Showing papers by "Olle Melander published in 2012"

Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes

Abstract: To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.

Plasma HDL cholesterol and risk of myocardial infarction: A mendelian randomisation study

Abstract: Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. – ¹³) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with noncarriers. This diff erence in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45–1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69–2·69, p=2×10

Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study

Abstract: Summary Background High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal. Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. Findings Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10−13) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45–1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69–2·69, p=2×10−10). Interpretation Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction. Funding US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.

Meta-analysis identifies six new susceptibility loci for atrial fibrillation

Abstract: Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.

Metabolite Profiling Identifies Pathways Associated With Metabolic Risk in Humans

Abstract: Background—Although metabolic risk factors are known to cluster in individuals who are prone to developing diabetes mellitus and cardiovascular disease, the underlying biological mechanisms remain poorly understood. Methods and Results—To identify pathways associated with cardiometabolic risk, we used liquid chromatography/mass spectrometry to determine the plasma concentrations of 45 distinct metabolites and to examine their relation to cardiometabolic risk in the Framingham Heart Study (FHS; n=1015) and the Malmo Diet and Cancer Study (MDC; n=746). We then interrogated significant findings in experimental models of cardiovascular and metabolic disease. We observed that metabolic risk factors (obesity, insulin resistance, high blood pressure, and dyslipidemia) were associated with multiple metabolites, including branched-chain amino acids, other hydrophobic amino acids, tryptophan breakdown products, and nucleotide metabolites. We observed strong associations of insulin resistance traits with glutamine (...

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals

Abstract: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

Seventy-five genetic loci influencing the human red blood cell

Abstract: Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.

Seventy-five genetic loci influencing the human red blood cell

Abstract: Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10−8, which together explain 4–9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.

Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci

Abstract: To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with similar to 2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 x 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 x 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 x 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 x 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 x 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.

Meta-analysis identifies multiple loci associated with kidney function–related traits in east Asian populations

Abstract: Chronic kidney disease (CKD), impairment of kidney function, is a serious public health problem, and the assessment of genetic factors influencing kidney function has substantial clinical relevance. Here, we report a meta-analysis of genome-wide association studies for kidney function-related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN). Our meta-analysis identified 17 loci newly associated with kidney function-related traits, including the concentrations of blood urea nitrogen, uric acid and serum creatinine and estimated glomerular filtration rate based on serum creatinine levels (eGFRcrea) (P < 5.0 × 10(-8)). We further examined these loci with in silico replication in individuals of European ancestry from the KidneyGen, CKDGen and GUGC consortia, including a combined total of ∼110,347 individuals. We identify pleiotropic associations among these loci with kidney function-related traits and risk of CKD. These findings provide new insights into the genetics of kidney function.

Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci

Abstract: Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.

Genomewide Association Study Using a High-Density Single Nucleotide Polymorphism Array and Case-Control Design Identifies a Novel Essential Hypertension Susceptibility Locus in the Promoter Region of Endothelial NO Synthase

Abstract: Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37-1.73]; combined P=2.58 · 10(-13)). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25-1.44; P=1.032 · 10(-14)). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16-3.66) for systolic and 1.40 (95% CI: 0.25-2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus.

Low Plasma Level of Atrial Natriuretic Peptide Predicts Development of Diabetes: The Prospective Malmö Diet and Cancer Study

