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No association between polymorphisms in CYP2E1, GSTM1, NAT1, NAT2 and the risk of gastric adenocarcinoma in the European prospective investigation into cancer and nutrition.

Supplemental Digital Content is available in the text., 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.

Hot stamping can be traced back to traditional Japanese sword making techniques of thirteenth–fourteenth centuries [1]. The earliest patent about “Presharten” (Press hardening) was granted in 1914 in Switzerland. The technique described in this patent has been used in agricultural products since 1930s [2]. Hot stamping, as we know it today differs from these applications since the quenching is done at the press die to reduce distortion. Although hot stamping has been commonly used since early to mid-2000s, the beginning was in 1970s.

Lymphomas are one of the few cancers that have been increasing in incidence over the past decades. So far, only a few established risk factors have been identified, including immunosuppression and viral infections. Recent evidence suggests etiologic heterogeneity of different lymphoma subtypes. Smoking may affect risk differently, depending on the lymphoma entity. The European Prospective Investigation into Cancer and Nutrition was used to study the role of smoking in the etiology of lymphomas and individual subtypes within a prospective study. Information on baseline and lifetime tobacco smoking by 478,590 participants was collected between 1992 and 2000. Cox proportional hazards regression was used to calculate multivariate-adjusted hazard ratios and 95% confidence intervals. During 3,567,410 person-years of follow-up, 1,371 lymphoma cases (1,304 non-Hodgkin's lymphomas and 67 Hodgkin's lymphomas) were identified. Relative risk for smokers at recruitment was more than twofold higher for Hodgkin's lymphoma (hazard ratio = 2.14, 95% confidence interval: 1.18, 3.87) but was not elevated for non-Hodgkin's lymphoma (hazard ratio = 1.06, 95% confidence interval: 0.94, 1.19) and individual B-cell non-Hodgkin's lymphoma subtypes. In this prospective study, smoking appeared to increase Hodgkin's lymphoma risk consistently in both genders, whereas B-cell non-Hodgkin's lymphoma risk was not associated. Future analysis should involve viral biomarkers and genetic susceptibility markers to elucidate potential mechanisms of smoking-induced carcinogenesis, particularly for Hodgkin's lymphoma. © The Author 2008. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved.

AIMS/HYPOTHESIS: Glucose-stimulated insulin secretion is dependent on the electrical activity of beta cells; hence, genes encoding beta cell ion channels are potential candidate genes for type 2 diabetes. The gene encoding the voltage-dependent Ca(2+) channel Ca(V)2.3 (CACNA1E), telomeric to a region that has shown suggestive linkage to type 2 diabetes (1q21-q25), has been ascribed a role for second-phase insulin secretion. METHODS: Based upon the genotyping of 52 haplotype tagging single nucleotide polymorphisms (SNPs) in a type 2 diabetes case-control sample (n = 1,467), we selected five SNPs that were nominally associated with type 2 diabetes and genotyped them in the following groups (1) a new case-control sample of 6,570 individuals from Sweden; (2) 2,293 individuals from the Botnia prospective cohort; and (3) 935 individuals with insulin secretion data from an IVGTT. RESULTS: The rs679931 TT genotype was associated with (1) an increased risk of type 2 diabetes in the Botnia case-control sample [odds ratio (OR) 1.4, 95% CI 1.0-2.0, p = 0.06] and in the replication sample (OR 1.2, 95% CI 1.0-1.5, p = 0.01 one-tailed), with a combined OR of 1.3 (95% CI 1.1-1.5, p = 0.004 two-tailed); (2) reduced insulin secretion [insulinogenic index at 30 min p = 0.02, disposition index (D (I)) p = 0.03] in control participants during an OGTT; (3) reduced second-phase insulin secretion at 30 min (p = 0.04) and 60 min (p = 0.02) during an IVGTT; and (4) reduced D (I) over time in the Botnia prospective cohort (p = 0.05). CONCLUSIONS/INTERPRETATION: We conclude that genetic variation in the CACNA1E gene contributes to an increased risk of the development of type 2 diabetes by reducing insulin secretion.

