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Background: Tumor development requires angiogenesis, and antiangiogenesis has been introduced in the treatment of cancer patients; however, how the cardiovascular phenotype correlates with cancer risk remains ill-defined. Here, we hypothesized that vasoactive peptides previously implicated in angiogenesis regulation predict long-term cancer risk.Methods: We measured midregional proatrial natriuretic peptide (MR-proANP), proadrenomedullin (MR-proADM), and C-terminal preprovasopressin (copeptin) in fasting plasma from participants of the Malmö Diet and Cancer Study that were free from cancer prior to the baseline exam in 1991 to 1994 (1,768 males and 2,293 females). We used Cox proportional hazards models to determine the time to first cancer event in relation to baseline levels of vasoactive peptides during a median follow-up of 15 years.Results: First cancer events occurred in 366 males and in 368 females. In males, one SD increase of MR-proANP, copeptin, and MR-proADM was independently related to incident cancer [HR (95% CI)] by 0.85 (0.74–0.96), P = 0.012; 1.17 (1.04–1.32), P = 0.009; and 1.12 (0.99–1.26), P = 0.065, respectively, and a summed biomarker score identified an almost 2-fold difference in cancer risk between the top and bottom quartile (P < 0.001). In younger males, the biomarker score identified a more than 3-fold increase in risk between the top and bottom quartile (P < 0.001). Among females, we found no relationship between biomarkers and cancer incidence.Conclusions: Our data suggest that vasoactive peptide biomarkers predict cancer risk in males, particularly in younger males.Impact: Our findings may have implications for cancer risk prediction and present novel, potentially drug modifiable, mechanisms underlying cancer development. Cancer Epidemiol Biomarkers Prev; 21(3); 513–22. ©2012 AACR.

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values 105 mL·min –1 ·1.73 m –2 , compared with those with eGFR between 60 and 105 mL·min –1 ·1.73 m –2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR –1 ·1.73 m –2 , with a 14% (95% CI, 3%–27%) higher CHD risk per 5 mL·min –1 ·1.73 m –2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min –1 ·1.73 m –2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

BackgroundLow resting heart rate and premature atrial contractions (PACs) predict incident atrial fibrillation (AF) and could be interdependent, since PACs occur in the gaps between normal beats.ObjectiveTo study the association between low heart rate at 24hECG, PACs and incident AF in a prospective population-based cohort.MethodsIn the Malmö Diet and Cancer study, 24hECGs were performed in 377 AF-free subjects. The endpoint was clinical AF retrieved from national hospital (mean follow-up 17 years). The interaction between increased supraventricular activity (SVA) top quartile of either PACs/hour or supraventricular tachycardias/hour) and mean heart rate (mHR) as regards AF risk was assessed in multivariable Cox regression analyses adjusted for age, sex, height, BMI, systolic blood pressure, antihypertensive medication, smoking and homeostasis model assessment of insulin resistance.ResultsThere were 80 (21%) incident cases of AF. Below median mHR (80 bpm/75 bpm for women/men) was associated with increased AF incidence (HR: 1.89, 95% CI 1.18 to 3.02, p=0.008). There was no correlation between mHR and SVA (p=0.6) or evidence of a multiplicative interaction between these factors for AF risk (p for interaction=0.6) In the group with both increased SVA and below median mHR (17% of the population) the relative risk of AF was very high (HR 4.5, 95% CI 2.2 to 9.1, p=0.001).ConclusionLow mHR at 24hECG independently predicts AF, but there is no association between mHR and SVA, and these factors are independent as regards AF risk. Subjects with both low mHR and increased SVA have high AF risk.

