Malmö Diet And Cancer Research Articles

Plasma levels of sCASP3 predicts carotid intima media thickness progression

Abstract Background Studies on human atherosclerotic plaques have shown that apoptosis is associated with rupture prone plaques and that apoptosis is a key process for fast plaque progression. In line with this, we showed that circulating levels of soluble Caspase-3 (sCaspase-3) predict atherosclerotic events. However, the relationship between circulating levels of apoptosis markers and plaque progression remains to be explored. Purpose Here we aimed to investigate if circulating levels of apoptosis markers could predict mean intima-media thickness in the common carotid artery (IMT-CCA) progression among individuals with atherosclerotic carotid plaques. Methods The Malmö Diet and Cancer (MDC) cardiovascular cohort was used. MDC is a prospective population-based cohort study. Baseline variables (blood, clinical information and carotid ultrasound measurements) were collected between 1991-1994 and the right carotid ultrasound re-examinations were performed between 1994-2001. IMT was measured at by ultrasound at baseline as well as at the re-examinations. The Olink Proximity Extension Assay (SciLifeLab, Uppsala, Sweden) was used to analyze plasma levels of sCaspase-3, sFADD, sCaspase-8, sTRAIL-R2 and sTNFR1 at baseline. Correlation and multiple linear regression analyses, adjusted for age, sex, and cardiovascular risk factors, were employed to evaluate the relationships between apoptosis biomarkers and IMT-CCA as well as average annual change in IMT-CCA. Results In total, 1929 participants (median age 60 years) with an ultrasound confirmed carotid plaque (focal IMT >1.2mm) at baseline were included. Subjects who underwent ultrasound IMT re-examination over a period of >4.5 years were divided into a discovery (n=406) and a validation (n=355) cohort. sCaspase-3 was identified as the marker with the strongest correlation to IMT-CCA at baseline (p=0.02) and upon re-examination (p=0.04), among the five apoptosis markers examined, in both the discovery and validation cohorts. sCaspase-3 also showed a correlation with the average annual change of IMT-CCA (r=0.12, p=8×10-4) in both cohorts. Furthermore, when diving the cohort into tertiles based on plasma levels of sCapase-3, subjects with high levels of sCaspase-3 (3rd tertile) had greater annual changes in IMT-CCA compared to the 1st tertile (p=0.03). Multiple linear regression analyses confirmed that sCapase-3 was associated with the average annual IMT-CCA change in both the discovery (beta=0.14, 95% confidence interval (CI) 0.04–0.24) cohort and the validation cohort (beta=0.11, 95%CI 0.01–0.21). Conclusion Using a large, population-based study with repeated IMT measurements, we demonstrated that circulating levels of sCapase-3 were associated with increasing IMT in the CCA. While further studies are warranted, these results suggest that sCapase-3 levels could serve as potential screening marker to identify individuals at higher risk for plaque progression.

Can non-participants in a follow-up be used to draw conclusions about incidences and prevalences in the full population invited at baseline? An investigation based on the Swedish MDC cohort

BackgroundParticipants in epidemiological cohorts may not be representative of the full invited population, limiting the generalizability of prevalence and incidence estimates. We propose that this problem can be remedied by exploiting data on baseline participants who refused to participate in a re-examination, as such participants may be more similar to baseline non-participants than what baseline participants who agree to participate in the re-examination are.MethodsWe compared background characteristics, mortality, and disease incidences across the full population invited to the Malmö Diet and Cancer (MDC) study, the baseline participants, the baseline non-participants, the baseline participants who participated in a re-examination, and the baseline participants who did not participate in the re-examination. We then considered two models for estimating characteristics and outcomes in the full population: one (“the substitution model”) assuming that the baseline non-participants were similar to the baseline participants who refused to participate in the re-examination, and one (“the extrapolation model”) assuming that differences between the full group of baseline participants and the baseline participants who participated in the re-examination could be extended to infer results in the full population. Finally, we compared prevalences of baseline risk factors including smoking, risky drinking, overweight, and obesity across baseline participants, baseline participants who participated in the re-examination, and baseline participants who did not participate in the re-examination, and used the above models to estimate the prevalences of these factors in the full invited population.ResultsCompared to baseline non-participants, baseline participants were less likely to be immigrants, had higher socioeconomic status, and lower mortality and disease incidences. Baseline participants not participating in the re-examination generally resembled the full population. The extrapolation model often generated characteristics and incidences even more similar to the full population. The prevalences of risk factors, particularly smoking, were estimated to be substantially higher in the full population than among the baseline participants.ConclusionsParticipants in epidemiological cohorts such as the MDC study are unlikely to be representative of the full invited population. Exploiting data on baseline participants who did not participate in a re-examination can be a simple and useful way to improve the generalizability of prevalence and incidence estimates.