Objectives were to investigate prospectively the ability of DNA adducts to predict cancer and to study the determinants of adducts, especially air pollutants. DNA adducts were measured in a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) investigation. Cases included newly diagnosed lung cancer (n = 115), upper respiratory cancers (pharynx and larynx; n = 82), bladder cancer (n = 124), leukemia (n = 166), and chronic obstructive pulmonary disease or emphysema deaths (n = 77) accrued after a median follow-up of 7 years among the EPIC former smokers and never-smokers. Three controls per case were matched for questionnaire analyses and two controls per case for laboratory analyses. Matching criteria were gender, age, smoking status, country of recruitment, and follow-up time. Individual exposure to air pollution was assessed using concentration data from monitoring stations in routine air quality monitoring networks. Leukocyte DNA adducts were analyzed blindly using 32P postlabeling technique. Adducts were associated with the subsequent risk of lung cancer, with an odds ratio (OR) of 1.86 [95% confidence interval (95% CI), 0.88-3.93] when comparing detectable versus nondetectable adducts. The association with lung cancer was stronger in never-smokers (OR, 4.04; 95% CI, 1.06-15.42) and among the younger age groups. After exclusion of the cancers occurring in the first 36 months of follow-up, the OR was 4.16 (95% CI, 1.24-13.88). A positive association was found between DNA adducts and ozone (O3) concentration. Our prospective study suggests that leukocyte DNA adducts may predict lung cancer risk of never-smokers. Besides, the association of DNA adduct levels with O3 indicates a possible role for photochemical smog in determining DNA damage.

Background: The suspect carcinogens, heterocyclic amines (HAAs), found in well-done meat require host-mediated metabolic activation before inducing DNA mutations. The role of SULT1A1 and of NAT2 on the activation of HAAs suggests that NAT2 rapid acetylator genotype and SULT1A1 allele variants can have an effect on HAA carcinogenicity. Methods: Data were collected as part of a case-control study nested within the EPIC cohort, the Gen Air investigation. EPIC is a prospective study designed to investigate the relationship between nutrition and cancer. Information was collected through a non-dietary questionnaire on lifestyle variables and through a dietary questionnaire. The subjects were restricted to non-smokers. We calculated the matched odds ratio for bladder cancer risk using logistic regression, controlling for potential confounders. Results: There were 227 bladder cases and 612 controls matched 1:3. Meat intake and NAT2 genotype were not independently associated with bladder cancer risk. A significant relationship was observed between bladder cancer risk and consumption of meat only among subjects with the rapid NAT2 genotype (odds ratios [OR] 2.9, 95% CI 1.0-7.9 for the 2nd quartile of meat intake; 3.6, 95% CI 1.3-9.7 for the 3rd quartile; and 3.5, 95% CI 1.2-9.7 for the 4th quartile), and was not present among subjects with the slow genotype. An interaction between NAT2 and meat intake was found in logistic regression (P = 0.034). No association was observed for SULT1A*1/2 genotype (1.0; 95% CI 0.7-1.5) and for SULT1A1*2/2 genotype (0.9; 95% CI 0.5-1.7). Conclusions: These results are suggestive of a role of meat intake and NAT2 on bladder cancer risk. They support the hypothesis that among subjects with the rapid NAT2 acetylation genotype higher levels of HAAs exposure are a bladder cancer risk factor. We did not observe an effect of SULT1A1 allele variants on this cancer. The present study adds new information on the possible long-term adverse effects of diets with high meat intake. © 2008 Springer Science+Business Media B.V.