Abstract: Context:The cardiac natriuretic peptides are involved in blood pressure regulation, and large cross-sectional studies have shown lower plasma levels of N-terminal pro-natriuretic peptide levels [N-terminal atrial natriuretic peptide (N-ANP) and N-terminal brain natriuretic peptide (N-BNP)] in patients with insulin resistance, obesity, and diabetes.Objective:In this study, we prospectively tested whether plasma levels of mid-regional ANP (MR-ANP) and N-BNP predict new-onset diabetes and long-term glucose progression.Design, Setting, and Patients:MR-ANP and N-BNP were measured in 1828 nondiabetic individuals of the Malmo Diet and Cancer cohort (mean age 60 yr; 61% women) who subsequently underwent a follow-up exam including an oral glucose tolerance test after a median follow-up time of 16 yr. Logistic regression was used to adjust for covariates.Results:During follow-up, 301 subjects developed new-onset diabetes. After full multivariate adjustment, MR-ANP was significantly inversely associated with incident diabetes (OR = 0.85; 95% CI = 0.73-0.99; P = 0.034) but not N-BNP (OR = 0.92; 95% CI = 0.80-1.06; P = 0.262). In fully adjusted linear regression models, the progression of fasting glucose during follow-up was significantly inversely related to baseline levels of MR-ANP (P = 0.004) but not N-BNP (P = 0.129). Quartile analyses revealed that the overall association was mainly accounted for by excess risk of incident diabetes in subjects belonging to the lowest quartile of MR-ANP. After full adjustment, the odds ratio for incident diabetes in the bottom compared with the top quartile of MR-ANP was 1.65 (OR = 1.08-2.51, P = 0.019) and 1.43 (OR = 1.04-1.96, P = 0.027) compared with all other subjects.Conclusion:Low plasma levels of MR-ANP predict development of future diabetes and glucose progression over time, suggesting a causal role of ANP deficiency in diabetes development.

Plasma Proneurotensin and Incidence of Diabetes, Cardiovascular Disease, Breast Cancer, and Mortality

Abstract: Neurotensin regulates both satiety and breast cancer growth in the experimental setting, but little is known about its role in the development of breast cancer or cardiometabolic disease in humans.

Total and differential leucocyte counts in relation to incidence of stroke subtypes and mortality: a prospective cohort study

Abstract: . Zia E, Melander O, Bjorkbacka H, Hedblad B, Engstrom G (Lund University, Malmo; Institute of Clinical Sciences, Lund University, Malmo; Skane University Hospital, Malmo; and Astra Zeneca RD 272: 298304. Objectives. Elevated levels of total leucocyte as well as leucocyte subtypes have been associated with increased risk of atherosclerotic disease. Atherosclerosis is an important cause of cerebral infarction, whereas its significance in intracerebral haemorrhage (ICH) is less clear. A small number of prospective studies have revealed the relationship between leucocyte counts and incident stroke, in particular incidence of stroke subtypes. We evaluated the associations between total leucocyte count (TLC) as well as leucocyte subtypes and the incidence of and mortality caused by different stroke subtypes. Design and subjects. Of 28 449 participants from the Malmo Diet and Cancer Study, 26 927 stroke-free subjects (mean age at screening, 58 +/- 8 years) were included in a prospective cohort study. The screening period was between 1991 and 1996. Incidence of stroke, 1-year mortality and 1-month case-fatality rate (CFR) were assessed by linkage to local and national registers. Cox regression analysis was used to assess stroke risk and 1-year mortality, and 1-month CFR was assessed by logistic regression analysis. Results. During a follow-up period of 13.6 +/- 3.3 years, 1515 participants had a first-ever stroke (cerebral infarction, n = 1314; ICH, n = 201). After adjustments for other risk factors, TLC and neutrophil count were significantly associated with increased incidence of cerebral infarction (hazards ratio (HR), 1.4; 95% confidence interval (CI), 1.21.7 and 1.3; 95% CI, 1.11.5, respectively). There was an inverse association between elevated TLC and incident ICH (HR, 0.7; 95% CI, 0.40.99). No associations were found between leucocyte counts and mortality for either stroke subtype. Conclusion. The results suggest that the relationships with inflammation for ischaemic stroke and ICH are different. (Less)

Genetic variation in PNPLA3 but not APOC3 influences liver fat in non-alcoholic fatty liver disease