Circulating soluble IL-6 receptor associates with plaque inflammation but not with atherosclerosis severity and cardiovascular risk

BackgroundThe residual cardiovascular risk in subjects receiving guideline-recommended therapy is related to persistent vascular inflammation and IL-6 represents a target for its treatment. IL-6 binds to receptors on leukocytes and hepatocytes and/or by forming complexes with soluble IL-6 receptors (sIL-6R) binding to gp130 which is present on all cells. Here we aimed to estimate the associations of these two pathways with risk of cardiovascular disease (CVD). MethodsIL-6 and sIL-6R were analyzed using the proximity extension assay. Baseline plasma samples were obtained from participants in the prospective Malmö Diet and Cancer (MDC) study (n = 4661), the SUMMIT VIP study (n = 1438) and the Carotid Plaque Imaging Project (CPIP, n = 285). Incident clinical events were obtained through national registers. Plaques removed at surgery were analyzed by immunohistochemistry and biochemical methods. ResultsDuring 23.1 ± 7.0 years follow-up, 575 subjects in the MDC cohort suffered a first myocardial infarction. Subjects in the highest tertile of IL-6 had an increased risk compared to the lowest tertile (HR and 95% CI 2.60 [2.08–3.25]). High plasma IL-6 was also associated with more atherosclerosis, increased arterial stiffness, and impaired endothelial function in SUMMIT VIP, but IL-6 was only weakly associated with plaque inflammation in CPIP. sIL-6R showed no independent association with risk of myocardial infarction, atherosclerosis severity or vascular function, but was associated with plaque inflammation. ConclusionsOur findings show that sIL-6R is a poor marker of CVD risk and associated vascular changes. However, the observation that sIL-6R reflects plaque inflammation highlights the complexity of the role of IL-6 in CVD.

Long-term ambient air pollution and venous thromboembolism in a population-based Swedish cohort

Air pollution is a major contributor to the global burden of disease and has been linked to several diseases and conditions, including cardiovascular disease. The biological mechanisms are related to inflammation and increased coagulability, factors that play an important role in the pathogenesis of venous thromboembolism (VTE, i.e., deep vein thrombosis or pulmonary embolism). This study investigates if long-term exposure to air pollution is associated with increased VTE incidence. The study followed 29 408 participants from the Malmö Diet and Cancer (MDC) cohort, which consists of adults aged 44–74 recruited in Malmö, Sweden between 1991 and 1996. For each participant, annual mean residential exposures to particulate matter <2.5 μg (PM2.5) and <10 μg (PM10), nitrogen oxides (NOx) and black carbon (BC) from 1990 up to 2016 were calculated. Associations with VTE were analysed using Cox proportional hazard models for air pollution in the year of the VTE event (lag0) and the mean of the prior 1–10 years (lag1-10). Annual air pollution exposures for the full follow-up period had the following means: 10.8 μg/m3 for PM2.5, 15.8 μg/m3 for PM10, 27.7 μg/m3 for NOx, and 0.96 μg/m3 for BC. The mean follow-up period was 19.5 years, with 1418 incident VTE events recorded during this period. Exposure to lag1-10 PM2.5 was associated with an increased risk of VTE (HR 1.17 (95%CI 1.01–1.37)) per interquartile range (IQR) of 1.2 μg/m3 increase in PM2.5 exposure. No significant associations were found between other pollutants or lag0 PM2.5 and incident VTE. When VTE was divided into specific diagnoses, associations with lag1-10 PM2.5 exposure were similarly positive for deep vein thrombosis but not for pulmonary embolism. Results persisted in sensitivity analyses and in multi-pollutant models. Long-term exposure to moderate concentrations of ambient PM2.5 was associated with increased risks of VTE in the general population in Sweden.

