Prevalence of Subclinical Coronary Artery Atherosclerosis in the General Population.

BACKGROUND: Early detection of coronary atherosclerosis using coronary computed tomography angiography (CCTA), in addition to coronary artery calcification (CAC) scoring, may help inform prevention strategies. We used CCTA to determine the prevalence, severity, and characteristics of coronary atherosclerosis and its association with CAC scores in a general population. METHODS: We recruited 30 154 randomly invited individuals age 50 to 64 years to SCAPIS (the Swedish Cardiopulmonary Bioimage Study). The study includes individuals without known coronary heart disease (ie, no previous myocardial infarctions or cardiac procedures) and with high-quality results from CCTA and CAC imaging performed using dedicated dual-source CT scanners. Noncontrast images were scored for CAC. CCTA images were visually read and scored for coronary atherosclerosis per segment (defined as no atherosclerosis, 1% to 49% stenosis, or ≥50% stenosis). External validity of prevalence estimates was evaluated using inverse probability for participation weighting and Swedish register data. RESULTS: In total, 25 182 individuals without known coronary heart disease were included (50.6% women). Any CCTA-detected atherosclerosis was found in 42.1%; any significant stenosis (≥50%) in 5.2%; left main, proximal left anterior descending artery, or 3-vessel disease in 1.9%; and any noncalcified plaques in 8.3% of this population. Onset of atherosclerosis was delayed on average by 10 years in women. Atherosclerosis was more prevalent in older individuals and predominantly found in the proximal left anterior descending artery. Prevalence of CCTA-detected atherosclerosis increased with increasing CAC scores. Among those with a CAC score >400, all had atherosclerosis and 45.7% had significant stenosis. In those with 0 CAC, 5.5% had atherosclerosis and 0.4% had significant stenosis. In participants with 0 CAC and intermediate 10-year risk of atherosclerotic cardiovascular disease according to the pooled cohort equation, 9.2% had CCTA-verified atherosclerosis. Prevalence estimates had excellent external validity and changed marginally when adjusted to the age-matched Swedish background population. CONCLUSIONS: Using CCTA in a large, random sample of the general population without established disease, we showed that silent coronary atherosclerosis is common in this population. High CAC scores convey a significant probability of substantial stenosis, and 0 CAC does not exclude atherosclerosis, particularly in those at higher baseline risk.

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

BACKGROUND AND PURPOSE: Extracellular adenosine triphosphate (ATP) regulates inflammatory cells by activation of the P2X(7) 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 P2X(7) 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.

Pulmonary dysfunction, smoking, socioeconomic status and the risk of developing rheumatoid arthritis.

OBJECTIVES: Environmental risk factors are of potential interest for both prevention and treatment of RA. The purpose of this study was to examine the effect of pulmonary function, smoking and socio-economic status on the future risk of RA. METHODS: Between 1974 and 1992, 22 444 men and 10 902 women were included in the Malmö Preventive Medicine Program (MPMP). Pulmonary function was assessed by a standard screening spirometry. Chronic obstructive pulmonary disease (COPD) and restrictive pulmonary dysfunction were defined based on pulmonary function tests. Individuals who developed RA were identified by linking the MPMP database to national and local RA registers. The patients were classified according to the 1987 ACR criteria for RA. Four matched controls for every case were selected. RESULTS: We identified 290 cases of incident RA (151 men/139 women; mean age at diagnosis 60 years). The median time from inclusion to diagnosis was 12 years. Forced vital capacity and forced expiratory volume within 1 s values were similar in cases and controls, overall and also in separate analysis of those screened ≤8 years before diagnosis. There was no association between COPD or restrictive pulmonary dysfunction and subsequent development of RA. Current smoking was a strong predictor for RA [odds ratio (OR) 1.79; 95% CI 1.32, 2.42]. Blue-collar workers had an increased risk of RA (OR 1.54; 95% CI 1.12, 2.10), independent of smoking. CONCLUSION: Pulmonary dysfunction did not predict RA, but smoking and low socio-economic status were independent risk factors for RA. Other effects of smoking may be important for RA susceptibility.

Long-term treatment with low-dose metoprolol CR/XL is associated with increased plaque echogenicity: the Beta-blocker Cholesterol-lowering Asymptomatic Plaque Study (BCAPS).