Research conducted predominantly in male populations on physical activity and lung cancer has yielded inconsistent results. We examined this relationship among 416,277 men and women from the European Prospective Investigation into Cancer and Nutrition (EPIC). Detailed information on recent recreational, household and occupational physical activity, smoking habits and diet was assessed at baseline between 1992 and 2000. Relative risks (RR) were estimated using Cox regression. During 6.3 years of follow-up we identified 607 men and 476 women with incident lung cancer. We did not observe an inverse association between recent occupational, recreational or household physical activity and lung cancer risk in either males or females. However, we found some reduction in lung cancer risk associated with sports in males (adjusted RR = 0.71; 95% confidence interval 0.50-0.98; highest tertile vs. inactive group), cycling (RR = 0.73; 0.54-0.99) in females and non-occupational vigorous physical activity. For occupational physical activity, lung cancer risk was increased for unemployed men (adjusted RR = 1.57; 1.20-2.05) and men with standing occupations (RR = 1.35; 1.02-1.79) compared with sitting professions. There was no evidence of heterogeneity of physical activity associations across countries, or across any of the considered cofactors. For some histologic subtypes suggestive sex-specific reductions, limited by subgroup sizes, were observed, especially with vigorous physical activity. In total, our study shows no consistent protective associations of physical activity with lung cancer risk. It can be assumed that the elevated risks found for occupational physical activity are not produced mechanistically by physical activity itself but rather reflect exposure to occupation-related lung cancer risk factors.

BACKGROUND The proportion of free- and complex-prostate specific antigen (PSA) in serum is used for differentiating between benign and malignant prostate disease. To further understand the physiological relationship between PSA in seminal plasma and blood, we have analyzed free-PSA (fPSA) and complex-PSA (cPSA) in blood and PSA in seminal plasma in young healthy men. We also compared age-related changes of PSA-forms in blood from young versus older men. METHODS Total-PSA (tPSA), fPSA, and cPSA were measured in (i) blood and semen from 289 male conscripts (mean age 18.1 years) and in (ii) blood from a representative population of 1,389 men (mean age 46.5 years) without diagnosis of prostate cancer (PCa) during long-term follow-up. RESULTS fPSA in serum (r = 0.40, P

Both benign and malignant prostate diseases elevate total prostate-specific antigen (tPSA), and the incidence of benign disease increases markedly with age. There is evidence, however, that free-to-total PSA ratio (%fPSA) and human kallikrein 2 (hK2) more closely reflect the malignant process. We tested the hypothesis that tPSA levels are more strongly predictive of cancer in younger when compared to older men, whereas %fPSA and hK2 are more strongly predictive in men tested closer to diagnosis. The study included 13,676 men age >/= 44 in Sweden, where PSA screening was uncommon during the study period. fPSA, tPSA and hK2 were measured in archived plasma collected during 1974-1986 in 501 men subsequently diagnosed with prostate cancer up to 1999 and in 1,292 matched controls. The predictive value of tPSA was lower in older men (p = 0.003) but was not strongly affected by time to diagnosis (p = 0.3); the predictive value of hK2 was higher closer to diagnosis (p < 0.0005) but was not modified by age (p = 0.7). A model including tPSA, fPSA and hK2 was superior (p = 0.02) to tPSA alone in older (AUC 0.819 vs. 0.794), but not in younger men (0.758 vs. 0.759). Total PSA can be used as a single marker at early middle age to predict long-term risk of prostate cancer and thus to determine intensity of subsequent screening. In contrast, %fPSA and hK2 add important predictive value in older men and much closer to diagnosis. Strategies for prostate cancer screening should be based on thorough understanding of the interaction of kallikrein-related biomarkers with prostate pathobiology.

Objectives:To describe and compare the consumption of dairy products in cohorts included in the European Prospective Investigation into Cancer and Nutrition (EPIC).Methods:Data from single 24-hour dietary recall interviews collected through a highly standardised computer-based program (EPIC-SOFT) in 27 redefined centres in 10 European countries between 1995 and 2000. From a total random sample of 36 900, 22 924 women and 13 031 men were selected after exclusion of subjects under 35 and over 74 years of age.Results:A high total consumption of dairy products was reported in most of the centres in Spain and in the UK cohort sampled from the general population, as well as in the Dutch, Swedish and Danish centres. A somewhat low consumption was reported in the Greek centre and in some of the Italian centres (Ragusa and Turin). In all centres and for both sexes, milk constituted the dairy sub-group with the largest proportion (in grams) of total dairy consumption, followed by yoghurt and other fermented milk products, and cheese. Still, there was a wide range in the contributions of the different dairy sub-groups between centres. The Spanish and Nordic centres generally reported a high consumption of milk, the Swedish and Dutch centres reported a high consumption of yoghurt and other fermented milk products, whereas the highest consumption of cheese was reported in the French centres.Conclusion:The results demonstrate both quantitative and qualitative disparities in dairy product consumption among the EPIC centres. This offers a sound starting point for analyses of associations between dairy intake and chronic diseases such as cancer.