Background/objectives: Studies on the health effects of whole grains typically use self-reported intakes which are prone to large measurement errors. Dietary biomarkers that can provide an objective measure of intake are needed. New alkylresorcinol (AR) metabolites (3,5-dihydroxycinnamic acid (DHCA), 2-(3,5-dihydroxybenzamido)acetic acid (DHBA-glycine) and 5-(3,5-dihydroxyphenyl) pentanoic acid (DHPPTA)) in 24 h urine samples have been suggested as biomarkers for whole grain (WG) wheat and rye intake but remain to be evaluated in spot urine samples. Subjects/methods: The reproducibility of the new AR metabolites (DHCA, DHBA-glycine and DHPPTA) was investigated in 4 repeated samples over a period of 2 wk in spot urine from 40 Swedish men and women enroled in the SCAPIS-study, after adjustment of creatinine. Metabolite concentrations were correlated with total whole grain intake estimated during the same period. Results: The medium-term reproducibility determined for DHCA, DHPPTA and DHBA-glycine varied from moderate to excellent (intra-class correlation coefficient = 0.35–0.67). Moreover, DHCA and DHBA-glycine were independently associated with self-reported total WG intake (β = 0.18, P = 0.08 and β = 0.18, P = 0.02, respectively) and all metabolites except for DHPPA were higher among women. Conclusions: This study supports the idea of using AR metabolites in one or several spot urine samples as biomarkers of whole grain intake. These findings need to be confirmed in different populations.

Background and aims Diet and smoking expose the general population to cadmium (Cd), which is a toxic metal that accumulates in the arterial wall. In experimental studies, Cd causes reductions in proliferation of smooth muscle cells and cellular synthesis of procollagen. The aim of this study was to examine whether blood Cd levels, a valid measure of Cd exposure, are associated with increased risk of abdominal aortic aneurysm (AAA). Methods All middle-aged men and women enrolled in the Malmo Diet and Cancer study (n = 30 447) were followed from the baseline examination in 1991–1996 through 2009. A total of 297 cases with AAA and two randomly selected control subjects for each case, matched for age and sex, were included. Blood Cd was analysed by inductively coupled plasma mass spectrometry. Diagnoses of AAA, thoracic aortic aneurysm and aortic dissection were obtained from registers. Results Increased blood Cd was associated with increased risk of incident AAA after adjustment for smoking and other established risk factors for AAA. The highest tertile of blood Cd concentrations had a rate ratio of 2.5 (95% confidence interval 1.3, 5.0) for incident AAA. Concentration of blood Cd (log transformed) was not associated with AAA in never-smokers (n = 24). Conclusions Blood Cd levels corresponding to the upper tertile of the distribution in the age- and sex-matched control group were associated with a 2.5-fold increase in rate ratio for incident AAA. This relationship was not found in the small group of never-smokers.

Aims: ST-depression at 24hECG has not been studied in relation to atrial fibrillation (AF) risk. We aimed to determine whether ST-depression at 24hECG was associated with incident AF in two Swedish population-based cohorts - a sub-cohort of the Malmo Diet and Cancer study (MDCS), and the cohort 'Men born in 1914', and to determine whether 24hECG could be used to predict AF development.Methods and results: There were 378 acceptable 24hECG recordings in the MDCS (mean age 64.5 years, 43% men) and 394 acceptable recordings in 'Men born in 1914' (mean age 68.8 years). Incidence of AF was monitored using national registers of hospitalizations and outpatient visits in Sweden. Mean follow-up ± SD (cumulative incidence) was 10.4 ± 2 years (11.3%) in MDCS, and 10.9 ± 4 years (7.3%) in 'Men born in 1914'. ST-depressions were independently associated with incident AF; hazard ratio (HR) (95% CI) 2.41 (1.29-4.50, P = 0.006) and 2.28 (1.05-4.95, P = 0.038) after adjustment [age, sex, height, weight, systolic blood pressure, smoking, anti-hypertensive drugs, LDL/total cholesterol, and HOMA-IR (in MDCS)]. AF incidence was substantially lower in individuals who had neither ST-depressions or high supraventricular activity (SVA, negative predictive value 0.97 and 0.94, in MDCS and 'Men born in 1914', respectively), and similar in men and women.Conclusion: ST-depression at 24h-ECG is independently associated with incident AF, and incidence is substantially lower in individuals with neither ST-depression or high SVA. 24hECG can be used not only to diagnose AF but also to identify individuals at high and low AF risk. (Less)