THE CAUSAL EFFECT OF ADIPOSITY MEASURES ON BLOOD PRESSURE TRAITS IN TWO URBAN SWEDISH COHORTS: A MENDELIAN RANDOMIZATION STUDY

Abstract Objective: Different adiposity traits may be causally related to hypertension in different ways. By using genetic variants as randomly allocated proxies for studying the effect of modifying adiposity traits, the Mendelian randomization approach can be used to investigate this. Design and method: In this study, we used four different genetic risk scores (GRSs: GRS-BMI565, GRS-WHR324, GRS-VAT208, GRS-BF81) including hundreds of single nucleotide polymorphisms (SNPs) associated with Body Mass Index (BMI), Waist to Hip Ratio (WHR), Visceral Adipose Tissue (VAT), and Body Fat (BF), respectively, using risk alleles and weight from largest available GWAS meta-analyses. These were applied as instrumental variables (IVs) in Mendelian Randomization analyses. Two Swedish urban-based cohort studies, the Malmö Diet and Cancer (MDC) and the Malmö Preventive Projects (MPP; subjects evaluated both at baseline and after an average follow-up of 23 ± 4.7 years), were used to obtain genetic association estimates with blood pressure (BP). Results: In both the MPP and MDC, with the exception of that for BF, all the GRSs were significantly associated with systolic BP and diastolic BP, but with different magnitude.: In particular, each standard deviation (SD) increase in the GRS-WHR324 doubled the likelihood of hypertension prevalence at MDC or MPP baseline exam. However, only the GRS-BMI565 was significantly associated to BP and with hypertension incidence during 23.6 ± 4.3 years of follow-up in MPP. Conclusions: In conclusion, we have confirmed a causal link between genetically mediated adiposity, especially WHR and BMI, and BP-related traits including hypertension prevalence and, for the first time to our knowledge, hypertension incidence. The differences in magnitude between these associations might suggest different mechanisms by which different adiposity traits mediate their effect on BP/hypertension and consequently may indicate that tailored interventions are needed to reduce cardiovascular risk.

EGFR-CYSTATINC/EGFR-CREATININE RATIO AS A POTENTIAL MARKER OF EARLY VASCULAR AND KIDNEY AGEING

Objective: Much of the research up to now has observed a link between cystatin C and pulse wave velocity (PWV) in patients with no or mild chronic kidney disease (CKD) that leads us to think that cystatin C is also related to arteriosclerosis. In fact, the relation between heart and kidney may be caused by common vascular changes giving rise to different elimination patterns for small and large molecules in kidneys. With this knowledge we propose that lower eGFRcystatin C/eGFRcreatinine ratio is potentially associated with early vascular aging (EVA). This relationship might be bidirectional, also incorporating early structural changes in glomerular filtration barrier, as a component of so-called “Shrunken pore syndrome” (SPS), further leading to CKD. Design and method: Data were extracted from the population based Malmö Diet and Cancer (MDC) study (n = 28 449) cardiovascular cohort (MDC CC) that enrolled a random sample of study subjects invited to participate in carotid artery disease epidemiological analysis (n = 6103) during the year 1991–1994. Our study sample consisted of 2685 subjects (1542 women, 834 men) who had carotid-femoral pulse wave velocity measurements and cystatin C available. Estimated glomerular filtration rate (eGFR) according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2012 creatinine-cystatin C equation was calculated. Carotid-femoral pulse wave velocity (cfPWV) and central hemodynamics were measured by applanation tonometry (SphygmoCor). Results: Study subjects were classified according eGFR-cystatinC/eGFR-creatinine ratio: 6% (n = 159) of subjects with lower that 0.7 ratio, representing SPS, 59% (n = 1591) – as ratio between 0.7 to 1.0, and 35% (n = 935) – as ratio &gt;1.0. There was pronounced sex specific trend because SPS group consisted mainly from women. We found that cfPWV was associated with the eGFR-cystatinC/eGFR-creatinine ratio, representing the decreased arterial stiffness at the ratio &gt;1.0 and stiffer arteries at the ratio lower than &lt; 0.7. We have identified factors that are related to early vascular ageing and on the opposite are related to better kidney function and lower arterial stiffness. Conclusions: The ratio of eGFR-cystatinC/eGFR-creatinine is a potential marker of early vascular ageing encompassing also early kidney function deteriorating.

