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Using a polygenic score of DNA sequence polymorphisms, the authors of this study quantified genetic risk and assessed four healthy lifestyle factors. Among participants at high genetic risk, a healthy lifestyle was associated with a reduced risk of coronary disease. Both genetic and lifestyle factors are key drivers of coronary artery disease, a complex disorder that is the leading cause of death worldwide. 1 A familial pattern in the risk of coronary artery disease was first described in 1938 and was subsequently confirmed in large studies involving twins and prospective cohorts. 2 – 6 Since 2007, genomewide association analyses have identified more than 50 independent loci associated with the risk of coronary artery disease. 7 – 15 These risk alleles, when aggregated into a polygenic risk score, are predictive of incident coronary events and provide a continuous and quantitative measure of genetic susceptibility. 16 – 24 Much . . .

Background A healthy lifestyle has been shown to reduce the risk of coronary artery disease (CAD). The extent to which lifestyle influences the risk of CAD for people with pre-existing non-modifiable risk factors is less studied. We therefore examined the associations between a favorable lifestyle and incidence of CAD in population subgroups based on gender, age, educational level, and parental history of myocardial infarction. Methods A total of 26,323 men and women from the Malmö Diet and Cancer study were prospectively followed-up for 18 years. A favorable lifestyle was determined using a four-component lifestyle score based on data collected at baseline: no smoking, no obesity, regular physical activity, and a healthy diet. Cox proportional hazards regression models were used to estimate the relative risk of CAD during follow-up and cumulative risk during a 10-year interval. Results A favorable lifestyle was associated with a 44% (95% confidence interval, 38–48%) lower risk of CAD compared to an unfavorable lifestyle. The relative risk was similarly reduced among subjects subdivided by gender, age group, educational level, and parental history of myocardial infarction. These findings corresponded with a reduced standardized 10-year incidence of CAD of around 40% in each subgroup. Conclusion In this population-based cohort, a favorable lifestyle was associated with a significant reduction of CAD across strata of non-modifiable risk factors. These findings provide support for lifestyle modification as a means for risk reduction in a range of subgroups within a general healthy population.

Background While a dose-response relationship between physical activity and risk of diabetes has been demonstrated, few studies have assessed the relative importance of different measures of physical activity on diabetes risk. The aim was to examine the association between different self-reported measures of physical activity and risk of type 2 diabetes in a prospective cohort study. Methods Out of 26,615 adults (45–74 years, 60% women) in the population-based Swedish Malmö Diet and Cancer Study cohort, 3791 type 2 diabetes cases were identified from registers during 17 years of follow-up. Leisure-time (17 activities), occupational and domestic physical activity were assessed through a questionnaire, and these and total physical activity were investigated in relation to type 2 diabetes risk. Results All physical activity measures showed weak to modest associations with type 2 diabetes risk. The strongest association was found in the lower end of leisure-time physical activity in dose-response analysis at levels approximately below 22 MET-hrs/week (300 min/week) representing around 40% of the population. Compared with the lowest quintile, the moderate leisure-time physical activity category had a 28% (95% CI: 0.71, 0.87) decreased risk of type 2 diabetes. Total physical activity showed a similar, but weaker, association with diabetes risk as to that of leisure-time physical activity. Domestic physical activity was positively and linearly related to diabetes risk, HR = 1.11 (95% CI: 0.99, 1.25) comparing highest to lowest quintile. There was no association between occupational physical activity and diabetes risk. Conclusion A curvilinear association was observed between leisure-time physical activity and risk of diabetes. Beyond a threshold level of approximately 22 MET-hrs/week or 300 min/week, no additional risk reduction was observed with increase in physical activity.

Background The solute carrier family 30 member 8 gene ( SLC30A8 ) encodes a zinc transporter in the pancreatic beta cells and the major C-allele of a missense variant (rs13266634; C/T; R325W) in SLC30A8 is associated with an increased risk of type 2 diabetes (T2D). We hypothesized that the association between zinc intake and T2D may be modified by the SLC30A8 genotype. Results We carried out a prospective study among subjects with no history cardio-metabolic diseases in the Malmö Diet and Cancer Study cohort ( N  = 26,132, 38% men; 86% with genotype data). Zinc intake was assessed using a diet questionnaire and food record. During a median follow-up of 19 years, 3676 T2D cases occurred. A BMI-stratified Cox proportional hazards regression model with attained age as the time scale was used to model the association between total and dietary zinc intake, zinc supplement use, zinc to iron ratio, and risk of T2D adjusting for putative confounding factors. The median total zinc intake was 11.4 mg/day, and the median dietary zinc intake was 10.7 mg/day. Zinc supplement users (17%) had a median total zinc intake of 22.4 mg/day. Dietary zinc intake was associated with increased risk of T2D ( P trend  < 0.0001). In contrast, we observed a lower risk of T2D among zinc supplement users (HR = 0.79, 95% CI 0.70–0.89). The SLC30A8 CC genotype was associated with a higher risk of T2D (HR = 1.16, 95% CI 1.07–1.24), and the effect was stronger among subjects with higher BMI ( P interaction  = 0.007). We observed no significant modification of the zinc-T2D associations by SLC30A8 genotype. However, a three-way interaction between SLC30A8 genotype, BMI, and zinc to iron ratio was observed ( P interaction  = 0.007). A high zinc to iron ratio conferred a protective associated effect on T2D risk among obese subjects, and the effect was significantly more pronounced among T-allele carriers. Conclusions Zinc supplementation and a high zinc to iron intake ratio may lower the risk of T2D, but these associations could be modified by obesity and the SLC30A8 genotype. The findings implicate that when considering zinc supplementation for T2D prevention, both obesity status and SLC30A8 genotype may need to be accounted for.