Background: Current evidence suggests that high red meat intake is associated with increased colorectal cancer risk. High fish intake may be associated with a decreased risk, but the existing evidence is less convincing. Methods: We prospectively followed 478 040 men and women from 10 European countries who were free of cancer at enrollment between 1992 and 1998. Information on diet and lifestyle was collected at baseline. After a mean follow-up of 4.8 years, 1329 incident colorectal cancers were documented. We examined the relationship between intakes of red and processed meat, poultry, and fish and colorectal cancer risk using a proportional hazards model adjusted for age, sex, energy (nonfat and fat sources), height, weight, work-related physical activity, smoking status, dietary fiber and folate, and alcohol consumption, stratified by center. A calibration substudy based on 36 994 subjects was used to correct hazard ratios (HRs) and 95% confidence intervals (CIs) for diet measurement errors. All statistical tests were two-sided. Results: Colorectal cancer risk was positively associated with intake of red and processed meat (highest [>160 g/day] versus lowest [80 g/day versus

A potential role of dietary factors on the risk of ovarian cancer (OVC) has been suggested by ecologic studies due to observed differences in international incidence rates ([1][1]). The contribution of dietary factors to the etiology of OVC has been suggested through the modulation of the endogenous

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 Malmo 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 (Less)

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.

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 Malmo 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.

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.

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 'Malmo 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. (Less)

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. Conclusion— PCA on lipoprotein subfractions yielded three independent components of CVD risk. Genetic analyses suggest these components represent independent mechanistic pathways for development of CVD.

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 × 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. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2734–44)

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 ‘Malmo 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 ≥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 ≥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 ∼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.

The aim of this study is to evaluate if two different physical activity (PA) questionnaires have similar ability to rank individuals, and to examine associations with cardiovascular-metabolic risk factors, compared to an objective measure. In a random sample (n=369, age: 65+/-6 years) from the population-based 'Malmo Diet and Cancer' (MDC) cohort, PA was measured by a leisure-time comprehensive questionnaire (MDC-score), a simple leisure-time questionnaire and by accelerometer-monitoring (CSA). Moderate correlations were observed between MDC-score and CSA in men and women (r=0.35 and 0.24, respectively). In men, both questionnaires and CSA were inversely associated with waist circumference, insulin resistance and metabolic syndrome. In women, the MDC-score was positively associated with high-density lipoprotein-cholesterol, and the simple questionnaire inversely associated with anthropometric indexes, but no association was seen between PA estimates and cardiovascular components. We conclude that both PA questionnaires distinguish health risks associated with anthropometric-metabolic risk factors, particularly in men.European Journal of Clinical Nutrition advance online publication, 29 July 2009; doi:10.1038/ejcn.2009.69.