Background: Lead exposure has been associated with increased incidence of adverse clinical cardiovascular outcomes. Atherosclerosis has been suggested as one of the underlying mechanisms, and findings from experimental studies support this, but human data are scarce. Objectives: Our objective was to determine the association between environmental lead exposure based on blood lead (B-Pb) concentrations and the prevalence of atherosclerotic plaque in the carotid artery. Methods: We used cross-sectional data from the Malmö Diet and Cancer Study cardiovascular cohort (MDCS-CC; recruitment in 1991–1994) covering 4,172 middle-aged men and women. B-Pb at baseline, measured by inductively coupled plasma mass spectrometry, was used as the exposure biomarker. The presence of atherosclerotic plaque in the carotid artery was determined by B-mode ultrasonography. We used logistic regression to estimate odds ratios (ORs) for prevalence of plaque in the carotid artery according to B-Pb quartiles. Results: The median B-Pb was 25μg/L (range: 1.5–258), and 36% of the cohort had any atherosclerotic plaque. After controlling for confounders and known cardiovascular risk factors, the OR for prevalence of plaque in the highest quartile (Q4) of B-Pb compared with the lowest quartile (Q1) was 1.35 (95% CI: 1.09, 1.66) in the total group, 1.58 (95% CI: 1.20, 2.08) among women, and 1.18 (95% CI: 0.83, 1.69) among men. Among women, associations were limited to those who were postmenopausal [OR for Q4 vs. Q1=1.72 (95% CI: 1.26, 2.34) vs. OR=0.96 (95% CI: 0.49, 1.89 in premenopausal women)]. Associations were weak and nonsignificant in never-smokers [OR for Q4 vs. Q1=1.14 (95% CI: 0.81, 1.61)]. Discussion: Our study shows an association between B-Pb concentrations and occurrence of atherosclerotic plaque in the carotid artery, adding evidence for an underlying pro-atherogenic role of lead in cardiovascular disease. Associations appeared to be limited to postmenopausal (vs. premenopausal) women. https://doi.org/10.1289/EHP5057

Background Cadmium is a toxic metal with multiple adverse health effects, including risk of cardiovascular disease (CVD). The mechanistic link between cadmium and CVD is unclear. Our aim was to examine the associations between blood cadmium (B-Cd) and 88 potential protein biomarkers of CVD. Methods B-Cd and 88 plasma proteins were measured in a community-based prospective cohort, the Malmö Diet and Cancer study. The primary analysis was performed in never smokers (n = 1725). Multiple linear regression was used with adjustments for age and sex, and correction for multiple comparisons using the false discovery rate method. Proteins significantly associated with B-Cd were replicated in long-term former smokers (n = 782). Significant proteins were then studied in relation to incidence of CVD (i.e., coronary events or ischemic stroke) in never smokers. Results Fifteen proteins were associated with B-Cd in never smokers. Eight of them were replicated in long-term former smokers. Kidney injury molecule-1, fibroblast growth factor-23 (FGF23), tumor necrosis factor receptor-2, matrix metalloproteinase-12, cathepsin L1, urokinase plasminogen activator receptor, C-C motif chemokine-3 (CCL3), and chemokine (C-X3-C motif) ligand-1 were associated with B-Cd both in never smokers and long-term former smokers. Except for CCL3 and FGF23, these proteins were also significantly associated with incidence of CVD. Conclusions B-Cd in non-smokers was associated with eight potential plasma biomarkers of CVD and kidney injury. The results suggest pathways for the associations between B-Cd and CVD and kidney injury.

Background The increasing prevalence of atrial fibrillation and novel therapeutic tools to prevent cardioembolic stroke has increased the need for risk markers. Objectives This study explored the relationship between the midregional sequence of pro-atrial natriuretic peptide (MR-proANP) levels with the risk of atrial fibrillation and stroke, and whether measurement of MR-proANP improves the prediction of these outcomes. Methods MR-proANP was measured in fasting blood samples of 5130 subjects (69% men, mean age 69.2 ± 6.2 years) without a history of atrial fibrillation or stroke from the general population. The incidence of atrial fibrillation and stroke was monitored over a median follow-up of 5.6 years. C-statistics and net reclassification improvement was used to assess the predictive ability of MR-proANP in addition to conventional risk factors. Results Log-normalized MR-proANP was significantly associated with the incidence of atrial fibrillation ( n = 362; hazard ratio (HR); 95% confidence interval (CI) per 1 standard deviation (SD) 2.05, 1.86-2.27) and stroke from all causes ( n = 195; HR 1.30; 95% CI 1.12-1.50). The HR for stroke events related to atrial fibrillation was 1.79 (95% CI 1.25-2.58) per 1 SD. MR-proANP significantly improved the prediction of atrial fibrillation when added to a risk score of conventional risk factors (C statistic 0.69 vs. 0.75), mainly by down-classifying subjects who did not develop atrial fibrillation. A smaller improvement in predictive ability was observed for stroke (C statistic 0.66 vs. 0.68). Conclusion High plasma levels of MR-proANP are associated with the incidence of atrial fibrillation and stroke in the middle-aged and elderly population. MR-proANP may be useful to identify individuals with an increased risk of atrial fibrillation.

