Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed-forward loop between LXR and autophagy.

BACKGROUND: Hyperlipidaemia is a major risk factor for cardiovascular disease, and atherosclerosis is the underlying cause of both myocardial infarction and stroke. We have previously shown that the Pro251 variant of perilipin-2 reduces plasma triglycerides and may therefore be beneficial to reduce atherosclerosis development. OBJECTIVE: We sought to delineate putative beneficial effects of the Pro251 variant of perlipin-2 on subclinical atherosclerosis and the mechanism by which it acts. METHODS: A pan-European cohort of high-risk individuals where carotid intima-media thickness has been assessed was adopted. Human primary monocyte-derived macrophages were prepared from whole blood from individuals recruited by perilipin-2 genotype or from buffy coats from the Karolinska University hospital blood central. RESULTS: The Pro251 variant of perilipin-2 is associated with decreased intima-media thickness at baseline and over 30 months of follow-up. Using human primary monocyte-derived macrophages from carriers of the beneficial Pro251 variant, we show that this variant increases autophagy activity, cholesterol efflux and a controlled inflammatory response. Through extensive mechanistic studies, we demonstrate that increase in autophagy activity is accompanied with an increase in liver-X-receptor (LXR) activity and that LXR and autophagy reciprocally activate each other in a feed-forward loop, regulated by CYP27A1 and 27OH-cholesterol. CONCLUSIONS: For the first time, we show that perilipin-2 affects susceptibility to human atherosclerosis through activation of autophagy and stimulation of cholesterol efflux. We demonstrate that perilipin-2 modulates levels of the LXR ligand 27OH-cholesterol and initiates a feed-forward loop where LXR and autophagy reciprocally activate each other; the mechanism by which perilipin-2 exerts its beneficial effects on subclinical atherosclerosis.

Circulating fatty acids in relation to alcohol consumption: Cross-sectional results from a cohort of 60-year-old men and women.

BACKGROUND & AIMS: Alcohol consumption is considered to affect circulating fatty acids (FAs) but knowledge about specific associations is limited. We aimed to assess the relation between alcohol consumption and serum FAs in 60-year-old Swedish men and women. METHODS: In a random sample of 1917 men and 2058 women residing in Stockholm county, cross-sectional associations between different categories of alcohol consumption and FAs were assessed using linear regression; ß1 coefficients with 95% confidence interval (CI) were calculated. Self-reported alcohol consumption was categorized as none, low (≤9.9 g/day) (reference), moderate (10-29.9 g/day) and high (≥30 g/day). Moderate alcohol consumption was further subdivided into consumption of beer, wine, liquor and their combinations. Thirteen serum cholesterol ester FAs were measured by gas chromatography and individual FAs were expressed as percentage of total FAs. RESULTS: Increasing alcohol consumption was associated to linear increase of saturated myristic acid, monounsaturated FAs and n-6 polyunsaturated (PUFA) arachidonic acid, whereas linear decrease was noted for saturated pentadecanoic acid and for n-6 PUFA linoleic acid. With non-linear associations, increasing alcohol consumption also associated to decreased saturated stearic acid, n-6 PUFA dihomo-gamma-linolenic acid, and n-3 PUFA docosahexaenoic acid and increased saturated palmitic acid, n-6 PUFA gamma-linolenic acid and n-3 PUFA eicosapentaenoic acid. Among types of beverages, wine consumption was associated with n-6 PUFA arachidonic acid (ß1 0.59; 95% CI: 0.30;0.88) and the n-3 PUFAs eicosapentaenoic acid (ß1 0.54; 95% CI: 0.30;0.78), and docosahexaenoic acid (ß1 0.06; 95% CI: 0.00;0.12). CONCLUSIONS: These findings may give important basis for further investigations to better understand biological mechanisms behind the dose-dependent associations between alcohol consumption and health outcomes observed in many previous studies.

Integrative studies implicate matrix metalloproteinase-12 as a culprit gene for large-artery atherosclerotic stroke.