OBJECTIVES: To examine whether the decrease in IMT progression rate in the carotid bulb induced by metoprolol CR/XL treatment (25mg once daily) observed in the ß-blocker Cholesterol-lowering Asymptomatic Plaque Study (BCAPS) was accompanied by an effect on carotid plaque echogenicity. METHODS: Gray scale median (GSM) in carotid plaques, used as a score of echogenicity, was measured at baseline and after 36 months in those 341 subjects (aged 49-69 years) with an asymptomatic moderate- to large-sized carotid plaque present at baseline and at follow-up. Participants were in a factorial design assigned to treatment with metoprolol CR/XL (25mg once daily), fluvastatin (40 mg once daily) or corresponding placebo. RESULTS: After 36 months plaques were more echogenic in participants treated compared to those not treated with metoprolol CR/XL (57.3 ± 16.8 versus 51.8 ± 20.0, p=0.006). GSM had increased more from baseline in the metoprolol CR/XL treated subjects (25 ± 15 versus 18 ± 20, p<0.001), and plaques that had become more echolucent were less frequent in the metoprolol CR/XL treated subjects (3.6% versus 17.0%, p<0.001). CONCLUSIONS: Long-term treatment with low dose metoprolol CR/XL in clinically healthy subjects with moderate-sized carotid plaques was associated with increase in plaque echogenicity, suggesting a potential beneficial effect of the ß-blocker treatment on plaque stability.

Increased cartilage turnover and circulating autoantibodies in different subsets before the clinical onset of rheumatoid arthritis.

BACKGROUND: Previous studies have indicated that autoantibodies may be detected years before the clinical onset of rheumatoid arthritis (RA). Cartilage biomarkers, such as cartilage oligomeric matrix protein (COMP), have not been studied previously in samples collected before the diagnosis of RA. METHODS: Between 1991 and 1996, 30 447 subjects were included in the Malmö Diet Cancer Study (MDCS). People who developed RA after inclusion were identified by linking the MDCS database to different Swedish registers. One matched control for each validated case was selected from the MDCS. IgG antibodies against cyclic citrullinated peptide (anti-CCP) and mutated citrullinated vimentin (anti-MCV) and IgM rheumatoid factor (IgM RF) were determined by ELISA. Serum COMP was measured with a sandwich ELISA. RESULTS: 172 incident cases of RA (median time from inclusion to diagnosis 5 years; range 1-13) were identified. Pre-RA cases were significantly more likely than controls to be positive for anti-CCP (21.9% vs 0.6%), anti-MCV (29.6% vs 3.0%) and IgM RF (18.9% vs 2.4%) (all p<0.001). Overall, mean serum COMP levels did not differ between cases and controls. Among pre-RA cases included 1-3 years before diagnosis, raised COMP (>12 U/l) was seen in a greater proportion of anti-CCP-negative than anti-CCP-positive subjects (50% vs 15%; p=0.04). CONCLUSIONS: Increased cartilage turnover, measured by COMP, and circulating RA-specific antibodies may be distinct processes in the preclinical phase of RA.

Occupation and risk of lymphoma: a multicentre prospective cohort study (EPIC).

OBJECTIVES: Evidence suggests that certain occupations and related exposures may increase the risk of malignant lymphoma. Farming, printing and paper industry, wood processing, meat handling and processing, welding, shoe and leather manufacturing and teaching profession are among the categories that have been implicated in previous studies. The relationship between occupation and malignant lymphoma has been investigated in a large European prospective study. METHODS: We investigated occupational risks for lymphomas in the European Prospective Investigation into Cancer and Nutrition (EPIC). The mean follow-up time for 348,555 subjects was 9 years (SD: 2 years). The analysis was based on 866 and 48 newly diagnosed cases of non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL). These were identified in the EPIC subcohorts with occupational data. Data on 52 occupations were collected through standardised questionnaires. Cox proportional hazard models were used to explore the association between occupation and risk of malignant lymphoma. RESULTS: The following occupations were positively associated with malignant NHL after adjustment for study centre, age, sex, socioeconomic status (SES), smoking and alcohol: butchers (HR=1.53, 95% CI 1.05 to 2.48, including multiple myeloma/plasmacytoma; HR=1.30, 95% CI 1.00 to 2.66, excluding multiple myeloma/plasmacytoma) and car repair workers (HR=1.50, 95% CI 1.01 to 2.00, including multiple myeloma/plasmacytoma; HR=1.51, 95% CI 1.01 to 2.31, excluding multiple myeloma/plasmacytoma). HL was associated with gasoline station occupation (HR=4.59, 95% CI 1.08 to 19.6). CONCLUSION: The findings in this current study of a higher risk of NHL among car repair workers and butchers and a higher risk of HL among gasoline station workers suggest a possible role from occupationally related exposures, such as solvents and zoonotic viruses, as risk factors for malignant lymphoma.

