| 1. |
- Mahajan, Anubha, et al.
(författare)
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:5, s. 560-572
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Tidskriftsartikel (refereegranskat)abstract
- We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background. Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.
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| 2. |
- Bosch, Jackie, et al.
(författare)
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n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia.
- 2012
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 367:4, s. 309-18
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The use of n-3 fatty acids may prevent cardiovascular events in patients with recent myocardial infarction or heart failure. Their effects in patients with (or at risk for) type 2 diabetes mellitus are unknown.METHODS: In this double-blind study with a 2-by-2 factorial design, we randomly assigned 12,536 patients who were at high risk for cardiovascular events and had impaired fasting glucose, impaired glucose tolerance, or diabetes to receive a 1-g capsule containing at least 900 mg (90% or more) of ethyl esters of n-3 fatty acids or placebo daily and to receive either insulin glargine or standard care. The primary outcome was death from cardiovascular causes. The results of the comparison between n-3 fatty acids and placebo are reported here.RESULTS: During a median follow up of 6.2 years, the incidence of the primary outcome was not significantly decreased among patients receiving n-3 fatty acids, as compared with those receiving placebo (574 patients [9.1%] vs. 581 patients [9.3%]; hazard ratio, 0.98; 95% confidence interval [CI], 0.87 to 1.10; P=0.72). The use of n-3 fatty acids also had no significant effect on the rates of major vascular events (1034 patients [16.5%] vs. 1017 patients [16.3%]; hazard ratio, 1.01; 95% CI, 0.93 to 1.10; P=0.81), death from any cause (951 [15.1%] vs. 964 [15.4%]; hazard ratio, 0.98; 95% CI, 0.89 to 1.07; P=0.63), or death from arrhythmia (288 [4.6%] vs. 259 [4.1%]; hazard ratio, 1.10; 95% CI, 0.93 to 1.30; P=0.26). Triglyceride levels were reduced by 14.5 mg per deciliter (0.16 mmol per liter) more among patients receiving n-3 fatty acids than among those receiving placebo (P<0.001), without a significant effect on other lipids. Adverse effects were similar in the two groups.CONCLUSIONS: Daily supplementation with 1 g of n-3 fatty acids did not reduce the rate of cardiovascular events in patients at high risk for cardiovascular events. (Funded by Sanofi; ORIGIN ClinicalTrials.gov number, NCT00069784.).
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| 3. |
- Gerstein, Hertzel C, et al.
(författare)
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Basal insulin and cardiovascular and other outcomes in dysglycemia.
- 2012
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 367:4, s. 319-28
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The provision of sufficient basal insulin to normalize fasting plasma glucose levels may reduce cardiovascular events, but such a possibility has not been formally tested.METHODS: We randomly assigned 12,537 people (mean age, 63.5 years) with cardiovascular risk factors plus impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes to receive insulin glargine (with a target fasting blood glucose level of ≤95 mg per deciliter [5.3 mmol per liter]) or standard care and to receive n-3 fatty acids or placebo with the use of a 2-by-2 factorial design. The results of the comparison between insulin glargine and standard care are reported here. The coprimary outcomes were nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes and these events plus revascularization or hospitalization for heart failure. Microvascular outcomes, incident diabetes, hypoglycemia, weight, and cancers were also compared between groups.RESULTS: The median follow-up was 6.2 years (interquartile range, 5.8 to 6.7). Rates of incident cardiovascular outcomes were similar in the insulin-glargine and standard-care groups: 2.94 and 2.85 per 100 person-years, respectively, for the first coprimary outcome (hazard ratio, 1.02; 95% confidence interval [CI], 0.94 to 1.11; P=0.63) and 5.52 and 5.28 per 100 person-years, respectively, for the second coprimary outcome (hazard ratio, 1.04; 95% CI, 0.97 to 1.11; P=0.27). New diabetes was diagnosed approximately 3 months after therapy was stopped among 30% versus 35% of 1456 participants without baseline diabetes (odds ratio, 0.80; 95% CI, 0.64 to 1.00; P=0.05). Rates of severe hypoglycemia were 1.00 versus 0.31 per 100 person-years. Median weight increased by 1.6 kg in the insulin-glargine group and fell by 0.5 kg in the standard-care group. There was no significant difference in cancers (hazard ratio, 1.00; 95% CI, 0.88 to 1.13; P=0.97).CONCLUSIONS: When used to target normal fasting plasma glucose levels for more than 6 years, insulin glargine had a neutral effect on cardiovascular outcomes and cancers. Although it reduced new-onset diabetes, insulin glargine also increased hypoglycemia and modestly increased weight. (Funded by Sanofi; ORIGIN ClinicalTrials.gov number, NCT00069784.).
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| 4. |
- Nead, Kevin T., et al.