BackgroundDiet and smoking are the main sources of cadmium exposure in the general population. Cadmium increases the risk of cardiovascular diseases, and experimental studies show that it induces inflammation. Blood cadmium levels are associated with macrophages in human atherosclerotic plaques. Soluble urokinase-type plasminogen activator receptor (suPAR) is an emerging biomarker for cardiovascular events related to inflammation and atherosclerotic plaques. The aim was to examine whether blood cadmium levels are associated with circulating suPAR and other markers of inflammation.MethodsA population sample of 4648 Swedish middle-aged women and men was examined cross-sectionally in 1991–1994. Plasma suPAR was assessed by ELISA, leukocytes were measured by standard methods, and blood cadmium was analysed by inductively coupled plasma mass spectrometry. Prevalent cardiovascular disease, ultrasound-assessed carotid plaque occurrence, and several possible confounding factors were recorded.ResultsAfter full adjustment for risk factors and confounding variables, a 3-fold increase in blood cadmium was associated with an 10.9% increase in suPAR concentration (p

Background and Purpose— Orosomucoid (α-1-acid glycoprotein) is an acute-phase protein that has been implicated in anti-inflammatory, immunomodulating, and angiogenic pathways. Orosomucoid has also been associated with coronary disease and stroke. The relationship between orosomucoid, carotid plaque, and stroke incidence were explored in this study. Methods— Plasma levels of orosomucoid were assessed in 4285 subjects (39.8% men; mean age 57.5±5.9 years) without cardiovascular disease, who participated in the Malmö Diet and Cancer Study, between 1991 and 1994. The right carotid artery was examined for plaque using B-mode ultrasound examination. Incidence of stroke was followed up during a median follow-up time of 17.7 years. Results— Carotid plaque was present in 43.5% at baseline. Orosomucoid was significantly higher in subjects with carotid plaque (mean±SD: 0.72±0.22 versus 0.69±0.20 g/L; P Conclusions— Elevated levels of orosomucoid are associated with increased occurrence of carotid plaque and increased incidence of ischemic stroke. The combination of high orosomucoid and carotid plaque substantially increase the risk of stroke.

Background: Cadmium exposure may increase the risk of cardiovascular disease. The only published longitudinal study on cadmium and incident cardiovascular disease was performed in American Indians with relatively high cadmium exposure. Objectives: Our aim was to examine the association between blood cadmium at baseline and incident cardiovascular events in a population-based study of Swedish men and women with cadmium levels similar to those of most European and U.S. populations. Methods: A Swedish population-based cohort (n = 6,103, age 46–67 years) was recruited between 1991 and 1994. After we excluded those with missing data on smoking, 4,819 participants remained. Acute coronary events, other major cardiac events, stroke, and cardiovascular mortality were followed until 2010. Associations with blood cadmium (estimated from cadmium in erythrocytes) were analyzed using Cox proportional hazards regression including potential confounders and important cardiovascular risk factors. Results: Hazard ratios for all cardiovascular end points were consistently increased for participants in the 4th blood cadmium quartile (median, 0.99 μg/L). In models that also included sex, smoking, waist circumference, education, physical activity, alcohol intake, serum triglycerides, HbA1c, and C-reactive protein, the hazard ratios comparing the highest and lowest quartiles of exposure were 1.8 (95% CI: 1.2, 2.7) for acute coronary events, and 1.9 (1.3, 2.9) for stroke. Hazard ratios in never-smokers were consistent with these estimates. Conclusions: Blood cadmium in the highest quartile was associated with incident cardiovascular disease and mortality in our population-based samples of Swedish adults. The consistent results among never-smokers are important because smoking is a strong confounder. Our findings suggest that measures to reduce cadmium exposures are warranted, even in populations without unusual sources of exposure. Citation: Barregard L, Sallsten G, Fagerberg B, Borné Y, Persson M, Hedblad B, Engström G. 2016. Blood cadmium levels and incident cardiovascular events during follow-up in a population-based cohort of Swedish adults: the Malmö Diet and Cancer Study. Environ Health Perspect 124:594–600; http://dx.doi.org/10.1289/ehp.1509735