Abstract: Background and Aim: A recent study in Indian subjects suggested common variants in apolipoprotein C3 (APOC3) (T-455C at rs2854116 and C-482T at rs2854117) to contribute to non-alcoholic fatty liver disease (NAFLD), plasma apoC3 and triglyceride concentrations. Our aim was to determine the contribution of genetic variation in APOC3 on liver fat content and plasma triglyceride and apoC3 concentrations in a larger European cohort. Methods: Atotal of 417 Finnish individuals were genotyped for rs2854116 and rs2854117 in APOC3 and the known rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3) influencing liver fat. Plasma apoC3 concentration was measured enzymatically, and liver fat by proton magnetic resonance spectroscopy. Results: APOC3 wild-type homozygotes and variant allele (T-455C or C-482T or both) carriers did not differ with regard to liver fat, apoC3 concentrations, triglyceride-, high density lipoprotein-, fasting plasma glucose, insulin-, alanine aminotransferase-and aspartate aminotransferase-concentrations, nor was there a difference in prevalence of NAFLD. In contrast, carriers of the PNPLA3 GG genotype at rs738409 had a 2.7-fold (median 11.3%) higher liver fat than those with the CC (median 4.2%) genotype. The PNPLA3 rs738409 was also an independent predictor of liver fat, together with age, gender, and body mass index. Conclusion: Genetic variants in PNPLA3 but not APOC3 contribute to the variance in liver fat content due to NAFLD. (Less)

A common missense variant in the ATP receptor P2X7 is associated with reduced risk of cardiovascular events.

Abstract: Background and Purpose: Extracellular adenosine triphosphate (ATP) regulates inflammatory cells by activation of the P2X7 receptor. We hypothesized that polymorphisms in P2RX7 influence the risk of ischemic heart disease (IHD), ischemic stroke (IS) and cardiovascular risk factors and tested this hypothesis using genetic association studies. Methods: Two loss-of-function SNPs in P2RX7 were genotyped in 1244 IHD cases and 2488 controls as well as 5969 individuals with cardiovascular risk factors. Eleven SNPs in a 250 kb region on chromosome 12 spanning P2RX7 as well as neighboring genes OASL, P2RX4 and CAMKK2 were genotyped in 4138 individuals with IS and 2528 controls. Association was examined using linear and logistic regression models with an additive genetic model. Results: The common loss-of-function variant rs3751143 was significantly associated with a decreased risk of IHD in smokers (P = 0.03) as well as decreased risk of IS (OR 0.89; 95% CI = 0.81-0.97; P = 0.012). In addition, an intronic SNP in CAMKK2, rs2686342, were associated with a decreased risk of IS (OR 0.89; 95% CI = 0.82-0.97; P = 0.011). In subgroup analyses, both SNPs were associated with decreased risk of IS in individuals with hypertension (P = 0.045 and 0.015, respectively). Conclusions: A common loss-of-function missense variant in the gene encoding the P2X7 receptor is associated with reduced risk of IS and with IHD in smokers. These findings might implicate a role of purinergic signaling in atherogenesis or atherothrombosis.

Incidence of Coronary Events and Case Fatality Rate in Relation to Blood Lymphocyte and Neutrophil Counts

Abstract: OBJECTIVE: Elevated levels of blood leukocytes have been associated with acute coronary events (CEs), but data on leukocyte subclasses are limited. This study aimed to explore whether blood lymphocyte and neutrophil counts are associated with incidence of CEs and with fatal outcome in subjects who subsequently experienced a first CE. METHODS AND RESULTS: Neutrophil and lymphocyte counts were measured in 27 419 subjects from the general population without a history of CEs, heart failure, or atrial fibrillation. Incidence of CEs was studied in relation to leukocyte counts during a mean follow-up of 13.6 years. Neutrophil but not lymphocyte counts were significantly associated with incidence of CEs. After adjustments for confounding factors, the hazard ratios (95% confidence interval) were 1.00 (reference), 1.07 (0.94-1.23), 1.09 (0.95-1.25), and 1.39 (1.22-1.59) for subjects with neutrophils in the first, second, third, and fourth (highest) sex-specific quartiles, respectively (P for trend <0.001). Of the 1965 subject who had a CE, 471 subjects died on the first day of the CE, in- or outside hospital. The proportions of subjects who died the first day were 19%, 21%, 25%, and 28%, respectively in the first, second, third, and fourth quartiles (P for trend <0.001). CONCLUSIONS: Increased neutrophil counts are associated with incidence of CEs and increased case-fatality rate after a CE.