Dimethylguanidino Valerate: A Lifestyle‐Related Metabolite Associated With Future Coronary Artery Disease and Cardiovascular Mortality

BackgroundIdentification of lifestyle modifiable metabolic pathways related to cardiometabolic disease risk is essential for improvement of primary prevention in susceptible individuals. It was recently shown that plasma dimethylguanidino valerate (DMGV) levels are associated with incident type 2 diabetes mellitus. Our aims were to investigate whether plasma DMGV is related to risk of future coronary artery disease and with cardiovascular mortality and to replicate the association with type 2 diabetes mellitus and pinpoint candidate lifestyle interventions susceptible to modulate DMGV levels.Methods and ResultsPlasma DMGV levels were measured using liquid chromatography‐mass spectrometry in a total of 5768 participants from the MDC (Malmö Diet and Cancer Study—Cardiovascular Cohort), MPP (Malmö Preventive Project), and MOS (Malmö Offspring Study). Dietary intake assessment was performed in the MOS. Baseline levels of DMGV associated with incident coronary artery disease in both the MDC (hazard ratio=1.29; CI=1.16–1.43; P<0.001) and MPP (odds ratio=1.25; CI=1.08–1.44; P=2.4e‐3). In the MDC, DMGV was associated with cardiovascular mortality and incident coronary artery disease, independently of traditional risk factors. Furthermore, the association between DMGV and incident type 2 diabetes mellitus was replicated in both the MDC (hazard ratio=1.83; CI=1.63–2.05; P<0.001) and MPP (odds ratio=1.65; CI=1.38–1.98; P<0.001). Intake of sugar‐sweetened beverages was associated with increased levels of DMGV, whereas intake of vegetables and level of physical activity was associated with lower DMGV.ConclusionsWe discovered novel independent associations between plasma DMGV and incident coronary artery disease and cardiovascular mortality, while replicating the previously reported association with incident type 2 diabetes mellitus. Additionally, strong associations with sugar‐sweetened beverages, vegetable intake, and physical activity suggest the potential to modify DMGV levels using lifestyle interventions.

Cardiovascular biomarkers and risk of low-energy fractures among middle-aged men and women-A population-based study.

BackgroundLow-energy fractures are a growing health challenge as their incidence increases with advancing age. As cardiovascular instability may be associated with higher likelihood of traumatic falls, we aimed to investigate the associations between four cardiovascular biomarkers and the risk of low-energy fractures in a middle-aged population.MethodsA total of 5291 individuals from the prospective Malmö Diet and Cancer (MDC) study (mean age, 57 years; 59% women) with data on baseline levels of four cardiovascular biomarkers: mid-regional-fragment of pro-adrenomedullin-peptide (MR-pro-ADM), mid-regional-fragment of pro-atrial-natriuretic-peptide (MR-proANP), N-terminal pro-brain natriuretic peptide (NT-pro-BNP) and C-terminal-pro-arginine-vasopressin (CT-pro-AVP/Copeptin) were included. The associations between biomarker levels and first incident low-energy fracture were tested in Cox proportional-hazard models, taking potential interactions and traditional risk factors into account.ResultsParticipants were followed for a median time of 21.0 years, during which 1002 subjects (19%) experienced at least one low-energy fracture. Subjects with incident fracture were older, more likely to be women, had lower BMI and higher prevalence of previous fractures. Among biomarkers, there was a significant interaction between gender and MR-pro-ADM on the risk of fracture (p = 0.002). MR-pro-ADM predicted fractures in men only (hazard ratio, 1.23; 95% CI 1.09–1.40; p = 0.001), whereas there was no association among women. Levels of MR-pro-ANP, NT-pro-BNP and CT-pro-AVP did not predict fractures.ConclusionsHigher circulating levels of MR-pro-ADM predict low-energy fractures among middle-aged-men, whereas levels of MR-pro-ANP, NT-pro-BNP and CT-pro-AVP are not associated with increased fracture risk. Further controlled studies should test the hypothesis whether MR-pro-ADM may improve prediction of bone fractures.