The purpose of the study was to investigate the long-term associations between smoking habits, environmental tobacco smoke exposure (ETS), carotid intima-media thickness (IMT) progression rate, and rate of lumen diameter reduction in the carotid artery during a 16-year follow-up. Another objective was to investigate if an effect of smoking on progression rate could be explained by increased low grade inflammation.The study population included 2992 middle-aged men and women in the 1991-1994 (baseline) and the 2007-2012 (re-examination) investigation of the Malmö Diet and Cancer Study cardiovascular cohort. Associations between smoking, progression of carotid IMT and lumen diameter reduction due to plaque protrusion were assessed by linear regression.IMT progression rates and rate of lumen diameter reduction increased from never smokers with no ETS through former, moderate and heavy smokers, even after adjustment for traditional risk factors (e.g., differences in yearly progression rates (mm/year) of maximal IMT in the carotid bifurcation compared to never smokers; former smokers 0.0074 (95% CI: 0.0018-0.0129), moderate smokers 0.0106 (95% CI: 0.0038-0.0175), and heavy smokers 0.0146 (95% CI: 0.0061-0.0230)). Former smokers showed distinct lowering of progression rates after more than five years since smoking cessation. Smoking and former smoking was associated with increased low grade inflammation, however, the effect of smoking on atherosclerotic progression rate remained fairly unchanged after such adjustment.The effect of smoking and former smoking on carotid IMT progression rates and change in lumen reduction due to plaque protrusion could not be explained by differences in traditional risk factors or low grade inflammation.

Background Atrial fibrillation (AF) episodes are thought to be started by an electrical trigger reaching susceptible atria. Such a trigger could be present long before the occurrence of sustained symptomatic arrhythmia. Objective We sought to determine whether supraventricular extrasystoles (SVESs) and supraventricular tachycardias (SVTs) measured at 24-hour Holter electrocardiogram were associated with an increased incidence of AF. Methods In 1998–2000, 389 individuals (44% men; mean age 65 years) were examined using 24-hour Holter electrocardiogram. Six individuals with known prevalent AF were excluded. After a mean follow-up of 10.3 years, there were 45 cases of incident AF. Hazard ratios (HRs) were computed using multivariable Cox regression adjusting for age, sex, systolic blood pressure, height, weight, smoking, and homeostatic model assessment of insulin resistance. Results Frequency of SVESs as well as SVT episodes per hour were independent predictors of incident AF (HR per log unit 1.38; 95% confidence interval 1.14–1.68; P = .001 and HR 1.95; 95% confidence interval 1.21–3.13; P = .006, respectively). Further adjustment for education level, alcohol use, use of medication, and physical activity did not substantially alter the results, nor did analysis using competing risks regression accounting for a competing risk of death. The maximum duration of SVT or the heart rate at SVT was not significantly associated with the incidence of AF. Conclusion SVESs and SVTs independently predict AF. The prognostic significance was similar for SVESs, SVTs, and a combination of the two. Repeated efforts to detect AF could be of merit in individuals with frequent supraventricular activity.

