| 31. |
- Turcot, Valerie, et al.
(författare)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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| 32. |
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| 33. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 34. |
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| 35. |
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| 36. |
- Camen, S., et al.
(författare)
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Temporal relations between atrial fibrillation and ischemic stroke and their prognostic impact on mortality
- 2018
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Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 39, s. 204-205
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Atrial fibrillation (AF) and stroke are common diseases and AF is a well-established risk factor for stroke. The physiological mechanism of atrial dysfunction, disturbed hemodynamics and arterial thromboembolism links the pathologies. However, limited evidence is available on the temporal relationship between stroke and AF and the impact of subsequent disease onset on mortality in the community.Methods and results: Across five prospective community cohorts (DanMONICA, FINRISK, Moli-Sani project, Northern Sweden MONICA study, The Tromsø Study) of the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE)-project we assessed baseline cardiovascular risk factors in 101164 individuals, median age 46.1 (25th, 75th percentile 35.8, 57.6) years, 48.4% men. We followed them for incident stroke and AF and determined the relation of subsequent disease diagnosis with overall mortality. Follow-up (FU) for stroke and AF was based upon linkage with national hospitalization registries or administrative registries for ambulatory visits to specialized hospitals.Over a median FU of 16.1 years N=4556 individuals were diagnosed solely with AF, N=2269 had a stroke but no AF diagnosed, and N=898 developed both stroke and AF during FU. Participants who developed either AF or stroke as the index event revealed a similar baseline risk factor profile. Temporal relations showed a peak of the diagnosis of both diseases within the years around the diagnosis of the other disease. The highest incidence rates of stroke were observed within a five-year interval prior to AF diagnosis. Cox regression showed an association of baseline stroke with diagnosis of AF during FU (hazard ratio (HR) 1.29; 95% confidence interval (CI) 1.11–1.50; p<0.001).In multivariable-adjusted Cox regression analyses with time-dependent covariates excluding individuals with diagnosis of both AF and stroke or death within 30 days, subsequent diagnosis of AF after stroke was associated with a higher overall mortality (HR, 3.51; 95% CI 1.87–6.59; p<0.001); subsequent stroke after the diagnosis of AF was associated with a HR of 2.39 (95% CI 1.59–3.60; p<0.001).Conclusions: Stroke and AF are common comorbidities in older adults with an overlapping risk factor profile. The temporal relations appear to be bidirectional, although uncertainty regarding disease onset remains due to the often paroxysmal and asymptomatic nature of AF. Stroke may precede detection of AF by years. The subsequent diagnosis of both diseases significantly increases mortality risk. Whether targeting modifiable risk factors or improved screening for AF after stroke would improve survival needs to be determined.
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| 37. |
- Csengeri, D., et al.
(författare)
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Alcohol consumption and risk of atrial fibrillation - results from the BiomarCaRE Consortium
- 2018
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Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 39, s. 902-903
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Atrial fibrillation (AF) is an arrhythmia with high impact on public health. Among modifiable risk factors for the disease the role of alcohol consumption (AC) has remained inconsistent.Purpose: To assess the association between AC and incident AF across European cohorts.Methods: To study the association between self-reported AC and incident AF in N=107,845 community-based individuals from the BiomarCaRE consortium, 106,915 individuals free of AF at baseline were followed up for AF and stroke after AF. We assessed AC using validated questionnaires. Biomarkers N-terminal pro B-type natriuretic peptide (Nt-proBNP) and high sensitivity troponin I (hsTnI) were measured.Results: The median age of individuals was 47.8 years, 48.3% were men. The median of right-winsorized AC was 3 g/day. N=6,055 individuals developed AF (median follow-up time: 13.9 years). In a linear multivariable-adjusted Cox regression analyses, AC was linearly and positively associated with incident AF (Figure), hazard ratio (HR) per g/day 1.009, 95% confidence interval (CI) 1.007- 1.012, P<0.001. For one drink (12g) per day the HR was 1.15, CI 1.12–1.18, P<0.001. There was a high heterogeneity in associations across cohorts.No significant interactions of the association by Nt-proBNP and hsTnI were observed. AC was positively related to stroke risk after diagnosis of AF (HR 1.18, 95% CI 1.04–1.34, P=0.012).Conclusions: In contrast to other cardiovascular diseases, we did not observe a U-shaped association of alcohol with incident AF in the community, but a rather linearly increasing relation.
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| 38. |
- Fuchsberger, Christian, et al.
(författare)
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The genetic architecture of type 2 diabetes
- 2016
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 536:7614, s. 41-47
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Tidskriftsartikel (refereegranskat)abstract
- The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
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| 39. |
- Laakso, M., et al.
(författare)
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Insulin sensitivity, insulin release and glucagon-like peptide-1 levels in persons with impaired fasting glucose and/or impaired glucose tolerance in the EUGENE2 study
- 2008
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 51:3, s. 502-11
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: We examined the phenotype of individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) with regard to insulin release and insulin resistance. METHODS: Non-diabetic offspring (n=874; mean age 40+/-10.4 years; BMI 26.6+/-4.9 kg/m(2)) of type 2 diabetic patients from five different European Centres (Denmark, Finland, Germany, Italy and Sweden) were examined with regard to insulin sensitivity (euglycaemic clamps), insulin release (IVGTT) and glucose tolerance (OGTT). The levels of glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) were measured during the OGTT in 278 individuals. RESULTS: Normal glucose tolerance was found in 634 participants, while 110 had isolated IFG, 86 had isolated IGT and 44 had both IFG and IGT, i.e. about 28% had a form of reduced glucose tolerance. Participants with isolated IFG had lower glucose-corrected first-phase (0-10 min) and higher second-phase insulin release (10-60 min) during the IVGTT, while insulin sensitivity was reduced in all groups with abnormal glucose tolerance. Similarly, GLP-1 but not GIP levels were reduced in individuals with abnormal glucose tolerance. CONCLUSIONS/INTERPRETATION: The primary mechanism leading to hyperglycaemia in participants with isolated IFG is likely to be impaired basal and first-phase insulin secretion, whereas in isolated IGT the primary mechanism leading to postglucose load hyperglycaemia is insulin resistance. Reduced GLP-1 levels were seen in all groups with abnormal glucose tolerance and were unrelated to the insulin release pattern during an IVGTT.
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| 40. |
- Scott, Robert A., et al.
(författare)
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A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease
- 2016
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 8:341
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Tidskriftsartikel (refereegranskat)abstract
- Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
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