Male infertility and prostate cancer risk: a nested case-control study.

The pathogenesis of prostate cancer is unclear, although experimental evidence implicates androgens as playing an important role. Infertile men frequently suffer from some degree of hypogonadism and may hence be hypothesized to be at lower risk of developing prostate cancer than fertile men. To test this hypothesis, we conducted a case-control study nested within "the Malmö Diet and Cancer Study" cohort in Sweden, inviting 661 prostate cancer cases and 661 age-matched controls to participate. Of the 975 (74%) respondents, we excluded 84 childless men with unknown fertility status. Thus, 891 men were included, providing 445 prostate cancer cases and 446 controls. Of these, 841 (94%) men were biological fathers and 50 (6%) men were infertile. Logistic regression showed that the infertile men were at significantly lower risk of being diagnosed with prostate cancer than the fertile men (odds ratio, 0.45; 95% confidence interval, 0.25-0.83). Conditional and unconditional multivariate models, adjusting for socioeconomic, anthropometric, and health-status-related factors, provided similar estimates. We conclude that enduring male infertility is associated with a reduced prostate cancer risk, thus corroborating the theory that normal testicular function, and hence most probably sufficient steroidogenesis, is an important contributing factor to the later development of this malignancy.

Plasma copeptin and the risk of diabetes mellitus.

BACKGROUND: Animal studies suggest that the arginine vasopressin system may play a role in glucose metabolism, but data from humans are limited. METHODS AND RESULTS: We analyzed plasma copeptin (copeptin), a stable C-terminal fragment of the arginine vasopressin prohormone. Using baseline and longitudinal data from a Swedish population-based sample (n=4742; mean age, 58 years; 60% women) and multivariable logistic regression, we examined the association of increasing quartiles of copeptin (lowest quartile as reference) with prevalent diabetes mellitus at baseline, insulin resistance (top quartile of fasting plasma insulin among nondiabetic subjects), and incident diabetes mellitus on long-term follow-up. New-onset diabetes mellitus was ascertained through 3 national and regional registers. All models were adjusted for clinical and anthropometric risk factors, cystatin C, and C-reactive protein. In cross-sectional analyses, increasing copeptin was associated with prevalent diabetes mellitus (P=0.04) and insulin resistance (P<0.001). During 12.6 years of follow-up, 174 subjects (4%) developed new-onset diabetes mellitus. The odds of developing diabetes mellitus increased across increasing quartiles of copeptin, even after additional adjustment for baseline fasting glucose and insulin (adjusted odds ratios, 1.0, 1.37, 1.79, and 2.09; P for trend=0.004). The association with incident diabetes mellitus remained significant in analyses restricted to subjects with fasting whole blood glucose <5.4 mmol/L at baseline (adjusted odds ratios, 1.0, 1.80, 1.92, and 3.48; P=0.001). CONCLUSIONS: Elevated copeptin predicts increased risk for diabetes mellitus independently of established clinical risk factors, including fasting glucose and insulin. These findings could have implications for risk assessment, novel antidiabetic treatments, and metabolic side effects from arginine vasopressin system modulation.

Vitamins B2 and B6 and genetic polymorphisms related to one-carbon metabolism as risk factors for gastric adenocarcinoma in the European prospective investigation into cancer and nutrition.

B vitamins and polymorphisms in genes coding for enzymes involved in one-carbon metabolism may affect DNA synthesis and methylation and thereby be implicated in carcinogenesis. Previous data on vitamins B2 and B6 and genetic polymorphisms other than those involving MTHFR as risk factors for gastric cancer (GC) are sparse and inconsistent. In this case-control study nested within the European Prospective Investigation into Cancer and Nutrition cohort, cases (n = 235) and controls (n = 601) were matched for study center, age, sex, and time of blood sampling. B2 and B6 species were measured in plasma, and the sum of riboflavin and flavin mononucleotide was used as the main exposure variable for vitamin B2 status, whereas the sum of pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid was used to define vitamin B6 status. In addition, we determined eight polymorphisms related to one-carbon metabolism. Relative risks for GC risk were calculated with conditional logistic regression, adjusted for Helicobacter pylori infection status and smoking status. Adjusted relative risks per quartile (95% confidence interval, P(trend)) were 0.85 (0.72-1.01, 0.06) for vitamin B2 and 0.78 (0.65-0.93, <0.01) for vitamin B6. Both relations were stronger in individuals with severe chronic atrophic gastritis. The polymorphisms were not associated with GC risk and did not modify the observed vitamin-cancer associations. In summary, results from this large European cohort study showed an inverse association between vitamin B2 and GC risk, which is borderline significant, and a significant inverse association between vitamin B6 and GC risk.