Plasma Concentration of Caspase-8 Is Associated With Short Sleep Duration and the Risk of Incident Diabetes Mellitus.

The biological mechanism for the association between sleep duration and incident diabetes mellitus (DM) is unclear. Sleep duration and caspase-8, a marker of apoptotic activity, have both been implicated in β-cell function. To investigate the associations between sleep duration and plasma caspase-8 and incident DM, respectively. Prospective cohort study. The Malmö Diet and Cancer (MDC) Study is a population-based, prospective study run in the city of Malmö, Sweden. A total of 4023 individuals from the MDC Study aged 45 to 68 years at baseline without a history of prevalent DM and with information on habitual sleep duration. Incident DM. Mean follow-up time was 17.8 years. Sleep duration was the only behavioral variable significantly associated with plasma caspase-8. Plasma caspase-8 was significantly associated with incident DM per standard deviation of its transformed continuous form [hazard ratio (HR) = 1.24; 95% confidence interval (CI), 1.13 to 1.36] and when dichotomized into high (quartile 4) (HR = 1.44; 95% CI, 1.19 to 1.74) compared with low (quartiles 1 to 3) concentrations. Caspase-8 interacted with sleep duration; compared with individuals who had 7 to 8 hours of sleep and low plasma caspase-8, those with high plasma caspase-8 and sleep duration <6 hours (HR = 3.54; 95% CI, 2.12 to 5.90), 6 to 7 hours (HR = 1.81; 95% CI, 1.24 to 2.65), and 8 to 9 hours (HR = 1.54; 95% CI, 1.09 to 2.18) were at significantly increased risks of incident DM. Sleep duration is associated with plasma caspase-8. Caspase-8 independently predicts DM years before disease onset and modifies the effect of sleep duration on incident DM. Future studies should investigate if change of sleep duration modifies plasma concentrations of caspase-8.

Variation in the Sweet Taste Receptor Gene and Dietary Intake in a Swedish Middle-Aged Population.

The preference for sweet taste is partially genetically determined. The major allele of the single nucleotide polymorphism rs12033832 in the sweet taste receptor (TAS1R2) has previously been associated with lower sugar sensitivity and higher sugar intake among overweight individuals. The aim of the present study was to examine the association between dietary intake and the TAS1R2 genotype in lean and overweight individuals in the population-based Malmö Diet and Cancer (MDC) cohort using dietary intake data with a high validity. In total, 3,602 participants (46-68 years old) from the MDC cohort who underwent baseline examinations between 1991 and 1994, who were non-smokers without diabetes, and for whom information regarding TAS1R2 rs7534618 (a proxy for rs12033832) was available were included in this study. After excluding individuals with potentially misreported and unstable food habits, 2,204 individuals were retained. A modified dietary history method, including a 7-day food diary of prepared meals, which was specifically designed for the MDC study was used. Only modest associations were observed between dietary intake and the TAS1R2 genotype. We observed slightly stronger associations after excluding individuals with potentially misreported and unstable food habits. Among the participants with a BMI ≥25, the major (T) allele carriers consumed more carbohydrates [TT = 45.2 percentage of energy intake (E%); TG = 45.2E%; GG = 43.7E%; p = 0.01] and less fat (p = 0.03), but these participants did not consume more sucrose than the G-allele carriers. No association was observed between the genotype and dietary intake among the participants with a BMI <25. Although the higher carbohydrate intake among the major allele carriers was consistent with that reported in a previous study, the magnitudes of the associations were substantially smaller. Because we observed no association with sucrose, this allele is unlikely to be useful as a marker of sugar intake in the MDC population.