Purpose In experimental studies, enkephalins (ENKs) and related opioids have been implicated as negative regulators of breast cancer development by enhancing immune-mediated tumoral defense as well as directly inhibiting cancer cells. We hypothesized that plasma levels of ENKs are predictive of the long-term breast cancer risk. Therefore, our objective was to measure pro-ENK A, a surrogate for mature ENK, and evaluate its predictive value for the development of breast cancer in a large population of middle-aged women and an independent study population. Patients and Methods We related pro-ENK in fasting plasma samples from 1,929 healthy women (mean age, 57.6 ± 5.9 years) of the Malmö Diet and Cancer study to breast cancer incidence (n = 123) during a median follow-up of 14.7 years. For replication, pro-ENK was related to risk of breast cancer (n = 130) in an older independent sample from the Malmö Preventive Project consisting of 1,569 women (mean age, 70.0 ± 4.4 years). Results In the Malmö Diet and Cancer study, pro-ENK was inversely related to the risk of incident breast cancer, with a hazard ratio per each standard deviation increment of logarithm-transformed pro-ENK of 0.72 (95% CI, 0.62 to 0.85; P < .001). The linear elevation of risk over pro-ENK quartiles 3, 2, and 1, with the fourth quartile as a reference, was 1.38 (95% CI, 0.73 to 2.64), 2.29 (95% CI, 1.26 to 4.15), and 3.16 (95% CI, 1.78 to 5.60; for the trend, P < .001), respectively. These results were replicated in the Malmö Preventive Project, where the continuous odds ratio for incident breast cancer was 0.63 (95% CI, 0.52 to 0.76; P < .001) and the risk over pro-ENK quartiles 3, 2, and 1, where the fourth quartile was the reference, was 2.48 (95% CI, 1.25 to 4.94), 2.94 (95% CI, 1.50 to 5.77), and 4.81 (95% CI, 2.52 to 9.18; for the trend, P < .001), respecitvely. Conclusion Low fasting plasma concentration of the opioid precursor peptide pro-ENK is associated with an increased risk of future breast cancer in middle-aged and postmenopausal women.

A high intake of omega-3 polyunsaturated fatty acids (ω-3 PUFAs), has been associated with reduced levels of blood pressure (BP). Their antihypertensive action may be due to the reduction of the ω-6/ω-3 ratio and the resulting competitive effect of ω-3 as compared to arachidonic acid (an ω-6 PUFA) as a substrate of cytochrome P450 (CYP450) enzymes involved in the production of vasoactive mediators. Some functional polymorphisms (SNPs), in genes which encode for the same enzymes, were associated with hypertension and ischemic stroke in the Malmö Diet and Cancer (MDC), a Swedish urban-based longitudinal study. The aim of this study was to evaluate the effect of the intake of different types of PUFAs on BP change over time (Δ-BP; mean follow-up 16.6±1.5 years; n=3.550 with complete phenotypic data), also considering the interaction with SNPs in genes involved in their metabolism via CYP450.PUFA intakes were collected by a modified diet history method, and functional SNPs in CYP4F2, CYP4A11, CYP2J2 and EPHX2 were genotyped by Taqman.We did not find any overall association between ω-6 and ω-3 PUFA intakes, or their ratio, with Δ-BP but observed an interaction between CYP4F2 V433M genotype and total omega-3, α-linolenic acid and linoleic/α-linolenic ratio, so that a higher ω-3 PUFA intake was significantly associated with a more pronounced BP decrease over time in subjects with the 433VV genotype (-0.041±0.018 mmHg/year; p=0.024; p-interaction=0.031) CONCLUSIONS: Our data do not support a major role of ω-6 or ω-3 PUFA intakes on BP change over time, but suggest a possible interaction of ω-3 PUFA with the CYP4F2 V433M.

Large-scale genome-wide association studies (GWAS) have so far identified 45 loci that are robustly associated with coronary heart disease (CHD) in data from adult men and women of European descent.To examine whether the CHD-associated loci are associated with measures of atherosclerosis in data from up to 9582 individuals of European ancestry.Forty-five SNPs representing the CHD-associated loci were genotyped in middle-aged to elderly individuals of European descent from four independent population-based studies (IMPROVE, MDC-CC, ULSAM and PIVUS). Intima-media thickness (IMT) was measured by external B-mode ultrasonography at the far wall of the bulb (sinus) and common carotid artery. Plaque presence was defined as a maximal IMT of the bulb1.5 mm. We meta-analysed single-SNP associations across the four studies, and combined them in a genetic predisposition score. We subsequently examined the association of the genetic predisposition score with prevalent CHD and the three indices of atherosclerosis, adjusting for sex, age and Framingham risk factors.As anticipated, the genetic predisposition score was associated with prevalent CHD, with each additional risk allele increasing the odds of disease by 5.5% (p = 4.1 × 10(-6)). Moreover, each additional CHD-risk allele across the 45 loci was associated with a 0.24% increase in IMT (p = 4.0 × 10(-3)), and with a 2.8% increased odds of plaque presence (p = 7.4 × 10(-6)) at the far wall of the bulb. The genetic predisposition score was not associated with IMT of the common carotid artery (p = 0.47).Our results suggest that the association between the 45 previously identified loci and CHD at least partly acts through atherosclerosis.

