 1.0002; 95% CI, 0.9999–1.0005; P, 0.1992) and MR Egger analysis (OR, 1.0003; 95% CI, 0.9995–1.0012; P, 0.4071) suggested similar effect estimates of DM on AAA. With the large P value for the intercept, the result of MR-Egger regression method indicated no evidence for the presence of horizontal pleiotropy (Egger regression intercept, 3.9e-05, P, 0.384). In a leave-one-out analysis, no single SNP was observed with strong driving effect of DM on AAA. Conclusions Through 25 genetically identified SNPs in this two sample MR study, DM is not associated the risk of AAA this large study using two-sample MR, which did not support the result from previous epidemiological data. In conclusions, this large MR study provides evidence to suggest that DM may not be causally associated with AAA.

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

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.

Circulating Phylloquinone Concentrations and Risk of Type 2 Diabetes: A Mendelian Randomization Study.

This study investigated the causal relation between circulating phylloquinone (vitamin K1) concentrations and type 2 diabetes by using a Mendelian randomization (MR) approach. We used data from three studies: the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, Diabetes Genetics Replication and Meta-analysis (DIAGRAM), and the UK Biobank, resulting in 69,647 subjects with type 2 diabetes. We calculated a weighted genetic risk score including four genetic variants previously found to be associated with circulating phylloquinone concentrations. Inverse-variance weighted analysis was used to obtain a risk ratio (RR) for the causal relation between circulating phylloquinone concentrations and risk of type 2 diabetes. Presence of pleiotropy and the robustness of the results were assessed using MR-Egger and weighted-median analyses. Genetically predicted concentrations of circulating phylloquinone were associated with lower risk of type 2 diabetes with an RR of 0.93 (95% CI 0.89; 0.97) per every natural logarithm (Ln)-nmol/L-unit increase in circulating phylloquinone. The MR-Egger and weighted median analyses showed RRs of 0.94 (0.86; 1.02) and 0.93 (0.88; 0.98), respectively, indicating no pleiotropy. In conclusion, our study supports that higher circulating phylloquinone may be causally related with lower risk of type 2 diabetes, highlighting the importance of sufficient phylloquinone in the human diet.

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

Background: As a biomarker of inflammation, C-reactive protein (CRP) attracted much attentions since its role in the incidence of type 2 Diabetes Mellitus (T2DM). Currently perspective studies observed a positive correlation between the level of serum CRP and T2DM. Recently studies reported that drugs for curing T2DM can also decrease the level of serum CRP. Whereas, it has not been clear whether the CRP level cause the T2DM. Materials and Methods: To expose this, we conducted a Mendelian Randomisation (MR) analysis using genetic variations as instrumental variables (IVs). The significant associated single nucleotide polymorphisms (SNPs) of CRP were from a genome-wide and replication study. There, 17,967 participants were utilized for the genome-wide association study (GWAS), and another 14,747 participants were utilized for replication of SNPs associated with CRP. The associations between SNPs and T2DM were from diabetes genetics replication and meta-analysis (DIAGRAM) consortium. After removing SNPs with linkage disequilibrium (LD) and T2DM-related SNPs, the four remained CRP-related SNPs were deemed as IVs. To evaluate the pooled influence of these IVs on the risk of T2DM through CRP, Penalized robust inverse-variance weighted (IVW) method were carried out. Results: The combined result (OR 1.114048; 95% CI 1.058656 to 1.172338; P = 0.024). 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). Conclusions: We validate the causal effect of high CRP increases the risk of T2DM, and take no effect on T1DM. Funding: This work was supported by the National Natural Science Foundation of China (Grant No. 61502125), Heilongjiang Postdoctoral Fund (Grant No. LBH-Z15179), and China Postdoctoral Science Foundation (Grant No. 2016M590291). Declaration of Interests: There is no conflict of interest of any authors in relation to the submission. Ethical Approval Statement: The protocol for the research project has been approved by a suitably constituted Ethics Committee of the institution within which the work was undertaken and that it conforms to the provisions of the Declaration of Helsinki (as revised in Fortaleza, Brazil, October 2013).

Controllability in an islet specific regulatory network identifies the transcriptional factor NFATC4, which regulates Type 2 Diabetes associated genes

Probing the dynamic control features of biological networks represents a new frontier in capturing the dysregulated pathways in complex diseases. Here, using patient samples obtained from a pancreatic islet transplantation program, we constructed a tissue-specific gene regulatory network and used the control centrality (Cc) concept to identify the high control centrality (HiCc) pathways, which might serve as key pathobiological pathways for Type 2 Diabetes (T2D). We found that HiCc pathway genes were significantly enriched with modest GWAS p-values in the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) study. We identified variants regulating gene expression (expression quantitative loci, eQTL) of HiCc pathway genes in islet samples. These eQTL genes showed higher levels of differential expression compared to non-eQTL genes in low, medium, and high glucose concentrations in rat islets. Among genes with highly significant eQTL evidence, NFATC4 belonged to four HiCc pathways. We asked if the expressions of T2D-associated candidate genes from GWAS and literature are regulated by Nfatc4 in rat islets. Extensive in vitro silencing of Nfatc4 in rat islet cells displayed reduced expression of 16, and increased expression of four putative downstream T2D genes. Overall, our approach uncovers the mechanistic connection of NFATC4 with downstream targets including a previously unknown one, TCF7L2, and establishes the HiCc pathways’ relationship to T2D.

Abstract P072: Circulating Phylloquinone Concentrations and Type 2 Diabetes Incidence: A Mendelian Randomization Study

Introduction: This study aims to investigate the causal relation of genetically conferred circulating phylloquinone levels and the risk of type 2 diabetes (T2D) via a Mendelian Randomization approach. Methods: We used data from the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study comprising 10,071 diabetes cases and 13,309 subcohort members from eight European countries. We calculated a weighted genetic risk score (wGRS) including four SNPs (rs2192574, rs6862071, rs4645543 and rs2108622) likely to be related to circulating phylloquinone levels from a genome wide association study. Inverse-variance weighted (IVW) analysis was used to obtain a Hazard Ratio (HR) for the unconfounded relation between circulating phylloquinone levels and T2D incidence. All analyses were adjusted for sex, center, principal components of ancestry, genetic platform, triglycerides and hours fasting. Furthermore, we assessed the robustness of our results with a MR Egger analyses. In follow-up analyses, we have included data from the Diabetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, increasing our dataset to 21,571 participants with diabetes. Results: The median follow-up time was 10.9 years. In IVW analysis, genetically conferred higher circulating phylloquinone levels were associated with a reduced risk of T2D with a HR of 0.87 (0.78;0.97) for every ln-nmol/L increase in circulating phylloquinone. The MR Egger method resulted in a HR of 0.88 (0.72;1.08).Adding DIAGRAM data resulted in a summary odds ratio of 0.90 (0.81;1.00). Conclusion: Our study suggests that the association between higher circulating phylloquinone levels and lower T2D incidence may be causal.