1. |
- Stitziel, Nathan O., et al.
(author)
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Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease
- 2016
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 374:12, s. 1134-1144
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Journal article (peer-reviewed)abstract
- BACKGROUND The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P = 4.2x10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P = 4.0x10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P = 0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P = 0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P = 2.0x10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P = 2.5x10(-7)). CONCLUSIONS We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease.
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2. |
- Kanoni, Stavroula, et al.
(author)
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Analysis with the exome array identifies multiple new independent variants in lipid loci
- 2016
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 25:18, s. 4094-4106
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Journal article (peer-reviewed)abstract
- It has been hypothesized that low frequency (1-5% minor allele frequency (MAF)) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here, we report an association analysis of lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27 312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were >1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF <5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1 to 5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5- and 2.5-fold increase in the proportion of heritability explained for the different lipid traits. Our findings suggest that rare coding variants contribute to the genetic architecture of lipid traits.
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3. |
- Andersson, Jonas, et al.
(author)
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Diabetes mellitus, high BMI and low education level predict sudden cardiac death within 24 hours of incident myocardial infarction
- 2016
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In: European Journal of Preventive Cardiology. - : Oxford University Press (OUP). - 2047-4873 .- 2047-4881. ; 23:17, s. 1814-1820
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Journal article (peer-reviewed)abstract
- BACKGROUND: More than half of cardiovascular mortality occurs outside the hospital, mainly due to consistently low survival rates from out-of-hospital cardiac arrest.METHODS: This is a prospective, nested, case-control study derived from the Västerbotten Intervention Programme and the World Health Organization's Multinational Monitoring of Trends and Determinants in Cardiovascular Disease study in northern Sweden (1986-2006). To determine predictors for sudden cardiac death risk factors for cardiovascular disease were compared between incident myocardial infarction with sudden cardiac death (n = 363) and survivors of incident myocardial infarction (n = 1998) using multivariate logistic regression analysis.RESULTS: Diabetes had the strongest association with sudden cardiac death out of all evaluated risk factors (odds ratio (OR) 1.83, 95% confidence interval (CI) 1.30-2.59), followed by low education (OR 1.55, 95% CI 1.19-2.01), high body mass index (OR 1.05, 95% CI 1.02-1.08) and male sex (OR 1.42, 95% CI 1.001-2.01).CONCLUSIONS: The pattern of risk factors for incident myocardial infarction is different among survivors and those who die within 24 hours. The risk factors that contribute the most to death within 24 hours are diabetes mellitus, high body mass index and low education level, and can be addressed at both the public health level and by general practitioners.
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