BACKGROUND: Ischaemic stroke and coronary heart disease are important contributors to the global disease burden and share atherosclerosis as the main underlying cause. Recent evidence from a genome-wide association study (GWAS) suggested that single nucleotide polymorphisms (SNP) near the MMP12 gene at chromosome 11q22.3 were associated with large-vessel ischaemic stroke. Here, we evaluated and extended these results by examining the relationship between MMP12 and atherosclerosis in clinical and experimental studies. METHODS AND RESULTS: Plasma concentrations of MMP12 were measured at baseline in 3394 subjects with high-risk for cardiovascular disease (CVD) using the Olink ProSeek CVD I array. The plasma MMP12 concentration showed association with incident cardiovascular and cerebrovascular events (130 and 67 events, respectively, over 36 months) and carotid intima-media thickness progression (P = 3.6 × 10-5 ). A GWAS of plasma MMP12 concentrations revealed that SNPs rs499459, rs613084 and rs1892971 at chr11q22.3 were independently associated with plasma MMP12 (P < 5 × 10-8 ). The lead SNPs showed associations with mRNA levels of MMP12 and adjacent MMPs in atherosclerotic plaques. MMP12 transcriptomic and proteomic levels were strongly significantly increased in carotid plaques compared with control arterial tissue and in plaques from symptomatic versus asymptomatic patients. By combining immunohistochemistry and proximity ligation assay, we demonstrated that MMP12 localizes to CD68 + macrophages and interacts with elastin in plaques. MMP12 silencing in human THP-1-derived macrophages resulted in reduced macrophage migration. CONCLUSIONS: Our study supports the notion that MMP12 is implicated in large-artery atherosclerotic stroke, functionally by enhancing elastin degradation and macrophage invasion in plaques.

Particulate matter air pollution components and risk for lung cancer.

BACKGROUND: Particulate matter (PM) air pollution is a human lung carcinogen; however, the components responsible have not been identified. We assessed the associations between PM components and lung cancer incidence. METHODS: We used data from 14 cohort studies in eight European countries. We geocoded baseline addresses and assessed air pollution with land-use regression models for eight elements (Cu, Fe, K, Ni, S, Si, V and Zn) in size fractions of PM2.5 and PM10. We used Cox regression models with adjustment for potential confounders for cohort-specific analyses and random effect models for meta-analysis. RESULTS: The 245,782 cohort members contributed 3,229,220 person-years at risk. During follow-up (mean, 13.1 years), 1878 incident cases of lung cancer were diagnosed. In the meta-analyses, elevated hazard ratios (HRs) for lung cancer were associated with all elements except V; none was statistically significant. In analyses restricted to participants who did not change residence during follow-up, statistically significant associations were found for PM2.5 Cu (HR, 1.25; 95% CI, 1.01-1.53 per 5 ng/m(3)), PM10 Zn (1.28; 1.02-1.59 per 20 ng/m(3)), PM10 S (1.58; 1.03-2.44 per 200 ng/m(3)), PM10 Ni (1.59; 1.12-2.26 per 2 ng/m(3)) and PM10 K (1.17; 1.02-1.33 per 100 ng/m(3)). In two-pollutant models, associations between PM10 and PM2.5 and lung cancer were largely explained by PM2.5 S. CONCLUSIONS: This study indicates that the association between PM in air pollution and lung cancer can be attributed to various PM components and sources. PM containing S and Ni might be particularly important.

Cross-sectional relationships between dietary fat intake and serum cholesterol fatty acids in a Swedish cohort of 60-year-old men and women.