(författare)
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Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity : a systematic review and meta-analysis with evidence from up to 331 175 individuals
- 2015
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 24:12, s. 3582-3594
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Tidskriftsartikel (refereegranskat)abstract
- Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) a parts per thousand yen 40 kg/m(2)], but their contribution to common obesity (BMI a parts per thousand yen 30 kg/m(2)) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 x 10(-6)) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 x 10(-7)). Similarly, significant associations were found with continuous BMI for rs6232 (beta = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (beta = 0.02, 95% CI 0.00-0.03; P = 5.57 x 10(-4)). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology.
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| 5. |
- Tschiderer, Lena, et al.
(författare)
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Association of Intima-Media Thickness Measured at the Common Carotid Artery With Incident Carotid Plaque : Individual Participant Data Meta-Analysis of 20 Prospective Studies
- 2023
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Ingår i: Journal of the American Heart Association. - : Ovid Technologies (Wolters Kluwer Health). - 2047-9980. ; 12:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: The association between common carotid artery intima-media thickness (CCA-IMT) and incident carotid plaque has not been characterized fully. We therefore aimed to precisely quantify the relationship between CCA-IMT and carotid plaque development.Methods and Results: We undertook an individual participant data meta-analysis of 20 prospective studies from the Proof-ATHERO (Prospective Studies of Atherosclerosis) consortium that recorded baseline CCA-IMT and incident carotid plaque involving 21 494 individuals without a history of cardiovascular disease and without preexisting carotid plaque at baseline. Mean baseline age was 56 years (SD, 9 years), 55% were women, and mean baseline CCA-IMT was 0.71 mm (SD, 0.17 mm). Over a median follow-up of 5.9 years (5th-95th percentile, 1.9-19.0 years), 8278 individuals developed first-ever carotid plaque. We combined study-specific odds ratios (ORs) for incident carotid plaque using random-effects meta-analysis. Baseline CCA-IMT was approximately log-linearly associated with the odds of developing carotid plaque. The age-, sex-, and trial arm-adjusted OR for carotid plaque per SD higher baseline CCA-IMT was 1.40 (95% CI, 1.31-1.50; I-2=63.9%). The corresponding OR that was further adjusted for ethnicity, smoking, diabetes, body mass index, systolic blood pressure, low- and high-density lipoprotein cholesterol, and lipid-lowering and antihypertensive medication was 1.34 (95% CI, 1.24-1.45; I-2=59.4%; 14 studies; 16 297 participants; 6381 incident plaques). We observed no significant effect modification across clinically relevant subgroups. Sensitivity analysis restricted to studies defining plaque as focal thickening yielded a comparable OR (1.38 [95% CI, 1.29-1.47]; I-2=57.1%; 14 studies; 17 352 participants; 6991 incident plaques).Conclusions: Our large-scale individual participant data meta-analysis demonstrated that CCA-IMT is associated with the long-term risk of developing first-ever carotid plaque, independent of traditional cardiovascular risk factors.
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| 6. |
- Anjana, Ranjit Mohan, et al.
(författare)
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Contrasting Associations Between Diabetes and Cardiovascular Mortality Rates in Low-, Middle-, and High-Income Countries: Cohort Study Data From 143,567 Individuals in 21 Countries in the PURE Study.
- 2020
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Ingår i: Diabetes care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 43:12, s. 3094-3101
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to compare cardiovascular (CV) events, all-cause mortality, and CV mortality rates among adults with and without diabetes in countries with differing levels of income.The Prospective Urban Rural Epidemiology (PURE) study enrolled 143,567 adults aged 35-70 years from 4 high-income countries (HIC), 12 middle-income countries (MIC), and 5 low-income countries (LIC). The mean follow-up was 9.0 ± 3.0 years.Among those with diabetes, CVD rates (LIC 10.3, MIC 9.2, HIC 8.3 per 1,000 person-years, P < 0.001), all-cause mortality (LIC 13.8, MIC 7.2, HIC 4.2 per 1,000 person-years, P < 0.001), and CV mortality (LIC 5.7, MIC 2.2, HIC 1.0 per 1,000 person-years, P < 0.001) were considerably higher in LIC compared with MIC and HIC. Within LIC, mortality was higher in those in the lowest tertile of wealth index (low 14.7%, middle 10.8%, and high 6.5%). In contrast to HIC and MIC, the increased CV mortality in those with diabetes in LIC remained unchanged even after adjustment for behavioral risk factors and treatments (hazard ratio [95% CI] 1.89 [1.58-2.27] to 1.78 [1.36-2.34]).CVD rates, all-cause mortality, and CV mortality were markedly higher among those with diabetes in LIC compared with MIC and HIC with mortality risk remaining unchanged even after adjustment for risk factors and treatments. There is an urgent need to improve access to care to those with diabetes in LIC to reduce the excess mortality rates, particularly among those in the poorer strata of society.