Homozygosity for the EPHX2 K55R polymorphism increases the long-term risk of ischemic stroke in men: a study in Swedes.

OBJECTIVES: The soluble epoxide hydrolase (gene name EPHX2) is responsible for metabolism of 8,9 11,12 and 14,15-epoxyeicosatrienoic acids, vasodilator and anti-inflammatory substances. There are several functional polymorphisms in the EPHX2 gene: two of them, the K55R and R287Q, showing an altered metabolic activity in vitro, were associated with coronary heart disease and ischemic stroke in previous studies. The aim of this study was to evaluate the effect of four polymorphisms in the EPHX2 gene on blood pressure levels, hypertension prevalence, and risk of incident cardiovascular events in a large sample of middle-aged Swedes. METHODS: The incidence of cardiovascular events (coronary events, n = 274; ischemic stroke, n = 197) was monitored over 10 years of follow-up. RESULTS: In the whole population, all polymorphisms had no effect on the studied parameters but a positive interaction between male sex and three SNPs including the K55R was evident: male, but not female, EPHX2 R55R homozygotes had significantly higher crude and adjusted systolic blood pressure and higher hypertension prevalence with respect to K-carriers. Kaplan-Meier curves showed higher incidence of ischemic strokes in male R55R homozygotes with respect to K-carriers (P = 0.015 by log-rank test). After adjustment for major cardiovascular risk factors, the hazard ratio for incident ischemic stroke in male R55R homozygotes remained significantly higher (hazard ratio: 4.8; 95% confidence interval: 1.2-19.9). CONCLUSION: The functional K55R polymorphism of the EPHX2 gene confers a higher risk of hypertension prevalence and increases the risk of incident ischemic stroke in male homozygotes. Additional studies are needed to confirm these data and to elucidate the interaction between sex and the EPHX2 K55R polymorphism.

Physical activity and lung cancer among non-smokers: a pilot molecular epidemiological study within EPIC.

The association between physical activity, potential intermediate biomarkers and lung cancer risk was investigated in a study of 230 cases and 648 controls nested within the European Prospective Investigation of Cancer and Nutrition. Data on white blood cell aromatic-DNA adducts by (32)P-post-labelling and glutathione (GSH) in red blood cells were available from a subset of cases and controls. Compared with the first quartile, the fourth quartile of recreational physical activity was associated with a lower lung cancer risk (odds ratio (OR) 0.56, 95% confidence interval (CI) 0.35-0.90), higher GSH levels (+1.87 micromol GSH g(-1) haemoglobin, p = 0.04) but not with the presence of high levels of adducts (OR 1.05, 95% CI 0.38-2.86). Despite being associated with recreational physical activity, in these small-scale pilot analyses GSH levels were not associated with lung cancer risk (OR 0.95, 95% CI 0.84-1.07 per unit increase in GSH levels). Household and occupational activity was not associated with lung cancer risk or biomarker levels.

A gene score of nine LDL and HDL regulating genes is associated with fluvastatin-induced cholesterol changes in women.

While conventional pharmacogenetic studies have considered single gene effects, we tested if a genetic score of nine LDL- and HDL-associated single nucleotide polymorphisms, previously shown to predict cardiovascular disease, is related to fluvastatin-induced lipid change. In patients with asymptomatic plaque in the right carotid artery, thus candidates for statin therapy, we related score LDL [APOB(rs693), APOE(rs4420638), HMGCR(rs12654264), LDLR(rs1529729), and PCSK9(rs11591147)] and score HDL [ABCA1(rs3890182), CETP(rs1800775), LIPC(rs1800588), and LPL(rs328)] as well as the combined score LDL+HDL to fluvastatin-induced LDL reduction (+/- metoprolol) (n = 395) and HDL increase (n = 187) following 1 year of fluvastatin treatment. In women, an increasing number of unfavorable alleles (i.e., alleles conferring higher LDL and lower HDL) of score LDL+HDL (P = 0.037) and of score LDL (P = 0.023) was associated with less pronounced fluvastatin-induced LDL reduction. Furthermore, in women, both score LDL+HDL (P = 0.001) and score HDL (P = 0.022) were directly correlated with more pronounced fluvastatin-induced HDL increase, explaining 5.9-11.6% of the variance in treatment response in women. There were no such associations in men. This suggests that a gene score based on variation in nine different LDL- and HDL-associated genes is of importance for the magnitude of fluvastatin HDL increase in women with asymptomatic plaque in the carotid artery.