Identification of the BCAR1-CFDP1-TMEM170A Locus as a Determinant of Carotid Intima-Media Thickness and Coronary Artery Disease Risk

Abstract: Background-Carotid intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. To date, large-scale investigations of genetic determinants of cIMT are sparse. Methods and Results-To identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. Segment-specific IMT measurements of common carotid, bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMTmean, IMTmax, and IMTmean-max), were analyzed. A replication stage investigating 42 single-nucleotide polymorphisms for association with common carotid IMT was undertaken in 5 independent European cohorts (total n=11 590). A locus on chromosome 16 (lead single-nucleotide polymorphism rs4888378, intronic in CFDP1) was associated with cIMT at significance levels passing multiple testing correction at both stages (array-wide significant discovery P=6.75x10(-7) for IMTmax; replication P=7.24x10(-6) for common cIMT; adjustments for sex, age, and population substructure where applicable; minor allele frequency 0.43 and 0.41, respectively). The protective minor allele was associated with lower carotid plaque score in a replication cohort (P=0.04, n=2120) and lower coronary artery disease risk in 2 case-control studies of subjects with European ancestry (odds ratio [95% confidence interval] 0.83 [0.77-0.90], P=6.53x10(-6), n=13 591; and 0.95 [0.92-0.98], P=1.83x10(-4), n= 82 297, respectively). Queries of human biobank data sets revealed associations of rs4888378 with nearby gene expression in vascular tissues (n=126-138). Conclusions-This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and coronary artery disease risk in individuals of European descent. (Circ Cardiovasc Genet. 2012;5:656-665.)

Genetic Variation Within the Interleukin-1 Gene Cluster and Ischemic Stroke

Abstract: Background and Purpose—Evidence is emerging that inflammation plays a key role in the pathophysiology of ischemic stroke (IS). The aim of this study was to investigate whether genetic variation in the interleukin-1α, interleukin-1β, and interleukin-1 receptor antagonist genes (IL1A, IL1B, and IL1RN) is associated with IS and/or any etiologic subtype of IS. Methods—Twelve tagSNPs were analyzed in the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), which comprises 844 patients with IS and 668 control subjects. IS subtypes were defined according to the Trial of Org 10172 in Acute Stroke Treatment criteria in SAHLSIS. The Lund Stroke Register and the Malmo Diet and Cancer study were used as a replication sample for overall IS (in total 3145 patients and 1793 control subjects). Results—The single nucleotide polymorphism rs380092 in IL1RN showed an association with overall IS in SAHLSIS (OR, 1.21; 95% CI, 1.02–1.43; P=0.03), which was replicated in the Lund Stroke Register and the Malmo Diet and Cancer ...

Association of central and peripheral pulse pressure with intermediate cardiovascular phenoytpes

Abstract: OBJECTIVE: We assessed the relationship between pulse pressure and intermediate cardiovascular phenotypes in a middle-aged cohort with high prevalence of hypertension. BACKGROUND: It has been suggested that central pulse pressure (cPP) is a better predictor of cardiovascular outcome than peripheral pulse pressure (pPP), particularly in the elderly. Yet, it is unclear if cPP provides additional prognostic information to pPP in younger individuals. METHODS: In 535 individuals we assessed cPP and pPP as well as the intermediate cardiovascular phenotypes pulse wave velocity (PWV; SphygmoCor, Complior, PulsePen), carotid intima-media thickness (C-IMT; carotid ultrasound), left-ventricular mass index (LVMI; echocardiography) and urinary albumin : creatinine ratio (ACR). cPP was derived noninvasively from brachial blood pressure by pulse wave analysis (PWA; SphygmoCor) based on radial pulse wave tonometry and a validated transfer function. RESULTS: The cohort contained 331 hypertensive participants of whom 84% were treated. The average age was 46 ± 16 years. When compared to pPP, cPP had stronger associations with PWV (r = 0.471 vs. r = 0.372; P < 0.01), C-IMT (r = 0.426 vs. r = 0.235; P < 0.01) and LVMI (r = 0.385 vs. r = 0.189; P < 0.01), but equal association with ACR (r = 0.236 vs. r = 0.226; P = n.s.). In contrast, after adjustment for age, mean arterial pressure, heart rate and hypertension status there was no significant difference between cPP and pPP for prediction of PWV (adjusted R, 0.399 vs. 0.413; P = 0.066), C-IMT (adjusted R, 0.399 vs. 0.413; P = 0.487) and LVMI (adjusted R, 0.181 vs. 0.170; P = 0.094) in multivariate analysis. CONCLUSION: In our middle-aged cohort with high prevalence of hypertension cPP is more closely correlated with cardiovascular phenotypes than pPP. When adjusted for relevant cofactors, however, cPP does not provide additional information beyond pPP. (Less)

