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- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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| 2. |
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| 3. |
- Albrektsen, G., et al.
(författare)
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Data on gender contrasts in the risk of incident myocardial infarction by age. The Tromso Study 1979-2012
- 2017
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Ingår i: Data in Brief. - : Elsevier BV. - 2352-3409. ; 13, s. 779-784
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Tidskriftsartikel (refereegranskat)abstract
- The data presented in this article relate to the research article entitled "Risk of incident myocardial infarction by gender: Interactions with serum lipids, blood pressure and smoking. The Tromso Study 1979-2012" (Albrektsen et al., 2017) [1]. Data quantify the gender differences in the risk of myocardial infarction (MI) in terms of incidence rate ratios (IRR), in subgroups defined by serum lipids, blood pressure and smoking among persons aged 35-54 years, 55-74 years and 75-94 years, respectively. Data also describe the age- and gender-specific linear associations with the coronary heart disease (CHD) risk factors. IRRs for combined categories of age, gender and a CHD risk factor, with each category compared to the same reference group, are also shown. IRRs were calculated as estimates of relative risk in Poisson regression analyses of person-years at risk. Among 33,859 individuals at risk, a total of 622,1308 and 816 were diagnosed with Ml at ages 35-54, 55-74 and 75-94 years, respectively. (C) 2017 The Authors. Published by Elsevier Inc.
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| 4. |
- Albrektsen, G., et al.
(författare)
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Lifelong gender gap in risk of incident myocardial infarction: The Tromsø study
- 2016
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Ingår i: JAMA Internal Medicine. - : American Medical Association (AMA). - 2168-6106. ; 176:11, s. 1673-1679
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE It is not clear to what extent the higher incidence of coronary heart disease (CHD) in men vs women is explained by differences in risk factor levels because few studies have presented adjusted risk estimates for sex. Moreover, the increase in risk of CHD in postmenopausal women, possibly hormone related, may eventually eliminate the sex contrast in risk, but age-specific risk estimates are scarce. OBJECTIVE To quantify the difference in risk of incidentmyocardial infarction (MI) between men and women. DESIGN, SETTING AND PARTICIPANTS Population-based prospective study from Tromsø, Norway, comprising 33 997 individuals (51% women). Median follow-up time during ages 35 to 102 years was 17.6 years. Incidence rates (IRs) and incidence rate ratios (IRRs, relative risk) of MI were calculated in Poisson regression analysis of person-years at risk. The data analysis was performed in November 2015. EXPOSURES Sex, age, birth cohort, serum lipid levels, blood pressure, lifestyle factors, diabetes. MAIN OUTCOMES AND MEASURES Incident MI. RESULTS A total of 2793 individuals (886 women) received a diagnosis of MI during follow-up in the period 1979 through 2012. The IR increased with age in both sexes, with lower rates for women until age 95 years. Adjusted for age and birth cohort, the overall IRR for men vs women was 2.72 (95%CI, 2.50-2.96). Adjustment for high-density lipoprotein cholesterol and total cholesterol levels had the strongest impact on the risk estimate for sex, followed by diastolic blood pressure and smoking. However, the sex difference remained substantial even after adjustment for these factors (IRR, 2.07; 95%CI, 1.89-2.26). Men had higher risk throughout life, but the IRRs decreased with age (3.64 [95%CI, 2.85-4.65], 2.00 [95%CI, 1.76-2.28], and 1.66 [95%CI, 1.42-1.95] for age groups 35-54, 55-74, and 75-94 years, respectively). Adjustment for systolic blood pressure, diabetes, body mass index, and physical activity had no notable impact. CONCLUSIONS AND RELEVANCE The observed sex contrast in risk of MI cannot be explained by differences in established CHD risk factors. The gender gap persisted throughout life but declined with age as a result of a more pronounced flattening of risk level changes in middle-aged men. The minor changes in IRs when moving from premenopausal to postmenopausal age in women make it unlikely that changes in female hormone levels influence the risk of MI.
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| 5. |
- Albrektsen, G., et al.
(författare)
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Risk of incident myocardial infarction by gender: Interactions with serum lipids, blood pressure and smoking. The Tromso Study 1979-2012
- 2017
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150. ; 261, s. 52-59
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Overall, men have roughly twice the risk of myocardial infarction (MI) compared to women, but what causes this contrast is unclear. Identification of subgroups where the gender contrast in risk is particularly low or high, may provide new insight. In the search for such subgroups, we focus on gender-specific effects of established coronary heart disease (CHD) risk factors. Heterogeneity across age groups is also explored. Methods: Population-based prospective study from Tromso, Norway, comprising 33,859 individuals (51% women); 2746 individuals (854 women) received a diagnosis of MI during follow-up at ages 35-94 years. Incidence rate ratios (IRR) were calculated as estimates of relative risk in Poisson regression analyses. Results: The association between total cholesterol and risk of MI was stronger for men than women, and IRR for men vs. women accordingly increased with increasing cholesterol, but the risk was higher for men in all subgroups (IRR in range 1.63-3.27), except among older people with low cholesterol levels. The adverse effect of increasing blood pressure (BP) was stronger for women, and IRR for gender diminished with increasing systolic (from 3.90 to 1.38) and diastolic BP (from 2.87 to 1.54). The gender contrast in risk was also substantially reduced in smokers >= 75 years. Associations with high-density lipoprotein cholesterol (HDL-C) did not differ between genders. Conclusions: Gender heterogeneity in associations with total cholesterol but not HDL-C indicates gender differences in associations with non-HDL-C. The stronger association with BP in women may relate to more severe hypertension-induced left ventricular hypertrophy. (C) 2017 Elsevier B.V. All rights reserved.
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