Genomic insights into the causes of type 2 diabetes.

Genome-wide association studies have implicated around 250 genomic regions in predisposition to type 2 diabetes, with evidence for causal variants and genes emerging for several of these regions. Understanding of the underlying mechanisms, including the interplay between β-cell failure, insulin sensitivity, appetite regulation, and adipose storage has been facilitated by the integration of multidimensional data for diabetes-related intermediate phenotypes, detailed genomic annotations, functional experiments, and now multiomic molecular features. Studies in diverse ethnic groups and examples from population isolates have shown the value and need for a broad genomic approach to this global disease. Transethnic discovery efforts and large-scale biobanks in diverse populations and ancestries could help to address some of the Eurocentric bias. Despite rapid progress in the discovery of the highly polygenic architecture of type 2 diabetes, dominated by common alleles with small, cumulative effects on disease risk, these insights have been of little clinical use in terms of disease prediction or prevention, and have made only small contributions to subtype classification or stratified approaches to treatment. Successful development of academia-industry partnerships for exome or genome sequencing in large biobanks could help to deliver economies of scale, with implications for the future of genomics-focused research

Prioritising Risk Factors for Type 2 Diabetes: Causal Inference through Genetic Approaches.

PURPOSE OF THE REVIEW: Causality has been demonstrated for few of the many putative risk factors for type 2 diabetes (T2D) emerging from observational epidemiology. Genetic approaches are increasingly being used to infer causality, and in this review, we discuss how genetic discoveries have shaped our understanding of the causal role of factors associated with T2D. RECENT FINDINGS: Genetic discoveries have led to the identification of novel potential aetiological factors of T2D, including the protective role of peripheral fat storage capacity and specific metabolic pathways, such as the branched-chain amino acid breakdown. Consideration of specific genetic mechanisms contributing to overall lipid levels has suggested that distinct physiological processes influencing lipid levels may influence diabetes risk differentially. Genetic approaches have also been used to investigate the role of T2D and related metabolic traits as causal risk factors for other disease outcomes, such as cancer, but comprehensive studies are lacking. Genome-wide association studies of T2D and metabolic traits coupled with high-throughput molecular phenotyping and in-depth characterisation and follow-up of individual loci have provided better understanding of aetiological factors contributing to T2D

Zur psychosozialen Situation ungeplant schwangerer Frauen

Diese Studie dokumentiert das Verhütungsverhalten ungeplant schwangerer Frauen und untersucht, welche Einflüsse mit unsicherem oder inkonsequentem Verhütungsverhalten in Zusammenhang stehen. Das Interesse galt außerdem Faktoren, die den Ausgang der Schwangerschaft beeinflussen. Fragebögen wurden an Beratungsstellen und gynäkologische Praxen verschickt; deren Mitarbeiter baten Frauen, die aktuell ungeplant schwanger waren, um ihre Teilnahme an der Studie. 37 Frauen schickten den anonymisierten Fragebogen zurück, diese entschieden sich zu ähnlichen Anteilen zur Abtreibung und Austragung der Schwangerschaft. Über zwei Drittel der Schwangeren hatten einen Verhütungsversuch unternommen, weniger als die Hälfte verhütete jedoch "konsequent" oder "sehr konsequent", und über 40% waren bei ihrer ungeplanten Schwangerschaft ein Risiko eingegangen

Estimating the Population Benefits of Blood Pressure Lowering: A Wide-Angled Mendelian Randomization Study in UK Biobank.

Background The causal relevance of elevated blood pressure for several cardiovascular diseases (CVDs) is uncertain, as is the population impact of blood pressure lowering. This study systematically assesses evidence of causality for various CVDs in a 2-sample Mendelian randomization framework, and estimates the potential reduction in the prevalence of these diseases attributable to long-term population shifts in the distribution of systolic blood pressure (SBP). Methods and Results We investigated associations of genetically predicted SBP as predicted by 256 genetic variants with 21 CVDs in UK Biobank, a population-based cohort of UK residents. The sample consisted of 376 703 participants of European ancestry, aged 40 to 69 years at recruitment. Genetically predicted SBP was positively associated with 14 of the outcomes (P<0.002), including dilated cardiomyopathy, endocarditis, peripheral vascular disease, and rheumatic heart disease. Using genetic variation to estimate the long-term impact of blood pressure lowering on disease in a middle-aged to early late-aged UK-based population, population reductions in SBP were predicted to result in an overall 16.9% (95% CI, 12.2%-21.3%) decrease in morbidity for a 5-mm Hg decrease from a population mean of 137.7 mm Hg, 30.8% (95% CI, 22.8%-38.0%) decrease for a 10-mm Hg decrease, and 56.2% (95% CI, 43.7%-65.9%) decrease for a 22.7-mm Hg decrease in SBP (22.7 mm Hg represents a shift from the current mean SBP to 115 mm Hg). Conclusions Risk of many CVDs is influenced by long-term differences in SBP. The burden of a broad range of CVDs could be substantially reduced by long-term population-wide reductions in the distribution of blood pressure

MTNR1B rs10830963 is associated with fasting plasma glucose, HbA1C and impaired beta-cell function in Chinese Hans from Shanghai.