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| 7. |
- Avdic, Tarik, et al.
(författare)
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Non-coronary arterial outcomes in people with type 1 diabetes mellitus: a Swedish retrospective cohort study.
- 2024
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Ingår i: The Lancet regional health - Europe. - 2666-7762. ; 39
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Tidskriftsartikel (refereegranskat)abstract
- Observational studies on long-term trends, risk factor association and importance are scarce for type 1 diabetes mellitus and peripheral arterial outcomes. We set out to investigate trends in non-coronary complications and their relationships with cardiovascular risk factors in persons with type 1 diabetes mellitus compared to matched controls.34,263 persons with type 1 diabetes mellitus from the Swedish National Diabetes Register and 164,063 matched controls were included. Incidence rates of extracranial large artery disease, aortic aneurysm, aortic dissection, lower extremity artery disease, and diabetic foot syndrome were analyzed using standardized incidence rates and Cox regression.Between 2001 and 2019, type 1 diabetes mellitus incidence rates per 100,000 person-years were as follows: extracranial large artery disease 296.5-84.3, aortic aneurysm 0-9.2, aortic dissection remained at 0, lower extremity artery disease 456.6-311.1, and diabetic foot disease 814.7-77.6. Persons with type 1 diabetes mellitus with cardiometabolic risk factors at target range did not exhibit excess risk of extracranial large artery disease [HR 0.83 (95% CI, 0.20-3.36)] or lower extremity artery disease [HR 0.94 (95% CI, 0.30-2.93)], compared to controls. Persons with type 1 diabetes with all risk factors at baseline, had substantially elevated risk for diabetic foot disease [HR 29.44 (95% CI, 3.83-226.04)], compared to persons with type 1 diabetes with no risk factors. Persons with type 1 diabetes mellitus continued to display a lower risk for aortic aneurysm, even with three cardiovascular risk factors at baseline [HR 0.31 (95% CI, 0.15-0.67)]. Relative importance analyses demonstrated that education, glycated hemoglobin (HbA1c), duration of diabetes and lipids explained 54% of extracranial large artery disease, while HbA1c, smoking and systolic blood pressure explained 50% of lower extremity artery disease and HbA1c alone contributed to 41% of diabetic foot disease. Income, duration of diabetes and body mass index explained 66% of the contribution to aortic aneurysm.Peripheral arterial complications decreased in persons with type 1 diabetes mellitus, except for aortic aneurysm which remained low. Besides glycemic control, traditional cardiovascular risk factors were associated with incident outcomes. Risk of these outcomes increased with additional risk factors present. Persons with type 1 diabetes mellitus exhibited a lower risk of aortic aneurysm compared to controls, despite presence of cardiovascular risk factors.Swedish Governmental and the county support of research and education of doctors, the Swedish Heart and Lung Foundation, Sweden and Åke-Wibergs grant.
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| 8. |
- Rautio, Aslak, et al.
(författare)
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The effect of basal insulin glargine on the fibrinolytic system and von Willebrand factor in people with dysglycaemia and high risk for cardiovascular events : Swedish substudy of the Outcome Reduction with an Initial Glargine Intervention trial
- 2017
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Ingår i: Diabetes & Vascular Disease Research. - : Sage Publications. - 1479-1641 .- 1752-8984. ; 14:4, s. 345-352
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Fibrinolytic factors, plasminogen activator inhibitor-1, tissue plasminogen activator, tissue plasminogen activator/plasminogen activator-complex and the haemostatic factor von Willebrand factor are known markers of cardiovascular disease. Their plasma levels are adversely affected in patients with dysglycaemia, and glucose normalization with insulin glargine might improve the levels of these factors. Methods: Prespecified Swedish substudy of the Outcome Reduction with an Initial Glargine Intervention trial (ClinicalTrials.gov number, NCT00069784). Tissue plasminogen activator activity, tissue plasminogen activator antigen, plasminogen activator inhibitor-1 antigen, tissue plasminogen activator/plasminogen activator inhibitor-1 complex and von Willebrand factor were analysed at study start, after 2 years and at the end of the study (median follow-up of 6.2 years). Results: Of 129 patients (mean age of 64 ± 7 years, females: 19%), 68 (53%) and 61 (47%) were randomized to the insulin glargine and standard care group, respectively. Allocation to insulin glargine did not significantly affect the studied fibrinolytic markers or von Willebrand factor compared to standard care. Likewise, there were no significant differences in plasminogen activator inhibitor-1, tissue plasminogen activator antigen and von Willebrand factor. During the whole study period, the within-group analysis revealed a curvilinear pattern and significant changes for tissue plasminogen activator/plasminogen activator inhibitor-1 complex, tissue plasminogen activator antigen and von Willebrand factor in the insulin glargine but not in the standard care group. Conclusion: In people with dysglycaemia and other cardiovascular risk factors, basal insulin does not improve the levels of markers of fibrinolysis or von Willebrand factor compared to standard glucose-lowering treatments.