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

Duner P, To F, Alm R, Goncalves I, Fredrikson GN, Hedblad B, Berglund G, Nilsson J, Bengtsson E (Malmo University Hospital, Lund University, Lund, Sweden). Immune responses against fibronectin modified by lipoprotein oxidation and their association with cardiovascular disease. J Intern Med 2009; doi: 10.1111/j.1365-2796.2008.02067.xObjectives. Accumulation and subsequent oxidation of LDL in the arterial wall are considered as key events in the development of atherosclerosis. We have investigated the possibility that LDL oxidation results in release of aldehydes that modify surrounding matrix proteins and that this may target immune responses against the plaque extracellular matrix and modulate the disease progression. Results. Using custom-made ELISAs we demonstrate that human plasma contains autoantibodies against aldehyde-modified fibronectin (FN) and to a lesser extent also other extracellular matrix proteins including collagen type I, type III, and tenascin-C. Immunohistochemistry and western blot analysis showed that aldehyde-modified FN is present in human atherosclerotic plaques and that aldehydes generated by oxidation of LDL formed adducts with FN in vitro. We also demonstrate that aldehyde-modification of FN results in a loss of its ability to promote basal secretion of cytokines and growth factors from cultured macrophages without affecting the ability of the cells to respond to stimulation with LPS. A prospective clinical study demonstrated that subjects that subsequently developed acute myocardial infarction or sudden cardiac death had lower baseline levels of autoantibodies against aldehyde-modified FN than matched controls. Conclusions. These observations demonstrate that oxidation of LDL in the arterial wall may lead to aldehyde-modification of surrounding extracellular matrix proteins and that these modifications may affect macrophage function and activate autoimmune responses of pathophysiological importance for the development of atherosclerosis. (Less)

Body fat, body cell mass, fasting blood sugar, glucose tolerance and fasting insulin have been determined in 106 hypertensive males aged 47–54 years and in 41 normotensive 50-year-old males. Both groups were derived from screening examinations in random population samples. The hypertensive subjects were more often obese and had more often an impaired glucose tolerance and a higher fasting insulin compared with the normotensive subjects. The metabolic differences were not explained simply by the higher degree of obesity in the hypertensive subjects, as the differences remained when the hypertensive subjects were matched for body fat with normotensive controls. The impaired glucose metabolism demonstrated quantitatively in an unselected group of hypertensive subjects, might be one of the factors explaining the variable prognosis in hypertensive subjects.

The relationship between blood pressure (BP) and the renin-angiotensin-aldosterone system was studied in a stratified random sample (n=120) of 49-year-old men selected from a BP screening and covering a wide range of BPs. Only subjects not on antihypertensive treatment were included. None had malignant or secondary hypertension. Plasma renin activity, plasma concentrations of angiotensin II, aldosterone, sodium, potassium and noradrenaline and the 24-hour urinary excretions of sodium, cortisol and noradrenaline were determined. Of these variables, only p-aldosterone was significantly correlated wtih BP, both in the whole study group (R=0.22, p less than 0.02, n=119) and in the subjects with the highest BP range (R=0.36, p less than 0.02, n=30). Of the clinical groups compared, the hypertensive subjects had significantly higher mean p-aldosterone than the borderline and normotensive subjects. Multiple regression analysis showed that the 24-hour urinary excretion of noradrenaline was the factor most strongly correlated to p-aldosterone, suggesting that the sympathetic nervous system might stimulate aldosterone secretion. Our findings indicate that aldosterone may be of importance for the development and maintenance of essential hypertension.

Renal function, measure as glomerular filtration rate (GFR), sodium excretion and osmolality after thirst, has been determined in untreated (n=35) and treated (n=22) hypertensives and in a reference group (n=80), all derived from a random population sample of 50-year-old men. Renal function was related to casual and resting BP and to relative body weight. Hypertension was defined as SBP greater than 175 or DBP greater than 115 mmHg on two separate occasions or current antihypertensive treatment. Mean GFR was 100 +/- 11.7 ml/min in the reference group and significantly lower, 94 +/- 15.7 ml/min, in the hypertension group. In the hypertension group, 20% had a reduced GFR, although the standard diagnostic procedure, serum creatinine, demonstrated only 4%. Hypertensives with reduced GFR were characterized by higher BP, lower urinary sodium excretion, reversed diurnal rhythm of salt and water excretion and a higher relative body weight, which was, however, explained by the correlation of BP to relative body weight. GFR was negatively correlated to DBP at rest and positively correlated to urinary sodium excretion. Untreated hypertensives with persistent high BP after rest and lower GFR, lower urinary sodium excretion and reversed diurnal rhythm of salt and water excretion, indicating high renal resistance. The results suggest that subjects with relatively severe hypertension as judged by BP and renal function have an increased renal vascular resistance.

