| 51. |
- Karvanen, Juha, et al.
(författare)
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The impact of newly identified loci on coronary heart disease, stroke and total mortality in the MORGAM prospective cohorts.
- 2009
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Ingår i: Genetic Epidemiology. - : Wiley. - 0741-0395 .- 1098-2272. ; 33:3, s. 237-246
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Tidskriftsartikel (refereegranskat)abstract
- Recently, genome wide association studies (GWAS) have identified a number of single nucleotide polymorphisms (SNPs) as being associated with coronary heart disease (CHD). We estimated the effect of these SNPs on incident CHD, stroke and total mortality in the prospective cohorts of the MORGAM Project. We studied cohorts from Finland, Sweden, France and Northern Ireland (total N=33,282, including 1,436 incident CHD events and 571 incident stroke events). The lead SNPs at seven loci identified thus far and additional SNPs (in total 42) were genotyped using a case-cohort design. We estimated the effect of the SNPs on disease history at baseline, disease events during follow-up and classic risk factors. Multiple testing was taken into account using false discovery rate (FDR) analysis. SNP rs1333049 on chromosome 9p21.3 was associated with both CHD and stroke (HR=1.20, 95% CI 1.08-1.34 for incident CHD events and 1.15, 0.99-1.34 for incident stroke). SNP rs11670734 (19q12) was associated with total mortality and stroke. SNP rs2146807 (10q11.21) showed some association with the fatality of acute coronary event. SNP rs2943634 (2q36.3) was associated with high density lipoprotein (HDL) cholesterol and SNPs rs599839, rs4970834 (1p13.3) and rs17228212 (15q22.23) were associated with non-HDL cholesterol. SNPs rs2943634 (2q36.3) and rs12525353 (6q25.1) were associated with blood pressure. These findings underline the need for replication studies in prospective settings and confirm the candidacy of several SNPs that may play a role in the etiology of cardiovascular disease.
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| 52. |
- Magnussen, Christina, et al.
(författare)
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Global effect of modifiable risk factors on cardiovascular disease and mortality
- 2023
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Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 389:14, s. 1273-1285
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Tidskriftsartikel (refereegranskat)abstract
- Background: Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking.Methods: We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality.Results: Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6).Conclusions: Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the German Center for Cardiovascular Research (DZHK); ClinicalTrials.gov number, NCT05466825.)
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| 53. |
- Magnussen, Christina, et al.
(författare)
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Global Effect of Modifiable Risk Factors on Cardiovascular Disease and Mortality
- 2023
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Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 389:14, s. 1273-1285
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Tidskriftsartikel (refereegranskat)abstract
- Background Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking.Methods We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality.Results Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6).Conclusions Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the German Center for Cardiovascular Research (DZHK); ClinicalTrials.gov number, NCT05466825.)Harmonized individual-level data from a global cohort showed that more than half the cases of incident cardiovascular disease and one fifth of deaths may be attributable to five modifiable risk factors.
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| 54. |
- Mahajan, Anubha, et al.
(författare)
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Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:4, s. 559-571
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Tidskriftsartikel (refereegranskat)abstract
- We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
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| 55. |
- Manning, Alisa, et al.
(författare)
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A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
- 2017
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Ingår i: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 66:7, s. 2019-2032
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Tidskriftsartikel (refereegranskat)abstract
- To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
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| 56. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 57. |
- McHugh Power, Joanna E., et al.
(författare)
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Comparisons of the discrepancy between loneliness and social isolation across Ireland and Sweden : findings from TILDA and SNAC-K
- 2019
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Ingår i: Social Psychiatry and Psychiatric Epidemiology. - : Springer Science and Business Media LLC. - 0933-7954 .- 1433-9285. ; 54:9, s. 1079-1088
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Loneliness may have different cultural meanings in different countries. This may manifest as differing levels of Social Asymmetry-the discrepancy between loneliness and social isolation. Since loneliness is thought to be low in Sweden relative to more southerly countries, we hypothesised that more number of individuals would also fall into the discordant robust category of Social Asymmetry, i.e. that more individuals in Sweden would have lower loneliness levels relative to social isolation than in Ireland. We also explored the clinical relevance of Social Asymmetry in both countries, by examining its association with cognitive functioning.Methods We derived Social Asymmetry metrics in two representative cohort studies: the Irish Longitudinal Study on Ageing (TILDA) and the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K). Data pertaining to a dementia-free sample of 4565 Irish participants and 3042 Swedish participants, all aged over 60 years, were analysed using a multilevel modelling approach, with country as a higher-order variable.Results Contrary to the expected, more individuals in Ireland were discordant robust than in Sweden. We also found evidence for superior performance in global cognitive functioning among those in the discordant robust category relative to those in the discordant susceptible (i.e. those with higher levels of loneliness than social isolation) category, beta = 0.61, p < .001, across both countries.Conclusions Irish older adults may be more robust to the impact of social isolation on loneliness than those in the Swedish cohort. Social Asymmetry was related to cognitive functioning in both countries, suggesting that Social Asymmetry is a clinically relevant construct.
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| 58. |
- Mons, Ute, et al.