Objective : To examine if overall diet quality is associated with cellular and soluble biomarkers of systemic inflammation in middle-aged individuals. Methods : A group of 667 individuals, aged 63–68 years, selected from the cardiovascular arm of the Malmo Diet and Cancer cohort, participated in this study. Baseline examinations consisted of an extensive socio-demographic questionnaire, anthropometric measurements, blood sampling and detailed dietary data. Mononuclear leukocytes frozen at baseline were thawed and analysed with flow cytometry to quantify monocyte subsets based on CD14 and CD16 expression. Plasma cytokines were measured using multiplexed immune assays. A diet quality index consisting of six components (saturated fatty acids, polyunsaturated fatty acids, fish and shellfish, dietary fibre, fruit and vegetables, and sucrose) was constructed to measure adherence to the Swedish Nutrition Recommendations/Dietary Guidelines. General linear models were used to investigate associations between index scores and several biomarkers of inflammation. Results : A higher percentage of women reported adherence to the nutritional recommendations and had better overall diet quality than men. Participants with higher diet quality were more likely to have a healthier lifestyle. The levels of high-sensitive CRP, S100A8/A9, TNF-α, white blood cells, neutrophils, lymphocytes and CD14 + CD16 ++ were lower in participants with higher index scores. The associations remained significant after adjustment for potential confounders. Conclusion : In this cross-sectional study, we found that a high diet quality is associated with lower systemic inflammation. As the incidence of cardiovascular disease and cancer is directly correlated with the levels of inflammation, our findings might indicate a protective role of high-quality diet.

Objective— Rupture of atherosclerotic plaques is the major cause of acute coronary events (CEs). Plaque destabilization is the consequence of an imbalance between inflammatory-driven degradation of fibrous tissue and smooth muscle cell–dependent tissue repair. Proinflammatory factors have been documented extensively as biomarkers of cardiovascular risk but factors that contribute to stabilization of atherosclerotic plaques have received less attention. The present study aimed to investigate whether plasma levels of the smooth muscle cell growth factor epidermal growth factor (EGF), heparin-binding-EGF (HB-EGF), and platelet-derived growth factor correlate with plaque phenotype and incidence of CEs. Approach and Results— HB-EGF, EGF and platelet-derived growth factor were measured in plasma from 202 patients undergoing carotid endarterectomy and in 384 incident CE cases and 409 matched controls recruited from the Malmö Diet and Cancer cohort. Significant positive associations were found between the plasma levels of all 3 growth factors and the collagen and elastin contents of the removed plaques. CE cases in the Malmö Diet and Cancer cohort had lower levels of HB-EGF in plasma, whereas no significant differences were found for EGF and platelet-derived growth factor. After adjusting for cardiovascular risk factors in a Cox proportional hazard model, the hazard ratio for the highest HB-EGF tertile was 0.61 (95% confidence interval, 0.47–0.82; P Conclusions— The associations between high levels of smooth muscle cell growth factors in plasma and a more fibrous plaque phenotype as well as the association between low levels of HB-EGF and incident CEs point to a potential clinically important role for factors that contribute to plaque stabilization by stimulating smooth muscle cells.