Left ventricular mass determined echocardiographically was related to blood pressure in a stratified random sample (n = 120) of 49-year-old men selected from a blood pressure screening and covering a wide range of blood pressures. Only subjects not on antihypertensive treatment were studied. Left ventricular mass was also related to sympathetic activity, the renin-angiotensin-aldosterone system and glucose metabolism. A poor correlation between left ventricular mass and blood pressure was found in the entire study group. In the upper blood pressure range only blood pressure during isometric exercise was significantly correlated with left ventricular mass. In this range there were significant correlations between left ventricular mass and 24 hour urinary noradrenaline excretion and plasma aldosterone. In the intermediate blood pressure range there was an association between left ventricular mass and blood glucose and plasma insulin. It is concluded that in mild to moderate hypertension other factors probably modify the hypertrophic response to rising arterial pressure.

The bias introduced by non-participation in a study depends on the size and the composition of the non-participant group. Out of 10,000 men invited to a screening examination in a large primary prevention trial in Goteborg, Sweden, 25% did not come to the examination. The non-participants could be shown to be registered by the Board of Social Welfare for social problems and alcohol abuse to a greater extent than the participants in the study. The annual mortality among the non-participants was about twice that of the participants during the entire follow-up period of 11.8 years. The incidence of non-fatal myocardial infarction was not significantly higher in non-participants. Coronary death, on the other hand, was significantly more common among those not attending the examination (3.5 vs. 7.6%). Participants registered for alcoholic problems had coronary death rates approaching those of the non-participants. Sudden coronary death accounted for most of the excess coronary mortality. Most of the excess mortality in the non-participant group was from other causes than cardiovascular diseases and cancer but even so, about one third of the excess deaths could be attributed to coronary heart disease. Possible explanations of this excess coronary mortality include that non-participants may smoke more, more frequently have alcoholic problems and that non-participation may reflect an unwillingness to seek medical care even in the event of illness. Language: en

Aiming at a better control of hypertension, a medical care program including nurse-run outpatient hypertension clinics was implemented in one half of the County of Skaraborg (265000 inhabitants), the other half forming a control area. The program was evaluated during a 5-year trial. Among patients registered and followed up for a minimum of one year (n = 2806), systolic and diastolic blood pressure decreased significantly, regardless of the patients' status of treatment prior to admission to the clinics. A baseline and a terminal population study revealed an increasing effectiveness in the treatment of hypertension in the study area. A consistent difference (mean 8/5 mmHg) was found in average blood pressure between patients treated at the hypertension clinics and patients treated in regular care. It is concluded that the medical care program increased the effectiveness of care and that this was due to the program organization.

A group of middle-aged male hypertensives, derived from a random sample of a Swedish urban population, has been treated and followed for 10 years. The development of angina pectoris, intermittent claudication and congestive heart failure have been analysed. The initial prevalence and the average yearly incidence of angina pectoris was 3.9% and 1.3% p.a., of intermittent claudication 1.7% and 0.6% p.a. and of heart failure 1.0% and 0.8% p.a. ECG signs indicating subclinical heart disease (major Q wave, ST depression, T wave inversion) were risk factors for development of angina pectoris and congestive heart failure. Heart enlargement on chest X-ray was also a risk factor for development of congestive heart failure, as were a high serum creatinine, body mass index, serum uric acid and proteinuria. Smoking was found to be a strong and independent risk factor for any one of these cardiovascular disorders. After 10 years about one fourth of all patients, still attending the clinic, had at least one cardiovascular complication. Hence, the risk of developing cardiovascular disorders is substantial and seems to be potentiated by the same risk factors known to operate in the general population.