BACKGROUND: The present study aimed to describe the relationship between self-reported dietary intake and serum cholesterol fatty acids (FAs) in a Swedish population of 60-year-old men and women. METHODS: Cross-sectional data collected in 1997-1998 from 4232 individuals residing in Stockholm County were used. Five diet scores were created to reflect the intake of saturated fats in general, as well as fats from dairy, fish, processed meat and vegetable oils and margarines. Gas chromatography was used to assess 13 FAs in serum cholesterol esters. The association between each diet score and specific FAs was assessed by percentile differences (PD) with 95% confidence intervals (CI) at the 10th, 25th, 50th, 75th and 90th percentile of each FA across levels of diet scores using quantile regression. RESULTS: Fish intake was associated with high proportions of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). For each point increase in fish score, the 50th PD in EPA and DHA was 32.78% (95% CI = 29.22% to 36.35%) and 10.63% (95% CI = 9.52% to 11.74%), respectively. Vegetable fat intake was associated with a high proportion of linoleic acid and total polyunsaturated fatty acids (PUFA) and a low proportion of total saturated fatty acids (SFA). The intake of saturated fats in general and dairy fat was slightly associated with specific SFA, although the intake of fat from meat was not. CONCLUSIONS: In the present study population, using a rather simple dietary assessment method, the intake of fish and vegetable fats was clearly associated with serum PUFA, whereas foods rich in saturated fats in general showed a weak relationship with serum SFA. Our results may contribute to increased knowledge about underlying biology in diet-cardiovascular disease associations.

The Swedish CArdioPulmonary BioImage Study: objectives and design.

Cardiopulmonary diseases are major causes of death worldwide, but currently recommended strategies for diagnosis and prevention may be outdated because of recent changes in risk factor patterns. The Swedish CArdioPulmonarybioImage Study (SCAPIS) combines the use of new imaging technologies, advances in large-scale 'omics' and epidemiological analyses to extensively characterize a Swedish cohort of 30 000 men and women aged between 50 and 64 years. The information obtained will be used to improve risk prediction of cardiopulmonary diseases and optimize the ability to study disease mechanisms. A comprehensive pilot study in 1111 individuals, which was completed in 2012, demonstrated the feasibility and financial and ethical consequences of SCAPIS. Recruitment to the national, multicentre study has recently started.

Prediction of cardiovascular disease by abdominal obesity measures is dependent on body weight and sex--results from two community based cohort studies.

AIM: To study waist-hip ratio (WHR), waist circumference (WC), sagittal abdominal diameter (SAD), and waist-hip-height ratio (WHHR) as predictors of CVD, in men and women stratified by BMI (cut-off ≥25). METHODS AND RESULTS: A cohort of n = 3741 (53% women) 60-year old individuals without CVD was followed for 11-years (375 CVD cases). To replicate the results, we also assessed another large independent cohort; The Malmö Diet and Cancer study - cardiovascular cohort (MDCC, (n = 5180, 60% women, 602 CVD cases during 16-years). After adjustment for established risk factors in normal-weight women, the hazard ratio (HR) per one standard deviation (SD) were; WHR; 1.91 (95% confidence interval (CI) 1.35-2.70), WC; 1.81 (95% CI 1.02-3.20), SAD; 1.25 (95% CI 0.74-2.11), and WHHR; 1.97 (95% CI 1.40-2.78). In men the association with WHR, WHHR and WC were not significant, whereas SAD was the only measure that significantly predicted CVD in men (HR 1.19 (95% CI 1.04-1.35). After adjustments for established risk factors in overweight/obese women, none of the measures were significantly associated with CVD risk. In men, however, all measures were significant predictors; WHR; 1.24 (955 CI 1.04-1.47), WC 1.19 (95% CI 1.00-1.42), SAD 1.21 (95% CI 1.00-1.46), and WHHR; 1.23 (95% CI 1.05-1.44). Only the findings in men with BMI ≥ 25 were verified in MDCC. CONCLUSION: In normal weight individuals, WHHR and WHR were the best predictors in women, whereas SAD was the only independent predictor in men. Among overweight/obese individuals all measures failed to predict CVD in women, whereas WHHR was the strongest predictor after adjustments for CVD risk factors in men.

The association between plasma homocysteine and coronary heart disease is modified by the MTHFR 677C>T polymorphism.