OP.7C.09] COFFEE, SMOKING HABITS AND BLOOD PRESSURE IN THE LIGHT OF A SINGLE NUCLEOTIDE POLIMORPHYSM OF CYP1A1/1A2 GENE

Objective: Between genetic variants pinpointed in genome wide association study there is the rs1378942 near the CYP1A1/CYP1A2 locus. Coffee consumption has been associated with blood pressure (BP) but with sometimes contrasting evidences. A part of BP-coffee relationship could be mediated by genetic mechanisms: that is single nucleotide polymorphisms (SNPs) nearby the CYP1A2 gene, which metabolize caffeine, could influence BP. Indeed, smoking habit induces the expression of the CYP1A2 enzyme whereas coffee consumption itself could increase CYP1A2 activity. The aim of the present study was to explore if coffee consumption and/or smoking habit may affect BP and BP change over time (delta-BP), considering the rs1378942A > C polimorphysm. Design and method: Coffee intake was collected by a modified diet history method and the rs1378942 was genotyped by Taqman in > 28,000 participant of the Malmö Diet and Cancer (MDC). We performed a replication in 3381 participants that were rescreened after a period (13–20 years) of follow-up (MDC-FU) and in the Malmö Preventive Project (MPP; n > 17,000). Results: In MDC, both systolic and diastolic BP were positively associated with the rs1378942A > C, suggesting that carrying the C variant could increase BP (for SBP β = 0.397 ± 0.185, p = 0.031; for DBP β = 0.220 ± 0.100, p = 0.028). Coffee consumption as well as smoking were negatively associated with both SBP and DBP (p < 0.0001 for coffee consumption; p < 0.05 for smoke). A significant interaction between smoke and coffee was found, and both coffee and smoke interact with the rs1378942A > C (pinteraction < 0.05 for all). After stratification, in non-smokers who drink at least 600 gr/day of coffee, carriers of the rs1378942C variant had a higher BP (p_trend < 0.01 for SBP and DBP). At MDC-FU, only in non-smokers who drink less than 300 gr/day, a lesser delta-DBP was shown for rs1378942C carriers (ptrend < 0.01). In the MPP we found an interaction between the rs1378942A > C and smoking (pinteraction < 0.05; data on coffe consumption not available). Conclusions: This study demonstrates that the effect of some genetic loci on BP could be highly influenced by voluptuary habits. In particular, coffee and smoke could influence the effect of the CYP1A1/CYP1A2 locus probably due to the metabolic action of the CYP1A2.

A High Diet Quality Based on Dietary Recommendations Is Not Associated with Lower Incidence of Type 2 Diabetes in the Malmö Diet and Cancer Cohort

A high diet quality index based on Swedish nutrition recommendations has previously been associated with reduced risk of cardiovascular disease and mortality in the Malmö Diet and Cancer (MDC) cohort. The aim of the present study was to investigate whether this diet quality index was associated with the risk for type 2 diabetes. Of 26,868 participants (44–74 years) in the MDC cohort study, 3838 type 2 diabetes cases were identified from registers during 17 years of follow-up. A diet quality index (from a modified diet history method) was constructed based on adherence to the recommended intakes of saturated fat, polyunsaturated fat, fish, fiber, fruit and vegetables, and sucrose. After adjusting for potential confounders, we observed no significant association between the diet quality index and type 2 diabetes risk. The HR for the highest vs. lowest index category was 1.06 (95% CI: 0.94, 1.20; p-trend = 0.56). Because of the protective associations shown for cardiovascular disease and mortality, the specific dietary components that were chosen to represent adherence to the recommendations may be less applicable to type 2 diabetes risk.

Soluble urokinase plasminogen activator receptor and incidence of venous thromboembolism.

Raised plasma levels of the soluble urokinase plasminogen activator receptor (suPAR) have been associated with increased incidence of cardiovascular diseases. Whether suPAR is associated with venous thromboembolism (VTE) is largely unknown. The purpose of the present study was to investigate the relationship between suPAR and incidence of VTE in a cohort study. suPAR was measured in 5,203 subjects (aged 46-68 years, 58 % women) from the general population, who participated in the Malmö Diet and Cancer (MDC) study between 1991 and 1994. Incident cases of VTE were identified from the Swedish patient register during a mean follow-up of 15.7 years. Of 5,203 subjects with measurements of suPAR, 239 had VTE during follow-up (127 venous thrombosis, 86 lung embolism, 26 both). Incidence of VTE was significantly higher in subjects with suPAR levels in the top quartile. Adjusted for age and sex, the HR (4th vs 1st quartile) was 1.74 (95 %CI: 1.2-2.6, p for trend=0.003). After adjustments for risk factors, the HR was 1.66 (95 %CI: 1.1-2.5, p for trend=0.016). High level of suPAR was a risk indicator for incidence of VTE in this population-based cohort study. The causal relationships between suPAR and VTE remain to be explored.