We have studied eight men with moderate hypertension to determine the atrial natriuretic peptide (alpha-hANP) response to acute volume expansion. Rapid infusion of 1,000 ml 0.9% saline (10-20 min) caused an increase in central venous pressure (4.7 +/- 1.6 cmH2O) while blood pressure and pulse pressure (arterial baroreceptor load) did not change. Stroke volume and heart rate were not affected by the volume load but plasma renin activity (PRA) was significantly suppressed (from 0.83 +/- 0.14 to 0.68 +/- 0.34 microgram AI I/ml-h; p less than 0.01). A significant hemodilution was also observed. Renal sodium excretion was significantly increased. Arterial alpha-hANP increased significantly from 21.1 +/- 6.1 to 30.5 +/- 4.0 pmol/l (p less than 0.02) during volume expansion. There was a significant correlation between corrected plasma volume increase (urine volume subtracted from the infused volume) and alpha-hANP plasma elevation (r = 0.78; p less than 0.05). There was also a significant negative correlation between changes alpha-hANP and PRA (r = -0.78, p less than 0.05). We conclude that only moderate volume loading in human hypertensives is a mechanism for increase in plasma alpha-hANP levels. The significant negative correlation between changes in alpha-hANP and PRA suggests that alpha-hANP may be the humoral factor at least partly responsible for suppression of renin in hypertensive man. Since increased fluid volume also affects sympathetic renal efferents as well as vasopressin secretion, our observed relationship between volume load and renin may well be related also to such mechanisms.

From a screening examination in a randomly selected third of the 50-year-old male population in Göteborg, Sweden, a 10% subsample was selected as a reference group (n=80). All untreated persons with SBP greater than 175 or DBP greater than 115 mmHg on two separate occasions made up the hypertension group (n=35). The reference group and the hypertension group were subjected to the same investigations, including BP measurement before and after rest and determination of plasma renin activity (PRA), urinary sodium and norepinephrine excretion and GFR. Plasma renin activity was approximately normally distributed in both the reference and the hypertension group. Mean values were 0.78 +/- 0.18 and 0.65 +/- 0.17 ng/ml/h respectively, the difference being almost statistically significant (0.10 greater than p greater than 0.05). There was no difference with respect to sodium excretion between the reference group and the hypertension group. In the reference group, heart rate was positively correlated to PRA and to urinary norepinephrine excretion during the day. No linear correlation between PAR and BP was found, either in the reference group, or in the hypertension group. Sodium excretion during the day was positively correlated to GFR in the hypertension group, but not in the reference group. Compared to hypertensives with normal or high sodium excretion during the day, the hypertensives with low sodium excretion during the day were characterized by a higher BP, a lower GFR and a reversed diurnal rhythm of urine excretion. Thus, low sodium excretion seemed to indicate more severe hypertension with increased renal resistance during the day. The hypertension group was also divided with regard to sodium excretion into a low, normal and high renin group. The low renin group had the lowest GFR and with rising renin group (from low via normal to high) there was a significant increase in GFR and a significant decrease in resting BP. The results indicate that low renin hypertension is not a more mild, but indeed rather a more severe form of hypertension.

Recent reports have suggested that genotypes at the FTO locus interact with physical activity to modify levels of obesity-related traits. We tested this hypothesis in two non-diabetic population-based cohorts, the first from southern Sweden and the second from the Botnia region of western Finland.In total 2,511 Finnish and 15,925 Swedish non-diabetic middle-aged adults were genotyped for the FTO rs9939609 variant. Physical activity was assessed by questionnaires and standard clinical procedures were conducted, including measures of height and weight and glucose regulation. Tests of gene x physical activity interaction were performed using linear interaction effects to determine whether the effect of this variant on BMI is modified by physical activity.The minor A allele at rs9939609 was associated with higher BMI in both cohorts, with the per allele difference in BMI being about 0.13 and 0.43 kg/m(2) in the Swedish and Finnish cohorts, respectively (p0.0001). The test of interaction between physical activity and the rs9939609 variant on BMI was not statistically significant after controlling for age and sex in either cohort (Sweden: p = 0.71, Finland: p = 0.18).The present report does not support the notion that physical activity modifies the effects of the FTO rs9939609 variant on obesity risk in the non-diabetic Swedish or Finnish adults studied here.