BACKGROUND: Genome-wide association studies (GWAS) in White Europeans have shown that genetic variation rs10830963 in melatonin receptor 1B gene (MTNR1B) is associated with fasting glucose and type 2 diabetes, which has also been replicated in several Asian populations. As a variant in the gene involved in the regulation of circadian rhythms, the effect of the variant on sleep status remains unknown. This study aimed to investigate the effects of MTNR1B rs10830963 on fasting glucose, type 2 diabetes and sleep status in Chinese Hans. METHODS: MTNR1B rs10830963 was genotyped in a population-based cohort including 3,210 unrelated Chinese Hans from Beijing and Shanghai, and tested for associations with risk of type 2 diabetes, diabetes-related traits and sleep status. RESULTS: We confirmed the associations of MTNR1B rs10830963 with fasting glucose (beta = 0.11 mmol/l, 95%CI [0.03, 0.18], P = 0.005), glycated hemoglobin (HbA1c) (beta = 0.07%, 95%CI [0.02,0.12], P = 0.004) and homeostasis model assessment of beta-cell function (HOMA-B) (beta = -5.01%, 95%CI [-8.24,-1.77], P = 0.003) in the Shanghai, but not in the Beijing subpopulation (P >or= 0.58). The effect size of MTNR1B rs10830963 on fasting glucose in Shanghai Chinese Hans was comparable to that reported from other Asian populations. We found no evidence of associations with type 2 diabetes (OR 1.05 [0.90-1.23], P = 0.54), homeostasis model assessment of insulin sensitivity (HOMA-S) (P = 0.86) or sleep status (P >or= 0.44). CONCLUSIONS: A common variant in MTNR1B was associated with fasting glucose, HbA1C and HOMA-B but not with sleep status in Chinese Hans from Shanghai, strengthening the role of MTNR1B rs10830963 in fasting glycemia and impaired beta-cell function.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Integrating Genetics and the Plasma Proteome to Predict the Risk of Type 2 Diabetes

Funder: University of CambridgeAbstract: Purpose of the Review: Proteins are the central layer of information transfer from genome to phenome and represent the largest class of drug targets. We review recent advances in high-throughput technologies that provide comprehensive, scalable profiling of the plasma proteome with the potential to improve prediction and mechanistic understanding of type 2 diabetes (T2D). Recent Findings: Technological and analytical advancements have enabled identification of novel protein biomarkers and signatures that help to address challenges of existing approaches to predict and screen for T2D. Genetic studies have so far revealed putative causal roles for only few of the proteins that have been linked to T2D, but ongoing large-scale genetic studies of the plasma proteome will help to address this and increase our understanding of aetiological pathways and mechanisms leading to diabetes. Summary: Studies of the human plasma proteome have started to elucidate its potential for T2D prediction and biomarker discovery. Future studies integrating genomic and proteomic data will provide opportunities to prioritise drug targets and identify pathways linking genetic predisposition to T2D development

High-throughput multivariable Mendelian randomization analysis prioritizes apolipoprotein B as key lipid risk factor for coronary artery disease.

BACKGROUND: Genetic variants can be used to prioritize risk factors as potential therapeutic targets via Mendelian randomization (MR). An agnostic statistical framework using Bayesian model averaging (MR-BMA) can disentangle the causal role of correlated risk factors with shared genetic predictors. Here, our objective is to identify lipoprotein measures as mediators between lipid-associated genetic variants and coronary artery disease (CAD) for the purpose of detecting therapeutic targets for CAD. METHODS: As risk factors we consider 30 lipoprotein measures and metabolites derived from a high-throughput metabolomics study including 24 925 participants. We fit multivariable MR models of genetic associations with CAD estimated in 453 595 participants (including 113 937 cases) regressed on genetic associations with the risk factors. MR-BMA assigns to each combination of risk factors a model score quantifying how well the genetic associations with CAD are explained. Risk factors are ranked by their marginal score and selected using false-discovery rate (FDR) criteria. We perform supplementary and sensitivity analyses varying the dataset for genetic associations with CAD. RESULTS: In the main analysis, the top combination of risk factors ranked by the model score contains apolipoprotein B (ApoB) only. ApoB is also the highest ranked risk factor with respect to the marginal score (FDR <0.005). Additionally, ApoB is selected in all sensitivity analyses. No other measure of cholesterol or triglyceride is consistently selected otherwise. CONCLUSIONS: Our agnostic genetic investigation prioritizes ApoB across all datasets considered, suggesting that ApoB, representing the total number of hepatic-derived lipoprotein particles, is the primary lipid determinant of CAD