Cadmium exposure and incidence of heart failure and atrial fibrillation: a population-based prospective cohort study

ObjectivesCadmium is a non-essential toxic metal with multiple adverse health effects. Cadmium has been shown to be associated with cardiovascular diseases, but few studies have investigated heart failure (HF) and...

Intakes of omega-3 polyunsaturated fatty acids and blood pressure change over time: Possible interaction with genes involved in 20-HETE and EETs metabolism

BackgroundA 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. MethodsPUFA intakes were collected by a modified diet history method, and functional SNPs in CYP4F2, CYP4A11, CYP2J2 and EPHX2 were genotyped by Taqman. ResultWe 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±0.018mmHg/year; p=0.024; p-interaction=0.031) ConclusionsOur 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.

A genetic risk score for hypertension associates with the risk of ischemic stroke in a Swedish case-control study.

Genetic risk scores (GRS), summing up the total effect of several single-nucleotide polymorphisms (SNPs) in genes associated with either coronary risk or cardiovascular risk factors, have been tested for association with ischemic stroke with conflicting results. Recently an association was found between a GRS based on 29 SNPs discovered by genome-wide association studies and hypertension. The aim of our study was to investigate the possible association of the same GRS with ischemic stroke on top of other 'traditional risk factors', also testing its potential improvement in indices of discrimination and reclassification, in a Swedish case-control study. Twenty-nine SNPs were genotyped in 3677 stroke cases and 2415 controls included in the Lund Stroke Register (LSR), the Malmö Diet and Cancer (MDC) study and the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). The analysis was conducted in the combined sample, and separately for the three studies. After adjustment for hypertension, diabetes mellitus and smoking habits, the GRS was associated with ischemic stroke in the combined sample (OR (95% CI) 1.086 (1.029-1.147) per SD increase in the GRS P=0.003) with similar trends in all three samples: LSR (1.050 (0.967-1.140); P=0.25), MDC (1.168 (1.060-1.288); P=0.002) and SAHLSIS (1.124 (0.997-1.267); P=0.055). Measures of risk discrimination and reclassification improved marginally using the GRS. A blood pressure GRS is independently associated with ischemic stroke risk in three Swedish case-control studies, however, the effect size is low and adds marginally to prediction of stroke on top of traditional risk factors including hypertension.

TheIRS1rs2943641 Variant and Risk of Future Cancer Among Morbidly Obese Individuals

Obesity and insulin resistance are risk factors for cancer development. The IRS1 rs2943641 genetic variant has been widely associated with insulin resistance. The aim of the study was to examine whether the IRS1 rs2943641 associates with cancer incidence in obese individuals. The IRS1 rs2943641 was genotyped in participants from the Swedish Obese Subjects (SOS) study, an intervention trial on the effect of bariatric surgery on mortality and morbidity compared with usual care and in the population-based Malmö Diet and Cancer (MDC) cohort. In both studies, the median follow-up for cancer incidence was about 15 years. Cancer incidence was assessed in both the SOS and the MDC cohorts through national and local registers. The IRS1 T allele was associated with lower insulin resistance in both the SOS and the MDC studies. A lower cancer incidence was found in T allele carriers from the SOS control group (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.62-0.96; P = .021) and was restricted to morbidly obese individuals (HR 0.67, 95% CI 0.50-0.91; P = .011). No evidence of such association was detected in the surgery group (interaction P = .005). In the MDC cohort, a nonsignificant tendency for lower cancer incidence in T allele carriers was observed only in morbidly obese individuals. A meta-analysis of morbidly obese individuals (body mass index > 40 kg/m(2)) from the two cohorts strengthened the evidence for the association (HR 0.66, 95% CI 0.50-0.87; P = .004). Our results suggest that the T allele of rs2943641 near IRS1 may associate with lower cancer incidence in morbidly obese individuals.