Background: Natural antibodies specific for phosphorylcholine (anti-PC) have been implicated as protective factors in atherosclerosis. We herein determined the relationship between IgM anti-PC and incidence of cardiovascular disease (CVD). Methods: We studied 349 incident cases (200 men) of first events of CVD (coronary heart disease (CHD; n = 203 or ischemic stroke; n = 146) and 693 age- and sex-matched controls identified through 12 years of follow-up (1991-2003) of subjects from the cardiovascular cohort within the Malmo Diet and Cancer Study. Relative risks (RR) of CVD with 95% confidence intervals (CI) of incident CVD with adjustments for age, smoking, total cholesterol and blood pressure were determined. Anti-PC-levels were measured using ELISA (Athera CVDefine (TM)). Results: As determined using Athera CVDefine (TM), significant associations were attained with values of anti-PC below 17 U/ml (corresponding to the lowest 9th percentile), which remained after taking confounders into account (RR: 1.79, 95% CI: 1.09-2.94, p=0.021). If men were studied separately, significance was evident at values below 17U/ml (RR: 2.01, 95% Cl: 1.11-3.67, p=0.022), which was not the case among women. Furthermore, values below 17 U/ml were also associated with ischemic stroke (RR = 3.67, 95% Cl: 1.34-10.1, p=0.01), but not with CHD. Conclusion: Low IgM anti-PC could be a novel risk marker for development of ischemic stroke in men. Further studies are needed to establish gender and subgroup differences. (C) 2008 Elsevier Ireland Ltd. All rights reserved. (Less)

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.

OBJECTIVE Recent advances in type 2 diabetes genetics have culminated in the discovery and confirmation of multiple risk variants. Two important and largely unanswered questions are whether this information can be used to identify individuals most susceptible to the adverse consequences of sedentary behavior and to predict their response to lifestyle intervention; such evidence would be mechanistically informative and provide a rationale for targeting genetically susceptible subgroups of the population. RESEARCH DESIGN AND METHODS Gene × physical activity interactions were assessed for 17 polymorphisms in a prospective population-based cohort of initially nondiabetic middle-aged adults. Outcomes were 1) impaired glucose regulation (IGR) versus normal glucose regulation determined with either fasting or 2-h plasma glucose concentrations (n = 16,003), 2) glucose intolerance (in mmol/l, n = 8,860), or 3) incident type 2 diabetes (n = 2,063 events). RESULTS Tests of gene × physical activity interactions on IGR risk for 3 of the 17 polymorphisms were nominally statistically significant:CDKN2A/B rs10811661 (Pinteraction = 0.015), HNF1B rs4430796 (Pinteraction = 0.026), and PPARG rs1801282 (Pinteraction = 0.04). Consistent interactions were observed for the CDKN2A/B (Pinteraction = 0.013) and HNF1B (Pinteraction = 0.0009) variants on 2-h glucose concentrations. Where type 2 diabetes was the outcome, only one statistically significant interaction effect was observed, and this was for the HNF1B rs4430796 variant (Pinteraction = 0.0004). The interaction effects for HNF1B on IGR risk and incident diabetes remained significant after correction for multiple testing (Pinteraction = 0.015 and 0.0068, respectively). CONCLUSIONS Our observations suggest that the genetic predisposition to hyperglycemia is partially dependent on a person's lifestyle.

Many measures have been proposed to summarize the prognostic ability of the Cox proportional hazards (CPH) survival model, although none is universally accepted for general use. By contrast, little work has been done to summarize the prognostic ability of the stratified CPH model; such measures would be useful in analyses of individual participant data from multiple studies, data from multi-centre studies, and in single study analysis where stratification is used to avoid making assumptions of proportional hazards. We have chosen three measures developed for the unstratified CPH model (Schemper and Henderson's V , Harrell's C-index and Royston and Sauerbrei's D), adapted them for use with the stratified CPH model and demonstrated how their values can be represented over time. Although each of these measures is promising in principle, we found the measure of explained variation V very difficult to apply when data are combined from several studies with differing durations of participant follow-up. The two other measures considered, D and the C-index, were more applicable under such circumstances. We illustrate the methods using individual participant data from several prospective epidemiological studies of chronic disease outcomes.