OBJECTIVE: An elevated level of total plasma homocysteine (tHcy) has been associated with risk of coronary heart disease (CHD). The level of tHcy is affected by lifestyle, in addition to genetic predisposition. The methylene tetrahydrofolate reductase (MTHFR) 677C>T polymorphism (rs1801133) is among the strongest genetic predictors of tHcy. We examined whether the association between tHcy and CHD is modified by the MTHFR 677C>T polymorphism. DESIGN AND SETTING: Data from two case-control studies of first-time myocardial infarction (MI), Stockholm Heart Epidemiology Programme (SHEEP), and for MI and unstable angina, INTERGENE, were analysed in parallel. PATIENTS: THcy was determined in a total of 1150 cases and 1753 controls. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The outcome comprised first-time MI and unstable angina, subsumed as CHD. Logistic regression was used to investigate the association between tHcy and CHD, and its modification by genotype. RESULTS: High tHcy was confirmed to be a risk factor for CHD in both studies. In SHEEP, the association between tHcy and MI was observed in MTHFR 677 C-homozygotes (OR=1.4, 95% CI 1.2 to 1.6, for a difference by 1 SD of log tHcy) and in heterozygotes (OR=1.3, 95% CI 1.1 to 1.6) but not in T-homozygotes, independent of smoking, physical activity and obesity. An effect modification of similar magnitude was observed but not statistically significant in the smaller INTERGENE study, and confirmed in a meta-analysis of both studies. CONCLUSIONS: Two Swedish case-control studies showed that the association between elevated tHcy and CHD was confined to carriers of the MTHFR 677 C-allele, which could have implications for the efficiency of tHcy-lowering treatment.

Novel and established anthropometric measures and the prediction of incident cardiovascular disease: a cohort study.

OBJECTIVES: The aim of this study was to compare novel and established anthropometrical measures in their ability to predict cardiovascular disease (CVD), and to determine whether they improve risk prediction beyond classical risk factors in a cohort study of 60-year-old men and women. We also stratified the results according to gender to identify possible differences between men and women. Furthermore, we aimed to replicate our findings in a large independent cohort (The Malmö Diet and Cancer study-cardiovascular cohort). METHODS: This was a population-based study of 1751 men and 1990 women, aged 60 years and without CVD at baseline, with 375 incident cases of CVD during 11 years of follow-up. Weight, height, waist circumference (WC), hip circumference and sagittal abdominal diameter (SAD) were measured at baseline. Body mass index (BMI), waist-hip ratio (WHR), waist-hip-height ratio (WHHR), WC-to-height ratio (WCHR) and SAD-to-height ratio (SADHR) were calculated. RESULTS: All anthropometric measures predicted CVD in unadjusted Cox regression models per s.d. increment (hazard ratios, 95% confidence interval), while significant associations after adjustments for established risk CVD factors were noted for WHHR 1.20 (1.08-1.33), WHR 1.14 (1.02-1.28), SAD 1.13 (1.02-1.25) and SADHR 1.17 (1.06-1.28). WHHR had higher increases in C-statistics, and model improvements (likelihood ratio tests (P<0.001)). In the replication study (MDC-CC, n=5180), WHHR was the only measure that improved Cox regression models in men (P=0.01). CONCLUSION: WHHR, a new measure reflecting body fat distribution, showed the highest risk estimates after adjustments for established CVD risk factors. These findings were verified in men but not women in an independent cohort.

LDL oxidative modification and carotid atherosclerosis: results of a multicenter study.