Orthostatic blood pressure response, carotid intima-media thickness, and plasma fibrinogen in older nondiabetic adults.

Abstract: OBJECTIVE:: Although recent studies have indicated that both orthostatic hypotension and orthostatic hypertension (OHTN) independently predict cardiovascular events, the underlying mechanisms are still debatable. METHODS:: A total of 700 nondiabetic adults (43% men, age 64 years) were examined by orthostatic blood pressure (BP) test, carotid artery ultrasonography, and biochemical tests including plasma fibrinogen and lipid profile. Multivariate-adjusted logistic regression was applied to assess association of intima-media thickness (IMT) and P-fibrinogen with orthostatic hypotension and OHTN. In addition, distribution of IMT and P-fibrinogen across quintiles of orthostatic systolic BP (SBP) response was analyzed. RESULTS:: Orthostatic hypotension and OHTN were found in 40 (5.7%) and 45 (6.4%) study participants, respectively. Both IMT [odds ratio (OR), 95% confidence interval (CI) per one-SD increment: 1.27, 1.01-1.60; P = 0.04] and P-fibrinogen (OR 1.44, 1.07-1.93; P = 0.02) were associated with orthostatic hypotension in a crude model. After adjustment relationship between orthostatic hypotension and IMT was slightly attenuated (OR 1.26, 0.96-1.65; P = 0.09) but was substantially unchanged in regard to P-fibrinogen (OR 1.45, 1.06-1.99; P = 0.02). In contrast, OHTN showed no association with either IMT or P-fibrinogen (adjusted OR 1.09, 0.78-1.52; P = 0.61, and 0.97, 0.70-1.34; P = 0.84, respectively). Distribution of IMT across quintiles of orthostatic SBP response was U-shaped, whereas that of fibrinogen was more linear but none of borderline quintiles (with pronounced hypertensive or hypotensive response) significantly differed from the middle quintiles in a fully adjusted model. CONCLUSION:: In older nondiabetic adults only orthostatic hypotension seems to independently correlate with increased carotid atherosclerosis and systemic inflammation. (Less)

Orthostatic hypotension and novel blood pressure-associated gene variants: Genetics of Postural Hemodynamics (GPH) Consortium

Abstract: Aims Orthostatic hypotension (OH), an independent predictor of mortality and cardiovascular events, strongly correlates with hypertension. Recent genome-wide studies have identified new loci influencing blood pressure (BP) in populations, but their impact on OH remains unknown. Methods and results A total of 38 970 men and women of European ancestry from five population-based cohorts were included, of whom 2656 (6.8%) met the diagnostic criteria for OH (systolic/diastolic BP drop ≥20/10 mmHg within 3 min of standing). Thirty-one recently discovered BP-associated single nucleotide polymorphisms (SNPs) were examined using an additive genetic model and the major allele as referent. Relations between OH, orthostatic systolic BP response, and genetic variants were assessed by inverse variance-weighted meta-analysis. We found Bonferroni adjusted ( P < 0.0016) significant evidence for association between OH and the EBF1 locus (rs11953630, per-minor-allele odds ratio, 95% confidence interval: 0.90, 0.85–0.96; P = 0.001), and nominal evidence ( P < 0.05) for CYP17A1 (rs11191548: 0.85, 0.75–0.95; P = 0.005), and NPR3- C5orf23 (rs1173771: 0.92, 0.87–0.98; P = 0.009) loci. Among subjects not taking BP-lowering drugs, three SNPs within the NPPA/NPPB locus were nominally associated with increased risk of OH (rs17367504: 1.13, 1.02–1.24; P = 0.02, rs198358: 1.10, 1.01–1.20; P = 0.04, and rs5068: 1.22, 1.04–1.43; P = 0.01). Moreover, an ADM variant was nominally associated with continuous orthostatic systolic BP response in the adjusted model ( P = 0.04). Conclusion The overall association between common gene variants in BP loci and OH was generally weak and the direction of effect inconsistent with resting BP findings. These results suggest that OH and resting BP share few genetic components.