(författare)
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Impact of smoking and smoking cessation on cardiovascular events and mortality among older adults : meta-analysis of individual participant data from prospective cohort studies of the CHANCES consortium
- 2015
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Ingår i: The BMJ. - : BMJ PUBLISHING GROUP. - 1756-1833. ; 350
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE To investigate the impact of smoking and smoking cessation on cardiovascular mortality, acute coronary events, and stroke events in people aged 60 and older, and to calculate and report risk advancement periods for cardiovascular mortality in addition to traditional epidemiological relative risk measures. DESIGN Individual participant meta-analysis using data from 25 cohorts participating in the CHANCES consortium. Data were harmonised, analysed separately employing Cox proportional hazard regression models, and combined by meta-analysis. RESULTS Overall, 503 905 participants aged 60 and older were included in this study, of whom 37 952 died from cardiovascular disease. Random effects meta-analysis of the association of smoking status with cardiovascular mortality yielded a summary hazard ratio of 2.07 (95% CI 1.82 to 2.36) for current smokers and 1.37 (1.25 to 1.49) for former smokers compared with never smokers. Corresponding summary estimates for risk advancement periods were 5.50 years (4.25 to 6.75) for current smokers and 2.16 years (1.38 to 2.39) for former smokers. The excess risk in smokers increased with cigarette consumption in a dose-response manner, and decreased continuously with time since smoking cessation in former smokers. Relative risk estimates for acute coronary events and for stroke events were somewhat lower than for cardiovascular mortality, but patterns were similar. CONCLUSIONS Our study corroborates and expands evidence from previous studies in showing that smoking is a strong independent risk factor of cardiovascular events and mortality even at older age, advancing cardiovascular mortality by more than five years, and demonstrating that smoking cessation in these age groups is still beneficial in reducing the excess risk.
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| 59. |
- Morgan, Roxroy C., et al.
(författare)
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TGF-β Promotes the Postselection Thymic Development and Peripheral Function of IFN-γ-Producing Invariant NKT cells
- 2023
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Ingår i: Journal of Immunology. - 0022-1767. ; 211:9, s. 1376-1384
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Tidskriftsartikel (refereegranskat)abstract
- IFN-γproducing invariant NKT (iNKT)1 cells are lipid-reactive innate-like lymphocytes that are resident in the thymus and peripheral tissues where they protect against pathogenic infection. The thymic functions of iNKT1 cells are not fully elucidated, but subsets of thymic iNKT cells modulate CD8 T cell, dendritic cell, B cell, and thymic epithelial cell numbers or function. In this study, we show that a subset of murine thymic iNKT1 cells required TGF-βinduced signals for their postselection development, to maintain hallmark TGF-βinduced genes, and for expression of the adhesion receptors CD49a and CD103. However, the residency-associated receptor CD69 was not TGFβ signalinγdependent. Recently described CD244+ c2 thymic iNKT1 cells, which produce IFNγ without exogenous stimulation and have NK-like characteristics, reside in this TGF-βresponsive population. Liver and spleen iNKT1 cells do not share this TGFβ gene signature, but nonetheless TGFβ impacts liver iNKT1 cell phenotype and function. Our findings provide insight into the heterogeneity of mechanisms guiding iNKT1 cell development in different tissues and suggest a close association between a subset of iNKT1 cells and TGF-βproducing cells in the thymus that support their development. The Journal of Immunology, 2023, 211: 1376-1384.
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| 60. |
- Müezzinler, Aysel, et al.
(författare)
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Smoking and All-cause Mortality in Older Adults : Results From the CHANCES Consortium
- 2015
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Ingår i: American Journal of Preventive Medicine. - : Elsevier BV. - 0749-3797 .- 1873-2607. ; 49:5, s. e53-e63
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Smoking is known to be a major cause of death among middle-aged adults, but evidence on its impact and the benefits of smoking cessation among older adults has remained limited. Therefore, we aimed to estimate the influence of smoking and smoking cessation on all-cause mortality in people aged ≥60 years.METHODS: Relative mortality and mortality rate advancement periods (RAPs) were estimated by Cox proportional hazards models for the population-based prospective cohort studies from Europe and the U.S. (CHANCES [Consortium on Health and Ageing: Network of Cohorts in Europe and the U.S.]), and subsequently pooled by individual participant meta-analysis. Statistical analyses were performed from June 2013 to March 2014.RESULTS: A total of 489,056 participants aged ≥60 years at baseline from 22 population-based cohort studies were included. Overall, 99,298 deaths were recorded. Current smokers had 2-fold and former smokers had 1.3-fold increased mortality compared with never smokers. These increases in mortality translated to RAPs of 6.4 (95% CI=4.8, 7.9) and 2.4 (95% CI=1.5, 3.4) years, respectively. A clear positive dose-response relationship was observed between number of currently smoked cigarettes and mortality. For former smokers, excess mortality and RAPs decreased with time since cessation, with RAPs of 3.9 (95% CI=3.0, 4.7), 2.7 (95% CI=1.8, 3.6), and 0.7 (95% CI=0.2, 1.1) for those who had quit <10, 10 to 19, and ≥20 years ago, respectively.CONCLUSIONS: Smoking remains as a strong risk factor for premature mortality in older individuals and cessation remains beneficial even at advanced ages. Efforts to support smoking abstinence at all ages should be a public health priority.
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