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| 9. |
- Rawshani, Araz, 1986, et al.
(författare)
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Non-coronary peripheral arterial complications in people with type 2 diabetes: a Swedish retrospective cohort study
- 2024
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Ingår i: LANCET REGIONAL HEALTH-EUROPE. - 2666-7762. ; 39
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Tidskriftsartikel (refereegranskat)abstract
- Background Few studies have explored long-term trends and risk factors for peripheral arterial complications in type 2 diabetes compared to the general population. Our research focuses on identifying optimal risk factors, their significance, risk associated with multifactorial risk factor control, and trends for these complications in diabetic patients versus general controls. Methods This study included persons with type 2 diabetes mellitus entered into the Swedish National Diabetes Register 2001 - 2019 and controls matched for age-, sex- and county of residence. Outcomes comprised of extracranial large artery disease, aortic aneurysm, aortic dissection, lower extremity arterial disease and diabetes foot disease. Standardized incidence rates and Cox regression were used for analyses. Findings The study comprises 655,250 persons with type 2 diabetes mellitus; average age 64.2; 43.8% women. Among persons with type 2 diabetes mellitus, the incidence rates per 100,000 person years for each non-coronary peripheral arterial complication event changed between 2001 and 2019 as follows: extracranial large artery disease 170.0 - 84.9; aortic aneurysm 40.6 - 69.2; aortic dissection 9.3 to 5.6; lower extremity artery disease from 338.8 to 190.8; and diabetic foot disease from 309.8 to 226.8. Baseline hemoglobin A1c (HbA1c), systolic blood pressure (SBP), smoking status and lipid levels were independently associated with all outcomes in the type 2 diabetes mellitus cohort. Within the cohort with type 2 diabetes mellitus, the risk for extracranial large artery disease and lower extremity artery disease increased in a stepwise fashion for each risk factor not within target. Excess risk for non -coronary peripheral arterial complications in the entire cohort for persons with type 2 diabetes mellitus, compared to matched controls, were as follows: extracranial large artery disease adjusted hazard ratio (HR) 1.69 (95% confidence interval (CI), 1.65 - 1.73), aortic aneurysm HR 0.89 (95% CI, 0.87 - 0.92), aortic dissection HR 0.51 (95% CI, 0.46 - 0.57) and lower extremity artery disease HR 2.59 (95% CI, 2.55 - 2.64). Interpretation The incidence of non-coronary peripheral arterial complications has declined significantly among persons with type 2 diabetes mellitus, with the exception of aortic aneurysm. HbA1c, smoking and blood pressure demonstrated greatest relative contribution for outcomes and lower levels of cardiometabolic risk factors are associated with reduced relative risk of outcomes.
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| 10. |
- Ross, Stephanie, et al.
(författare)
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Association of cyclooxygenase-2 genetic variant with cardiovascular disease
- 2014
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 35:33, s. 2242-2248
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Tidskriftsartikel (refereegranskat)abstract
- Aim Agenetic variant (rs20417) of the PTGS2 gene, encoding for COX-2, has been associated with decreased COX-2 activity and a decreased risk of cardiovascular disease (CVD). However, this genetic association and the role of COX-2 in CVD remain controversial. Methods and results The association of rs20417 with CVD was prospectively explored in 49 232 subjects (ACTIVE-A, CURE, epiDREAM/DREAM, ONTARGET, RE-LY, and WGHS) and the effect of potentially modifiable risk factors on the genetic association was further explored in 9363 INTERHEART participants. The effect of rs20417 on urinary thromboxane and prostacyclin metabolite concentrations was measured in 117 healthy individuals. Carriage of the rs20417 minor allele was associated with a decreased risk of major CVD outcomes (OR = 0.78, 95% CI: 0.70-0.87; P = 1.2 x 10(-5)). The genetic effect was significantly stronger in aspirin users (OR: 0.74, 95% CI: 0.64-0.84; P = 1.20 x 10(-5)) than non-users (OR: 0.87, 95% CI: 0.72-1.06; P = 0.16) (interaction P-value: 0.0041). Among patients with previous coronary artery disease (CAD), rs20417 carriers had a stronger protective effect on risk of major adverse events when compared with individuals without previous CAD (interaction P-value: 0.015). Carriers had significantly lower urinary levels of thromboxane (P = 0.01) and prostacyclin (P = 0.01) metabolites when compared with non-carriers. Conclusion The rs20417 polymorphism is associated with a reduced risk of major cardiovascular events and lower levels of thromboxane and prostacyclin. Our results suggest that a genetic decrease in COX-2 activity may be beneficial with respect to CVD risk, especially, in higher risk patients on aspirin.
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