OBJECTIVE: Serum LDL conjugated diene concentration is a marker of oxidative modification of LDL. We investigated the relationship between LDL conjugated dienes and cross-sectional subclinical atherosclerosis assessed by carotid IMT in high-risk subjects of a multicenter study. METHODS: Serum LDL conjugated dienes and ultrasonographically assessed carotid intima-media thickness (IMT(mean), IMT(max) and IMT(mean-max)) were available for 553 subjects from Finland, France, Italy, the Netherlands, and Sweden. RESULTS: In multivariate regression analysis, gender (p < 0.001), age (p < 0.001), systolic blood pressure (IMT(mean), p = 0.01; IMT(mean-max), p = 0.05) and serum LDL conjugated dienes (p = 0.02 for both IMT(mean) and IMT(mean-max)) were the strongest determinants of IMT variation, adjusted for study center, ultrasound videotape reader and serum LDL cholesterol. Pack-years of smoking, added into the regression model, did not destroy the significant association between increased serum LDL conjugated dienes and IMT. Ratio of LDL conjugated dienes to LDL particle cholesterol was higher in subjects of Northern recruiting centers than of Southern centers (r = 0.39, p < 0.0001). CONCLUSIONS: There was a cross-sectional association between in vivo increased LDL oxidative modification and subclinical atherosclerosis after adjustment for traditional risk factors. The subjects in Northern countries of Europe had more oxidatively modified lipids per cholesterol in LDL particle than subjects in Southern countries.

Telomere length and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study.

Short telomeres are associated with aging and age-related diseases. Our aim was to determine whether short leukocyte telomere length is associated with risk factors and cardiovascular diseases in a high-risk hypertensive population. We measured leukocyte telomere lengths at recruitment in 1271 subjects with hypertension and left ventricular hypertrophy (LVH) participating in the Lifestyle Interventions and Independence for Elders (LIFE) study. At baseline, short mean telomere length was associated with coronary artery disease in males (odds ratio (OR) 0.61, 95% confidence interval (CI) 0.39-0.95), and transient ischemic attack in females (OR 0.62 95% CI 0.39-0.99). Proportion of short telomeres (shorter than 5 kb) was associated with Framingham risk score (r=0.07, P<0.05), cerebrovascular disease (OR 1.18, 95% CI 1.01-1.15) and type 2 diabetes in men (OR 1.07, 95% CI 1.02-1.11). During follow-up, proportion of short telomeres was associated with combined cardiovascular mortality, stroke or angina pectoris (hazard ratio 1.04, 95% CI 1.01-1.07). Telomere length was not associated with smoking, body mass index, pulse pressure or self-reported use of alcohol. Our data suggest that reduced leukocyte telomere length is associated with cardiovascular risk factors and diseases as well as type 2 diabetes, and is a predictor of cardiovascular disease in elderly patients with hypertension and LVH.

Plasma CD93 concentration is a potential novel biomarker for coronary artery disease.

OBJECTIVES: A common nonsynonymous single nucleotide polymorphism (SNP) in the CD93 gene (rs3746731, Pro541Ser) has been associated with risk of coronary artery disease (CAD). CD93 is a transmembrane glycoprotein, which is detectable in soluble form in human plasma. We investigated whether the concentration of soluble CD93 in plasma is related to risk of myocardial infarction (MI) and CAD, using a case-control study of premature MI (n = 764) and a nested case-control analysis of a longitudinal cohort study of 60-year-old subjects (analysis comprising 844 of 4232 subjects enrolled at baseline). In addition, SNPs in the CD93 gene were studied in relation to plasma CD93 concentration and CD93 mRNA expression. METHODS AND RESULTS: A sensitive and specific enzyme-linked immunosorbent assay was established for determination of the plasma CD93 concentration. Subjects were divided into three groups according to tertiles of the distribution of CD93 concentration. Lower odds ratios for risk of MI and incidence of CAD were observed in the middle CD93 tertile (142-173 µg L(-1) ): odds ratio (95% confidence interval), 0.69 (0.49-0.97) and 0.61 (0.40-0.94), respectively. These associations were independent of traditional CAD risk factors. The minor allele of a SNP in the 3' untranslated region of CD93 (rs2749812) was associated with increased plasma CD93 concentrations (P = 0.03) and increased CD93 mRNA expression levels (P = 0.02). CONCLUSION: The results of the present study suggest that the concentration of soluble CD93 in plasma is a potential novel biomarker for CAD, including MI.

