Katrine L. Rasmussen

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP–CAD associations (P < 5 × 10−8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

Plasma levels of apolipoprotein E and risk of dementia in the general population

The apolipoprotein E (APOE) ε4 allele is a major genetic risk factor for Alzheimer disease and dementia. However, it remains unclear whether plasma levels of apoE confer additional risk. We tested this hypothesis.

Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review

Dementia is one of the major causes of disability in later life, and ischemic heart disease is a leading cause of morbidity and mortality. Apolipoprotein E (apoE) plays a pivotal role in lipoprotein metabolism in the brain and in the periphery, and is implicated in both dementia and ischemic heart disease. Peripherally, liver-derived apoE is the main source of plasma apoE. Approximately half of plasma apoE is associated with triglyceride-rich lipoproteins, where apoE serves as the main ligand for the low density lipoprotein (LDL) receptor and the LDL receptor Related Protein (LRP). In the brain, apoE is produced mainly by astrocytes. Astrocyte-derived apoE is pivotal for cerebral cholesterol metabolism and clearance of β-amyloid, a major pathological hallmark of Alzheimer disease. Plasma levels of apoE and other lipids and lipoproteins are under strong genetic influence by the APOE polymorphism, and the ε4 allele is a strong genetic risk factor for Alzheimer disease. The characteristics of the APOE polymorphism thus suggest the qualitative importance of apoE, whereas studies of familial absolute apoE deficiency suggest a quantitative importance of plasma apoE levels in lipid metabolism. Whether plasma levels of apoE are associated with increased risk of dementia and ischemic heart disease, and whether these associations are independent of the APOE polymorphism and of lipids and lipoproteins has only recently been established. The aim of this review is to summarize and discuss the current epidemiological and biological evidence for an association of plasma levels of apoE with risk of dementia and ischemic heart disease.

Plasma levels of apolipoprotein E and risk of ischemic heart disease in the general population

BACKGROUND AND AIMS Triglyceride-rich lipoproteins are causally associated with high risk of ischemic heart disease (IHD), and apolipoprotein E (apoE) has a central role in their plasma clearance. While both quantitative and qualitative changes of apoE are established causes of rare dyslipidemia syndromes, it remains unclear whether plasma levels of apoE are associated with risk of IHD in the general population. METHODS We tested whether plasma levels of apoE at enrollment were associated with future risk of IHD and myocardial infarction (MI) in 91,695 individuals from the general population. RESULTS Multifactorially adjusted hazard ratios (HRs) for highest versus lowest apoE tertile were 1.15 (1.04-1.27) for IHD and 1.16 (1.00-1.36) for MI in men, and 0.94 (0.84-1.05) and 1.04 (0.85-1.26) in women. These associations were attenuated by adjustments for triglyceride levels. Corresponding HRs for highest versus lowest apoE tertile in ε33 carriers were 1.18 (1.03-1.36) for IHD and 1.21 (0.98-1.49) for MI in men, and 0.91 (0.78-1.06) and 0.93 (0.71-1.21) in women. Thus, the present associations were independent of APOE genotype. CONCLUSION These findings suggest that high plasma levels of apoE are associated with IHD in men but not in women. Triglyceride-rich lipoproteins may partly explain these associations.

Plasma apolipoprotein E levels and risk of dementia—A Mendelian randomization study of 106,562 individuals

In recent prospective studies, low plasma levels of apolipoprotein E (apoE) are associated with high risk of dementia. Whether this reflects a causal association remains to be established.

Data on plasma levels of apolipoprotein E, correlations with lipids and lipoproteins stratified by APOE genotype, and risk of ischemic heart disease

Data on correlations of plasma apoE with levels of lipids and lipoproteins stratified by APOE genotypes as well as data exploring the association between plasma levels of apoE and risk of ischemic heart disease (IHD) are wanted. The present data on 91,695 individuals from the general population provides correlations between plasma levels of apoE and lipids and lipoproteins for the three APOE genotypes ε33, ε44 and ε22, representing each of the three apoE isoforms. Further, data on extreme groups of plasma apoE (highest 5%) versus lower levels of apoE at enrollment explores risk of IHD and myocardial infarction (MI) and is given as hazard ratios. In addition, IHD and MI as a function of apoE/high-density lipoprotein (HDL) cholesterol ratio, as well as data on lipids, lipoproteins and apolipoproteins are given as hazard ratios. Data is stratified by gender and presented for the Copenhagen General Population Study and the Copenhagen City Heart Study combined.