Modern medicine is overwhelmed by a plethora of both established risk factors and novel biomarkers for diseases. The majority of this information is expressed by probabilistic measures of association such as the odds ratio (OR) obtained by calculating differences in average “risk” between exposed and unexposed groups. However, recent research demonstrates that even ORs of considerable magnitude are insufficient for assessing the ability of risk factors or biomarkers to distinguish the individuals who will develop the disease from those who will not. In regards to coronary heart disease (CHD), we already know that novel biomarkers add very little to the discriminatory accuracy (DA) of traditional risk factors. However, the value added by traditional risk factors alongside simple demographic variables such as age and sex has been the subject of less discussion. Moreover, in public health, we use the OR to calculate the population attributable fraction (PAF), although this measure fails to consider the DA of the risk factor it represents. Therefore, focusing on CHD and applying measures of DA, we re-examine the role of individual demographic characteristics, risk factors, novel biomarkers and PAFs in public health and epidemiology. In so doing, we also raise a more general criticism of the traditional risk factors’ epidemiology. We investigated a cohort of 6103 men and women who participated in the baseline (1991–1996) of the Malmö Diet and Cancer study and were followed for 18 years. We found that neither traditional risk factors nor biomarkers substantially improved the DA obtained by models considering only age and sex. We concluded that the PAF measure provided insufficient information for the planning of preventive strategies in the population. We need a better understanding of the individual heterogeneity around the averages and, thereby, a fundamental change in the way we interpret risk factors in public health and epidemiology., Highlights • There is a plethora of differences in “average” risk between exposed and unexposed groups of individuals. • Individual heterogeneity around average values is seldom considered in Public Health. • Measures of discriminatory accuracy (DA) informs on the underlying individual heterogeneity. • Most know risk factors and other categorizations associated with diseases have low DA. • We need a fundamental change in the way we investigate risk factors and other categorizations in Public Health.

Environmental lead exposure has been associated with decreased kidney function, but evidence from large prospective cohort studies examining low exposure levels is scarce. We assessed the association of low levels of lead exposure with kidney function and kidney disease.Prospective population-based cohort.4,341 individuals aged 46 to 67 years enrolled into the Malmö Diet and Cancer Study-Cardiovascular Cohort (1991-1994) and 2,567 individuals subsequently followed up (2007-2012).Blood lead concentrations in quartiles (Q1-Q4) at baseline.Change in estimated glomerular filtration rate (eGFR) between the baseline and follow-up visit based on serum creatinine level alone or in combination with cystatin C level. Chronic kidney disease (CKD) incidence (185 cases) through 2013 detected using a national registry.Multivariable-adjusted linear regression models to assess associations between lead levels and eGFRs at baseline and follow-up and change in eGFRs over time. Cox regression was used to examine associations between lead levels and CKD incidence. Validation of 100 randomly selected CKD cases showed very good agreement between registry data and medical records and laboratory data.At baseline, 60% of study participants were women, mean age was 57 years, and median lead level was 25 (range, 1.5-258) μg/L. After a mean of 16 years of follow-up, eGFR decreased on average by 6mL/min/1.73mLead level measured only at baseline, moderate number of CKD cases, potential unmeasured confounding.Low-level lead exposure was associated with decreased kidney function and incident CKD. Our findings suggest lead nephrotoxicity even at low levels of exposure.

Purpose: This study explored whether complement factor 3 (C3) in plasma is associated with incidence of diabetes in a population-based cohort. We also identified genetic variants related to C3 and explored whether C3 and diabetes share common genetic determinants.Methods: C3 was analyzed in plasma from 4368 nondiabetic subjects, 46 to 68 years old, from the Malmo Diet and Cancer Study. Incidence of diabetes was studied in relationship to C3 levels during 17.7± 4.4 years of follow-up. Genotypes associated with C3 were identified in a genome-wide association study. Diabetes Genetics Replication and Meta-Analysis and the European Genetic Database were used for in silico look-up.Results: In all, 538 (12.3%) subjects developed diabetes during 18 years of follow-up. High C3 was significantly associated with incidence of diabetes after risk factor adjustments (hazard ratio comparing 4th vs 1st quartile, 1.54 (95% confidence interval, 1.13 to 2.09; P = 0.005). C3 was associated with polymorphisms at the complement factor H locus (P < 10-8). However, no relationship with diabetes was observed for this locus. Another eight loci were associated with C3 with P < 10-5. One of them, the glucose kinase regulatory protein (GCKR) locus, has been previously associated with diabetes. The relationship between C3 levels and the GCKR locus was replicated in the European Genetic Database cohort.Conclusions: Plasma concentration of C3 is a risk marker for incidence of diabetes. The results suggest that this association could, in part, be explained by pleiotropic effects related to the GCKR gene. (Less)