The common functional polymorphism -50G>T of the CYP2J2 gene is not associated with ischemic coronary and cerebrovascular events in an urban-based sample of Swedes.

BACKGROUND: CYP2J2 is responsible for the production of 5,6 8,9 11,12 and 14,15-epoxyeicosatrienoic acids, vasodilator and anti-inflammatory substances. It is abundantly expressed in human heart and also present in kidney and vasculature. Carriers of a common polymorphism, the CYP2J2 -50G>T, rs890293, have reduced expression of CYP2J2 mRNA level in the heart putatively through the interference with a binding site for a transcription factor with consequently reduced circulating levels of CYP2J2 epoxygenase metabolites in vivo. AIM: The aim of the present study was to evaluate the effect of this functional polymorphism on blood pressure (BP) levels, hypertension prevalence, and risk of incident cardiovascular events in middle-aged Swedes. METHODS: The CYP2J2 polymorphism was genotyped in 5740 participants of the cardiovascular cohort of the 'Malmö Diet and Cancer' study. The incidence of cardiovascular events (coronary events, n = 261; ischemic stroke, n = 185) was monitored over 10 years of follow-up. RESULTS: In the whole population the polymorphism had no effect on BP and hypertension prevalence and no interaction was found between the polymorphism and sex, age or body mass index. Before and after adjustment for major cardiovascular risk factors, the hazard ratio for incident ischemic stroke and coronary events was not significantly different in carriers of different genotypes. CONCLUSIONS: Our data do not support a major role for the CYP2J2 -50G>T variant in determining BP level and incident ischemic events. Other studies are needed to elucidate if other polymorphisms in the same gene could have a role in BP homeostasis or incidence of cardiovascular events.

Orthostatic hypotension predicts all-cause mortality and coronary events in middle-aged individuals (The Malmo Preventive Project).

AIMS: Orthostatic hypotension (OH) has been linked to increased mortality and incidence of cardiovascular disease in various risk groups, but determinants and consequences of OH in the general population are poorly studied. METHODS AND RESULTS: Prospective data of the Swedish 'Malmö Preventive Project' (n = 33 346, 67.3% men, mean age 45.7 +/- 7.4 years, mean follow-up 22.7 +/- 6.0 years) were analysed. Orthostatic hypotension was found in 6.2% of study participants and was associated with age, female gender, hypertension, antihypertensive treatment, increased heart rate, diabetes, low BMI, and current smoking. In Cox regression analysis, individuals with OH had significantly increased all-cause mortality (in particular those aged less than 42 years) and coronary event (CE) risk. Mortality and CE risk were distinctly higher in those with systolic blood pressure (BP) fall >or=30 mmHg [hazard ratio (HR): 1.6, 95% CI 1.3-1.9, P < 0.0001 and 1.6, 95% CI 1.2-2.1, P = 0.001] and diastolic BP fall >or=15 mmHg (HR: 1.4, 95% CI 1.1-1.9, P = 0.024 and 1.7, 95% CI 1.1-2.5, P = 0.01). In addition, impaired diastolic BP response had relatively greater impact (per mmHg) on CE incidence than systolic reaction. CONCLUSION: Orthostatic hypotension can be detected in approximately 6% of middle-aged individuals and is often associated with such comorbidities as hypertension or diabetes. Presence of OH increases mortality and CE risk, independently of traditional risk factors. Although both impaired systolic and diastolic responses predict adverse events, the diastolic impairment shows stronger association with coronary disease.

Consequences of orthostatic blood pressure variability in middle-aged men (The Malmö Preventive Project).