Plasma procalcitonin and the risk of cardiovascular events and death: a prospective population-based study.

Abstract: Objectives: A number of inflammatory biomarkers such as C reactive protein (CRP) are independent predictors of cardiovascular risk. The inflammatory biomarker procalcitonin (PCT) has previously been shown to be associated with coronary atherosclerosis and the metabolic syndrome. We evaluated the ability of PCT to predict future cardiovascular events in a population of apparently healthy individuals. Design: We measured plasma PCT levels in 3713 subjects with no previous history of cardiovascular disease, randomly selected from the Malmo Diet and Cancer cohort. The correlation between PCT concentration and the incidence of coronary events, stroke and cardiovascular death over a median follow-up period of 13.7 years was studied using a Cox regression analysis corrected for age, sex, CRP level, traditional risk factors and renal function. Results: Age and sex were strong determinants of PCT; the concentration of PCT was significantly higher in men than in women. PCT was associated with several of the established cardiovascular risk factors (CRP, hypertension, diabetes and renal function,) as determined by multivariate linear regression. Of note, PCT was inversely correlated with HDL and smoking. We found significant correlations between PCT levels, coronary events and cardiovascular death. However, these relationships lost statistical significance when the analysis was corrected for CRP and the traditional risk factors. Conclusions: This is the largest population-based prospective study to demonstrate a positive association between plasma PCT levels and cardiovascular risk in subjects with no previous history of acute cardiovascular events. However, the high degree of covariation between PCT and other cardiovascular risk factors limits the value of PCT as an independent cardiovascular risk predictor. © 2012 The Association for the Publication of the Journal of Internal Medicine. (Less)

The Renalase Asp37Glu polymorphism is not associated with hypertension and cardiovascular events in an urban-based prospective cohort: the Malmö Diet and cancer study

Abstract: Renalase (gene name RNLS), a recently discovered enzyme with monoamine oxidase activity, is implicated in the degradation of catecholamines. Recent studies delineate a possible role of this enzyme in blood pressure (BP) maintenance and cardiac protection and two single nucleotide polymorphisms, RNLS rs2576178 A > G and rs2296545 C > G have been associated with hypertension. The latter SNP leads to a non synonymous Asp to Glu substitution deleting a flavin adenine dinucleotide (FAD) binding site with possible impaired functionality. We tested the hypothesis that these polymorphisms could affect BP levels, hypertension prevalence, and risk of incident cardiovascular events in middle-aged Swedes. The polymorphisms were genotyped in 5696 participants of the population-based Cardiovascular Cohort of the "Malmo Diet and Cancer" (MDC-CC). The incidence of cardiovascular events (coronary events [n = 408], strokes [n = 330], heart failure [n = 190] and atrial fibrillation/flutter [n = 406]) was monitored for an average of approximately 15 years of follow-up. Both before and after adjustment for sex, age and BMI the polymorphisms did not show any effect on BP level and hypertension prevalence. Before and after adjustment for major cardiovascular risk factors, the hazard ratio for cardiac and cerebrovascular events was not significantly different in carriers of different genotypes. A significant interaction was found between the rs2296545 C > G and age with respect to BP/hypertension. Our data do not support a major role for these RNLS polymorphisms in determining BP level and incident events at population level. The positive interaction with age suggest that the effect of the rs2296545 C > G polymorphism, if any, could vary between different ages.