Complement C3 and Risk of Diabetic Microvascular Disease: A Cohort Study of 95202 Individuals from the General Population

BACKGROUND Whether the complement system is involved in the development of diabetic microvascular disease is unknown. We tested the hypothesis that high concentrations of complement C3 are associated with increased risk of diabetic retinopathy, nephropathy, and neuropathy in individuals from the general population. METHODS We studied 95202 individuals from the general population with baseline measurements of complement C3, genotyped for rs1065489, rs429608, and rs448260 determining concentrations of complement C3, and enrolled in the Copenhagen General Population Study from 2003 through 2013, following them until April 10, 2013. Rs1065489, rs429608, and rs448260 were identified with genome-wide association scans in 3752 individuals from the Copenhagen City Heart Study. RESULTS The cumulative incidence was increased from the lowest tertile to the highest tertile of complement C3 for diabetic retinopathy (log-rank trend, P = 1 × 10-20), nephropathy (P = 7 × 10-15), and neuropathy (P = 5 × 10-10). Multifactorially adjusted hazard ratios for a 1 SD higher concentration of complement C3 were 1.87 (95% CI, 1.61-2.18) for diabetic retinopathy, 1.90 (1.62-2.23) for diabetic nephropathy, and 1.56 (1.29-1.89) for diabetic neuropathy. The multifactorially adjusted hazard ratio for individuals with the highest vs lowest tertile of complement C3 was 3.29 (1.78-6.07) for retinopathy, 2.71 (1.42-5.16) for nephropathy, and 2.40 (1.26-4.54) for neuropathy. CONCLUSIONS High baseline concentrations of complement C3 were associated with increased risk of diabetic retinopathy, nephropathy, and neuropathy in individuals from the general population. These epidemiological findings were substantiated by a Mendelian randomization approach, potentially indicating causality.

Absolute 10-year risk of dementia by age, sex and APOE genotype: a population-based cohort study

BACKGROUND: Dementia is a major cause of disability, and risk-factor reduction may have the potential to delay or prevent the disease. Our aim was to determine the absolute 10-year risk of dementia, by age, sex and apolipoprotein E (APOE) genotype. METHODS: We obtained data from the Copenhagen General Population Study (from 2003 to 2014) and the Copenhagen City Heart Study (from 1991 to 1994 and 2001 to 2003). Participants underwent a questionnaire, physical examination and blood sampling at baseline. Diagnoses of dementia and cerebrovascular disease were obtained from the Danish National Patient Registry up to Nov. 10, 2014. RESULTS: Among 104 537 individuals, the absolute 10-year risk of Alzheimer disease in 3017 women and men who were carriers of the APOE ɛ44 genotype was, respectively, 7% and 6% at age 60–69 years, 16% and 12% at age 70–79 years, and 24% and 19% at age 80 years and older. Corresponding values for all dementia were 10% and 8%, 22% and 19%, and 38% and 33%, respectively. Adjusted hazard ratios (HRs) for all dementia increased by genotype, from genotype ɛ22 to ɛ32 to ɛ33 to ɛ42 to ɛ43 to ɛ44 (p for trend < 0.001). Compared with ɛ33 carriers, ɛ44 carriers were more likely to develop Alzheimer disease (adjusted HR 8.74, 95% confidence interval [CI] 7.08–10.79), vascular dementia (adjusted HR 2.87, 95% CI 1.54–5.33), unspecified dementia (adjusted HR 4.68, 95% CI 3.74–5.85) and all dementia (adjusted HR 5.77, 95% CI 4.89–6.81). INTERPRETATION: Age, sex and APOE genotype robustly identify high-risk groups for Alzheimer disease and all dementia. These groups can potentially be targeted for preventive interventions.

An updated Alzheimer hypothesis: Complement C3 and risk of Alzheimer's disease—A cohort study of 95,442 individuals

We tested the hypothesis that low plasma complement C3 is observationally and genetically associated with high risk of Alzheimers disease (AD).