OBJECTIVE: To investigate the determinants and consequences of orthostatic hypotension in the middle-aged segment of the general population. METHODS: A population of 5722 men aged 52.6 +/- 3.6 years, previously included in the Malmö Preventive Project (n = 22 444 men), was re-screened after 5.6 +/- 1.0 years and thereafter followed up over a period of 19.6 +/- 5.3 years. RESULTS: At re-screening, 566 (9.9%) participants were found to have orthostatic hypotension according to international consensus criteria, of these 365 (64.5%) demonstrated systolic impairment only. In a multivariate adjusted logistic regression model, age, low BMI, hypertension, increased heart rate, antihypertensive treatment, diabetes and current smoking independently determined orthostatic hypotension, but systolic impairment also showed association with higher pulse pressure and reduced glomerular filtration rate. In a multivariate adjusted Cox proportional hazard model, men with orthostatic hypotension demonstrated a higher risk of incident coronary event, stroke and all-cause mortality than men without orthostatic hypotension. Systolic impairment was a better predictor of all studied endpoints than were the combined criteria of orthostatic hypotension. Moreover, participants with orthostatic hypotension at both baseline and re-screening showed the highest risk of any adverse event (hazard risk 1.76, 95% confidence interval 1.28-2.43, P = 0.001), exceeding the risk predicted by orthostatic hypotension at re-screening only (hazard risk 1.22, 95% confidence interval 1.07-1.38, P = 0.003). CONCLUSION: Orthostatic hypotension may be found in up to 10% of middle-aged men and correlates with well known cardiovascular risk factors such as hypertension, smoking, diabetes and kidney failure. Orthostatic impairment seems to constitute an independent cardiovascular risk factor and may be practically estimated by systolic reaction only. As orthostatic reaction may vary over time, repeated measurements or more accurate diagnostic methods are recommended to identify high-risk patients with persistent orthostatic hypotension.

Common genetic variants on chromosome 9p21 confers risk of ischemic stroke: a large-scale genetic association study.

BACKGROUND: Epidemiological studies indicate a genetic contribution to ischemic stroke risk, but specific genetic variants remain unknown, with the exception of a few rare variants. Recent genome-wide association studies identified and replicated common genetic variants on chromosome 9p21 to confer risk of coronary heart disease. We examined whether these variants are associated with ischemic stroke. METHODS AND RESULTS: We genotyped 6 common genetic variants on chromosome 9p21, previously associated with coronary artery disease in genome-wide association studies, in 2 population-based studies in southern Sweden, the Lund Stroke Register (n=1837 cases, 947 controls) and the Malmö Diet and Cancer study (MDC; n=888 cases, 893 controls). We examined association in each study and in the pooled dataset. Adjustments were made for cardiovascular risk factors and further for previous myocardial infarction in MDC. We found a modest increase in ischemic stroke risk for 2 common (minor allele frequencies 0.46 to 0.49) variants, rs2383207 (P=0.04 in Lund Stroke Register, P=0.01 in MDC) and rs10757274 (P=0.03 in Lund Stroke Register, P=0.03 in MDC), in each sample independently. The strength of the association increased when samples were pooled with an odds ratio of 1.15 (95% CI, 1.05 to 1.25; P=0.002) for the strongest variant rs2383207. Results were similar after adjustment for clinical covariates. rs1333049 also showed significant association in MDC, which increased in the pooled sample (P=0.004). CONCLUSIONS: In this large sample (n=4565), we detected common genetic determinants for ischemic stroke on chromosome 9p21. Our findings indicate that ischemic stroke shares pathophysiological determinants with coronary heart disease and other arterial diseases and highlight the need for large sample sizes in stroke genetics.

CYP19A1 genetic variation in relation to prostate cancer risk and circulating sex hormone concentrations in men from the Breast and Prostate Cancer Cohort Consortium.

Sex hormones, particularly the androgens, are important for the growth of the prostate gland and have been implicated in prostate cancer carcinogenesis, yet the determinants of endogenous steroid hormone levels remain poorly understood. Twin studies suggest a heritable component for circulating concentrations of sex hormones, although epidemiologic evidence linking steroid hormone gene variants to prostate cancer is limited. Here we report on findings from a comprehensive study of genetic variation at the CYP19A1 locus in relation to prostate cancer risk and to circulating steroid hormone concentrations in men by the Breast and Prostate Cancer Cohort Consortium (BPC3), a large collaborative prospective study. The BPC3 systematically characterized variation in CYP19A1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNP) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,166 prostate cancer cases and 9,079 study-, age-, and ethnicity-matched controls. CYP19A1 htSNPs, two common missense variants and common haplotypes were not significantly associated with risk of prostate cancer. However, several htSNPs in linkage disequilibrium blocks 3 and 4 were significantly associated with a 5% to 10% difference in estradiol concentrations in men [association per copy of the two-SNP haplotype rs749292-rs727479 (A-A) versus noncarriers; P = 1 x 10(-5)], and with inverse, although less marked changes, in free testosterone concentrations. These results suggest that although germline variation in CYP19A1 characterized by the htSNPs produces measurable differences in sex hormone concentrations in men, they do not substantially influence risk of prostate cancer.