Immigrant status and increased risk of heart failure: the role of hypertension and life-style risk factors

BackgroundStudies from Sweden have reported association between immigrant status and incidence of cardiovascular diseases. The nature of this relationship is unclear. We investigated the relationship between immigrant status and risk of heart failure (HF) hospitalization in a population-based cohort, and to what extent this is mediated by hypertension and life-style risk factors. We also explored whether immigrant status was related to case-fatality after HF.Methods26,559 subjects without history of myocardial infarction (MI), stroke or HF from the community-based Malmö Diet and Cancer (MDC) cohort underwent a baseline examination during 1991-1996. Incidence of HF hospitalizations was monitored during a mean follow-up of 15 years.Results3,129 (11.8%) subjects were born outside Sweden. During follow-up, 764 subjects were hospitalized with HF as primary diagnosis, of whom 166 had an MI before or concurrent with the HF. After adjustment for potential confounding factors, the hazard ratios (HR) for foreign-born were 1.37 (95% CI: 1.08-1.73, p = 0.009) compared to native Swedes, for HF without previous MI. The results were similar in a secondary analysis without censoring at incident MI. There was a significant interaction (p < 0.001) between immigrant status and waist circumference (WC), and the increased HF risk was limited to immigrants with high WC. Although not significant foreign-born tended to have lower one-month and one-year mortality after HF.ConclusionsImmigrant status was associated with long-term risk of HF hospitalization, independently of hypertension and several life-style risk factors. A significant interaction between WC and immigrant status on incident HF was observed.

High disaccharide intake associates with atherogenic lipoprotein profile

Increased plasma concentrations of small LDL particles denote an atherogenic lipoprotein phenotype (ALP) that is correlated with increased circulating TAG and reduced HDL-cholesterol. Principal component analyses of subfraction concentrations have previously been used in the Swedish population-based Malmö Diet and Cancer (MDC) cohort to identify three independent components, one pattern representing the ALP. The aim of the present study was to examine the associations between macronutrient intakes and the principal component representing the ALP. We examined 4301 healthy subjects (46-68 years old, 60 % women) at baseline in the MDC cohort. Dietary data were collected using a modified diet history method. Plasma lipoprotein subfractions were measured using a high-resolution ion mobility method. The principal component corresponding to the ALP was significantly associated with a higher intake of disaccharides, and inversely related to protein and alcohol consumption (P < 0·001 for all). The present findings indicate that the ALP may be improved by a low intake of disaccharides, and moderate intakes of protein and alcohol.

FTO, Type 2 Diabetes, and Weight Gain Throughout Adult Life

OBJECTIVEFTO is the most important polygene identified for obesity. We aimed to investigate whether a variant in FTO affects type 2 diabetes risk entirely through its effect on BMI and how FTO influences BMI across adult life span.RESEARCH DESIGN AND METHODSThrough regression models, we assessed the relationship between the FTO single nucleotide polymorphisms rs9939609, type 2 diabetes, and BMI across life span in subjects from the Norwegian population-based HUNT study using cross-sectional and longitudinal perspectives. For replication and meta-analysis, we used data from the Malmö Diet and Cancer (MDC) and Malmö Preventive Project (MPP) cohorts, comprising a total sample of 41,504 Scandinavians.RESULTSThe meta-analysis revealed a highly significant association for rs9939609 with both type 2 diabetes (OR 1.13; P = 4.5 × 10−8) and the risk to develop incident type 2 diabetes (OR 1.16; P = 3.2 × 10−8). The associations remained also after correction for BMI and other anthropometric measures. Furthermore, we confirmed the strong effect on BMI (0.28 kg/m2 per risk allele; P = 2.0 × 10−26), with no heterogeneity between different age-groups. We found no differences in change of BMI over time according to rs9939609 risk alleles, neither overall (∆BMI = 0.0 [−0.05, 0.05]) nor in any individual age stratum, indicating no further weight gain attributable to FTO genotype in adults.CONCLUSIONSWe have identified that a variant in FTO alters type 2 diabetes risk partly independent of its observed effect on BMI. The additional weight gain as a result of the FTO risk variant seems to occur before adulthood, and the BMI difference remains stable thereafter.