Hypothesis-Based Analysis of Gene-Gene Interactions and Risk of Myocardial Infarction

Abstract: The genetic loci that have been found by genome-wide association studies to modulate risk of coronary heart disease explain only a fraction of its total variance, and gene-gene interactions have been proposed as a potential source of the remaining heritability. Given the potentially large testing burden, we sought to enrich our search space with real interactions by analyzing variants that may be more likely to interact on the basis of two distinct hypotheses: a biological hypothesis, under which MI risk is modulated by interactions between variants that are known to be relevant for its risk factors; and a statistical hypothesis, under which interacting variants individually show weak marginal association with MI. In a discovery sample of 2,967 cases of early-onset myocardial infarction (MI) and 3,075 controls from the MIGen study, we performed pair-wise SNP interaction testing using a logistic regression framework. Despite having reasonable power to detect interaction effects of plausible magnitudes, we observed no statistically significant evidence of interaction under these hypotheses, and no clear consistency between the top results in our discovery sample and those in a large validation sample of 1,766 cases of coronary heart disease and 2,938 controls from the Wellcome Trust Case-Control Consortium. Our results do not support the existence of strong interaction effects as a common risk factor for MI. Within the scope of the hypotheses we have explored, this study places a modest upper limit on the magnitude that epistatic risk effects are likely to have at the population level (odds ratio for MI risk 1.3-2.0, depending on allele frequency and interaction model).

A myocardial infarction genetic risk score is associated with markers of carotid atherosclerosis

Abstract: Objective: To assess whether a genetic risk score that was previously shown to be associated with myocardial infarction and coronary artery disease is also associated with markers of carotid atherosclerosis. Design: A total of 4022 middle-aged subjects from the general Swedish population were genotyped and individually assigned a genetic risk score based on 13 single-nucleotide polymorphisms (SNPs), previously associated with myocardial infarction and coronary artery disease. The genetic score (Score-MI) was then related to carotid bulb intima-media thickness (IMT), common carotid artery IMT and to the occurrence of carotid plaques in the study population. Results: Score-MI was associated with IMT of the bulb (P<0.001) and the common carotid artery (P<0.001) in unadjusted analyses, and with IMT of the bulb after adjustment for cardiovascular risk factors (P=0.003). The effect size of Score-MI on IMT of the bulb was similar to that of LDL cholesterol. After adjustment for cardiovascular risk factors, Score-MI was also associated with the occurrence of carotid plaques (odds ratio per quintile of Score-MI=1.11; 95% confidence interval 1.04-1.18; P=0.001). In addition to SNPs with known effects on LDL levels, Score-MI showed nominal associations with increasing systolic blood pressure and decreasing C-reactive protein levels. Conclusions: This genetic risk score was independently associated with carotid bulb IMT and carotid plaques, providing evidence of an association with early markers of atherosclerosis. This might imply that the genetic myocardial infarction risk conferred by the score is related to early atherosclerosis and that the risk score may identify at an early stage candidates at risk of developing intermediate phenotypes of atherosclerosis. Further studies should test whether assessing the genetic score could be valuable for early treatment decisions in these subjects. (Less)

Genetic polymorphisms for estimating risk of atrial fibrillation in the general population: a prospective study.

Abstract: Atrial fibrillation (AF) is a common cardiac disease and major risk factor for stroke, heart failure and death. Tools for prediction of AF have been developed to identify individuals who might benefit from preventive therapies, incorporating conventional cardiovascular risk factors, and the effects of such risk factors have been evaluated across several cohorts.1,2 Recently, a heritable component to AF has been reported and polymorphisms in three genetic regions have been reproducibly associated with AF: chromosome 4q25, located 150 kb from the closest gene - a transcription factor (PITX2) involved in cardiac development; chromosome 16q22, intronic to another transcription factor of unknown function, expressed in cardiac tissue (ZFHX3); and an amino acid-altering variant in KCNH2, one of the major cardiac voltage-gated potassium channels.3–5 Rare genetic variants segregating with AF are typically exclusive to individual families and unlikely to contribute to AF prediction at the population level but genetic polymorphisms could provide important predictive information.