Prevalence of blood lipid disturbances in Swedish and foreign-born 60-year-old men and women in Stockholm, Sweden.

BACKGROUND AND AIMS: Some immigrant groups in Sweden show a higher incidence of cardiovascular diseases, especially coronary heart disease. There is a lack of data of pattern of blood lipids among these. The aim of this study was to estimate the prevalence of dyslipidaemia in men and women of foreign-born origin compared to Swedish-born. METHODS AND RESULTS: A cross-sectional study of a random sample of the population in Stockholm County, Sweden, with total of 4228 60-year-old men and women. Medical, lifestyle and socio-economic data were collected by questionnaires, and anthropometric and laboratory data through medical examination. Outcomes were odds ratios (OR) with 95% confidence interval (95% CI) for dyslipidaemia in different groups, with Swedish-born as reference group, with adjustment for anthropometric, medical, lifestyle and socio-economic factors. Among non-European immigrants, the fully adjusted OR of high cholesterol was 0.57 (95% CI 0.37-0.88), of high LDL-cholesterol was 0.62 (95% CI 0.40-0.96), and of low HDL-cholesterol was 2.06 (95% CI 1.35-3.15). When only adjusting for sex, Finnish-born and non-European immigrants showed higher risk of high triglycerides, OR 1.31 (95% CI 1.01-1.71) and OR 1.98 (95% CI 1.34-2.93), respectively, and of high apoB/apoA-I ratio, OR 1.29 (95% CI 1.00-1.66) and OR 1.57 (95% CI 1.06-2.33), respectively. CONCLUSION: The finding of blood lipid disturbances among immigrants in this study partly explain the higher cardiovascular morbidity shown in previous studies. Non-European immigrants showed a different lipid pattern, with lower HDL-cholesterol, which could possibly be of genetic background.

Sagittal abdominal diameter as a screening tool in clinical research: cutoffs for cardiometabolic risk.

Background. Waist girth and BMI are commonly used as markers of cardiometabolic risk. Accumulating data however suggest that sagittal abdominal diameter (SAD) or "abdominal height" may be a better marker of intra-abdominal adiposity and cardiometabolic risk. We aimed to identify cutoffs for SAD using a cardiometabolic risk score. Design. A population-based cross-sectional study. Methods. In 4032 subjects (1936 men and 2096 women) at age 60, different anthropometric variables (SAD, BMI, waist girth, and waist-to-hip ratio) were measured and cardiometabolic risk score calculated. ROC curves were used to assess cutoffs. Results. Among men SAD showed the strongest correlations to the majority of the individual risk factors; whereas in women SAD was equal to that of waist girth. In the whole sample, the area under the ROC curve was highest for SAD. The optimal SAD cutoff for an elevated cardiometabolic risk score in men was approximately 22 cm (95%CI; 21.6 to 22.8) and in women approximately 20 cm (95%CI; 19.4 to 20.8). These cutoffs were similar if the Framingham risk score was used. Conclusions. These cutoffs may be used in research and screening to identify "metabolically obese" men who would benefit from lifestyle and pharmacological interventions. These results need to be verified in younger age groups.

Associations of long- and short-term air pollution exposure with markers of inflammation and coagulation in a population sample.