Ion mobility analysis of lipoprotein subfractions identifies three independent axes of cardiovascular risk.

OBJECTIVE: Whereas epidemiological studies show that levels of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) predict incident cardiovascular disease (CVD), there is limited evidence relating lipoprotein subfractions and composite measures of subfractions to risk for CVD in prospective cohort studies. METHODS AND RESULTS: We tested whether combinations of lipoprotein subfractions independently predict CVD in a prospective cohort of 4594 initially healthy men and women (the Malmö Diet and Cancer Study, mean follow-up 12.2 years, 377 incident cardiovascular events). Plasma lipoproteins and lipoprotein subfractions were measured at baseline with a novel high-resolution ion mobility technique. Principal component analysis (PCA) of subfraction concentrations identified 3 major independent (ie, zero correlation) components of CVD risk, one representing LDL-associated risk, a second representing HDL-associated protection, and the third representing a pattern of decreased large HDL, increased small/medium LDL, and increased triglycerides. The last corresponds to the previously described "atherogenic lipoprotein phenotype." Several genes that may underlie this phenotype-CETP, LIPC, GALNT2, MLXIPL, APOA1/A5, LPL-are suggested by SNPs associated with the combination of small/medium LDL and large HDL. CONCLUSIONS: PCA on lipoprotein subfractions yielded three independent components of CVD risk. Genetic analyses suggest these components represent independent mechanistic pathways for development of CVD.

Novel and conventional biomarkers for prediction of incident cardiovascular events in the community.

CONTEXT: Prior studies have demonstrated conflicting results regarding how much information novel biomarkers add to cardiovascular risk assessment. OBJECTIVE: To evaluate the utility of contemporary biomarkers for predicting cardiovascular risk when added to conventional risk factors. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of 5067 participants (mean age, 58 years; 60% women) without cardiovascular disease from Malmö, Sweden, who attended a baseline examination between 1991 and 1994. Participants underwent measurement of C-reactive protein (CRP), cystatin C, lipoprotein-associated phospholipase 2, midregional proadrenomedullin (MR-proADM), midregional proatrial natriuretic peptide, and N-terminal pro-B-type natriuretic peptide (N-BNP) and underwent follow-up until 2006 using the Swedish national hospital discharge and cause-of-death registers and the Stroke in Malmö register for first cardiovascular events (myocardial infarction, stroke, coronary death). MAIN OUTCOME MEASURES: Incident cardiovascular and coronary events. RESULTS: During median follow-up of 12.8 years, there were 418 cardiovascular and 230 coronary events. Models with conventional risk factors had C statistics of 0.758 (95% confidence interval [CI], 0.734 to 0.781) and 0.760 (0.730 to 0.789) for cardiovascular and coronary events, respectively. Biomarkers retained in backward-elimination models were CRP and N-BNP for cardiovascular events and MR-proADM and N-BNP for coronary events, which increased the C statistic by 0.007 (P = .04) and 0.009 (P = .08), respectively. The proportion of participants reclassified was modest (8% for cardiovascular risk, 5% for coronary risk). Net reclassification improvement was nonsignificant for cardiovascular events (0.0%; 95% CI, -4.3% to 4.3%) and coronary events (4.7%; 95% CI, -0.76% to 10.1%). Greater improvements were observed in analyses restricted to intermediate-risk individuals (cardiovascular events: 7.4%; 95% CI, 0.7% to 14.1%; P = .03; coronary events: 14.6%; 95% CI, 5.0% to 24.2%; P = .003). However, correct reclassification was almost entirely confined to down-classification of individuals without events rather than up-classification of those with events. CONCLUSIONS: Selected biomarkers may be used to predict future cardiovascular events, but the gains over conventional risk factors are minimal. Risk classification improved in intermediate-risk individuals, mainly through the identification of those unlikely to develop events.