Common Genetic Determinants of Glucose Homeostasis in Healthy Children: The European Youth Heart Study

OBJECTIVE-The goal of this study was to investigate whether the effects of common genetic variants associated with fasting glucose in adults are detectable in healthy children.RESEARCH DESIGN AND METHODS-Single nucleotide polymorphisms in MTNR1B (rs10830963), G6PC2 (rs560887), and GCK (rs4607517) were genotyped in 2,025 healthy European children aged 9-11 and 14-16 years. Associations with fasting glucose, insulin, homeostasis model assessment (HOMA)-insulin resistance (IR) and HOMA-B were investigated along with those observed for type 2 diabetes variants available in this study (CDKN2A/B, IGF2BP2, CDKAL1, SLC30A8, HHEX-IDE, and Chr 11p12).RESULTS-Strongest associations were observed for G6PC2 and MTNR1B, with mean fasting glucose levels (95% Cl) being 0.084 (0.06-0.11) mmol/l, P = 7.9 x 10(-11) and 0.069 (0.04-0.09) mmol/l, p = 1.9 x 10(-7) higher per risk allele copy, respectively. A similar but weaker trend was observed for GCK (0.028 [-0.006 to 0.06] mmol/l, P = 0.11). All three variants were associated with lower P-cell function (HOMA-B P = 9.38 x 10(-5), 0.004, and 0.04, respectively). SLC30A8 (rs13266634) was the only type 2 diabetes variant associated with higher fasting glucose (0.033 mmol/l [0.01-0.06], P = 0.01). Calculating a genetic predisposition score adding the number of risk alleles of G6PC2, MTNR1B, GCK, and SLC30A8 showed that glucose levels were successively higher in children carrying a greater number of risk alleles (P = 7.1 x 10(-17)), with mean levels of 5.34 versus 4.91 mmol/l comparing children with seven alleles (0.6% of all children) to those with none (0.5%). No associations were found for fasting insulin or HOMA-IR with any of the variants.CONCLUSIONS-The effects of common polymorphisms influencing fasting glucose are apparent in healthy children, whereas the presence of multiple risk alleles amounts to a difference of >1 SD of fasting glucose. Diabetes 58:2939-2945, 200

Association between circulating 25-hydroxyvitamin D and incident type 2 diabetes: a mendelian randomisation study.

BACKGROUND: Low circulating concentrations of 25-hydroxyvitamin D (25[OH]D), a marker of vitamin D status, are associated with an increased risk of type 2 diabetes, but whether this association is causal remains unclear. We aimed to estimate the unconfounded, causal association between 25(OH)D concentration and risk of type 2 diabetes using a mendelian randomisation approach. METHODS: Using several data sources from populations of European descent, including type 2 diabetes cases and non-cases, we did a mendelian randomisation analysis using single nucleotide polymorphisms (SNPs) within or near four genes related to 25(OH)D synthesis and metabolism: DHCR7 (related to vitamin D synthesis), CYP2R1 (hepatic 25-hydroxylation), DBP (also known as GC; transport), and CYP24A1 (catabolism). We assessed each SNP for an association with circulating 25(OH)D concentration (5449 non-cases; two studies), risk of type 2 diabetes (28 144 cases, 76 344 non-cases; five studies), and glycaemic traits (concentrations of fasting glucose, 2-h glucose, fasting insulin, and HbA1c; 46 368 non-cases; study consortium). We combined these associations in a likelihood-based mendelian randomisation analysis to estimate the causal association of 25(OH)D concentration with type 2 diabetes and the glycaemic traits, and compared them with that from a meta-analysis of data from observational studies (8492 cases, 89 698 non-cases; 22 studies) that assessed the association between 25(OH)D concentration and type 2 diabetes. FINDINGS: All four SNPs were associated with 25(OH)D concentrations (p0·25). INTERPRETATION: The association between 25(OH)D concentration and type 2 diabetes is unlikely to be causal. Efforts to increase 25(OH)D concentrations might not reduce the risk of type 2 diabetes as would be expected on the basis of observational evidence. These findings warrant further investigations to identify causal factors that might increase 25(OH)D concentration and also reduce the risk of type 2 diabetes. FUNDING: UK Medical Research Council Epidemiology Unit and European Union Sixth Framework Programme.This is the final published version. It is available from Elsevier in The Lancet Diabetes & Endocrinology here: http://www.sciencedirect.com/science/article/pii/S2213858714701846