BACKGROUND: Exposure to elevated levels of ambient air pollutants can lead to adverse cardiovascular effects. Potential mechanisms include systemic inflammation and perturbation of the coagulation balance. OBJECTIVES: To investigate long- and short-term effects of air pollution exposure on serum levels of inflammatory (IL-6, TNF-alpha and CRP) and coagulation (fibrinogen and PAI-1) markers relevant for cardiovascular pathology. METHODS: The study group consisted of a population sample of 1028 men and 508 women aged 45-70 years from Stockholm. Long-term air pollution exposure was assessed using spatial modelling of traffic-related NO(2) and heating-related SO(2) emissions at each subject's residential addresses over retrospective periods of 1, 5 and 30 years. Short-term exposure was assessed as averages of rooftop measurements over 12-120 h before blood sampling. RESULTS: Long-term exposures to both traffic-NO(2) and heating-SO(2) emissions showed consistent associations with IL-6 levels. 30-year average traffic-NO(2) exposure was associated with a 64.5% (95% CI 6.7% to 153.8%) increase in serum IL-6 per 28.8 microg/m(3) (corresponding to the difference between the 5th and 95th percentile exposure value), and 30-year exposure to heating-SO(2) with a 67.6% (95% CI 7.1% to 162.2%) increase per 39.4 microg/m(3) (5th-95th percentile value difference). The association appeared stronger in non-smokers, physically active people and hypertensive subjects. We observed positive non-significant associations of inflammatory markers with NO(2) and PM(10) during 24 h before blood sampling. Short-term exposure to O(3) was associated with increased, and SO(2) with decreased, fibrinogen levels. CONCLUSIONS: Our results suggest that exposure to moderate levels of air pollution may influence serum levels of inflammatory markers.

Genetic variants of TNFSF4 and risk for carotid artery disease and stroke.

In two independent human cohorts, the minor allele of SNP rs3850641 in TNFSF4 was significantly more frequent in individuals with myocardial infarction than in controls. In mice, Tnfsf4 expression is associated with increased atherosclerosis. The expression of TNFSF4 in human atherosclerosis and the association between genotype and cerebrovascular disease have not yet been investigated. TNFSF4 messenger RNA (mRNA) levels were significantly higher in human atherosclerotic lesions compared with controls (730 +/- 30 vs 330 +/- 65 arbitrary units, p < 0.01). TNFSF4 was mainly expressed by macrophages in atherosclerotic lesions. In cell culture, endothelial cells upregulated TNFSF4 in response to tumor necrosis factor alpha (TNF-alpha; 460 +/- 110 vs 133 +/- 8 arbitrary units, p < 0.001 after 6 h of stimulation). We analyzed the TNFSF4 gene in 239 patients who had undergone carotid endarterectomy and 138 matching controls from The Biobank of Karolinska Carotid Endarterectomies and Stockholm Heart Epidemiology Program cohorts and 929 patients and 1,382 matching controls from the Sahlgrenska Academy Study on Ischemic Stroke and Case Control Study of Stroke cohorts, limiting inclusion to patients with ischemic stroke. Participants were genotyped for the rs3850641 SNP in TNFSF4. Genotype associations were neither found with TNFSF4 mRNA levels nor with atherosclerosis associated systemic factors or risk for stroke. This study shows that TNFSF4 is expressed on antigen-presenting cells in human carotid atherosclerotic lesions but provides no evidence for an association of TNFSF4 gene variation with the risk for ischemic stroke.

Golf: a game of life and death--reduced mortality in Swedish golf players.

The specific health benefits achieved from different forms and patterns of leisure-time physical activity are not established. We analyzed the mortality in a cohort of Swedish golf players. We used the Swedish Golf Federation's membership registry and the nationwide Mortality Registry. We calculated standardized mortality ratios (SMR) with stratification for age, sex, and socioeconomic status. The cohort included 300 818 golfers, and the total number of deaths was 1053. The overall SMR was 0.60 [95% confidence intervals (CIs): 0.57-0.64]. The mortality reduction was observed in men and women, in all age groups, and in all socioeconomic categories. Golfers with the lowest handicap (the most skilled players) had the lowest mortality; SMR=0.53 (95% CI: 0.41-0.67) compared with 0.68 (95% CI: 0.61-0.75) for those with the highest handicap. While we cannot conclude with certainty that all the 40% decreased mortality rates are explained by the physical activity associated with playing golf, we conclude that most likely this is part of the explanation. To put the observed mortality reduction in context, it may be noted that a 40% reduction of mortality rates corresponds to an increase in life expectancy of about 5 years.