Background Serum potassium levels have been positively associated with cardiovascular mortality, but little is known about the association with cancer mortality and death due to other causes. We examined whether serum levels of potassium were associated with long-term mortality in a healthy cohort. Methods Oslo Ischemia Study invited 2341 initially healthy men aged 40–59 years with no use of medication to a comprehensive health survey in 1972. Fasting serum level of potassium (mmol/L) was ascertained at baseline for 1989 men. We have complete follow-up for death throughout 2017. Cox proportional hazard models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) and adjusted for multiple confounders. Results After a median follow-up of 30 years (interquartile range 21.2–38.7), 1736 deaths were observed, of which 494 were cancer deaths, 688 cardiovascular deaths, and 536 deaths related to other causes. Restricted cubic spline analysis showed that potassium level was linearly and positively associated with long-term cancer mortality; HR per mmol/L 1.8, 95% CI 1.4–2.4. Compared with low levels of potassium (≤ 4.0 mmol/L), men with high levels (≥4.6 mmol/L) showed a significantly 78% higher risk of cancer death. A positive linear association was found for all-cause mortality (HR per mmol/L 1.6, 95% CI 1.4–1.8), and for cardiovascular (HR per mmol/L 1.4, 95% CI 1.1–1.7) and other cause mortality (HR per mmol/L 1.7, 95% CI 1.3–2.2). Conclusions These findings suggest that serum potassium level appears to predict long-term mortality in healthy middle-aged men, and it might imply future surveillance strategies for individuals with high serum potassium levels.

Acute lower limb ischemia (ALI) is a life and limb threatening event often affecting patients with type 2 diabetes mellitus (T2DM). Little is known about how T2DM affects the risk of adverse events in patients revascularized for ALI. This study aimed to investigate if there were differences in major outcomes between ALI patients with and without T2DM. Between 2010 and 2014, 615 patients underwent revascularization for ALI, according to the Swedish Vascular Registry (SWEDVASC). Using the National Diabetes Registry (NDR), 245 (39.8%) of the patients were identified as having T2DM. Uni- and multivariable Cox or logistic regression analyses were performed to evaluate risk differences for major amputation, mortality, major adverse cardiovascular events (MACE), and fasciotomy between patients with and without T2DM. The rates of major amputation and mortality at one year were 32.7% and 21.6% in the T2DM group, compared to 21.9% and 31.9% in the non-DM group, respectively, resulting in a hazard ratio (HR) of 1.52 (95% confidence interval [CI] 1.12-2.07) for major amputation and HR of 0.64 (95% CI 0.46-0.88) for mortality. At one year, the HR for major amputation was 1.45 (95% CI 0.99-2.11), HR for mortality 0.92 (95% CI 0.61-1.39), HR for combined major amputation/mortality 1.27 (95% CI 0.94-1.72), and HR for MACE 1.24 (95% CI 0.92-1.67) for those with T2DM compared to those without in the multivariable Cox-regression analyses. The multivariable logistic regression analysis showed significantly lower odds of fasciotomy, OR 0.1 (95% CI 0.01-0.51) in the T2DM-group. T2DM was not significantly associated with higher hazard of major amputation, mortality, combined major amputation/mortality, or MACE after revascularization for ALI, compared to patients without T2DM. Patients with T2DM had significantly lower odds of fasciotomy.

The association between blood pressure (BP) and bladder cancer (BC) risk remains unclear with confounding by smoking being of particular concern. We investigated the association between BP and BC risk among men using conventional survival-analysis, and by Mendelian Randomization (MR) analysis in an attempt to disconnect the association from smoking. We additionally investigated the interaction between BP and N-acetyltransferase-2 ( NAT2 ) rs1495741, an established BC genetic risk variant, in the association. Populations consisting of 188,167 men with 502 incident BC’s in the UK-biobank and 27,107 men with 928 incident BC’s in two Swedish cohorts were used for the analysis. We found a positive association between systolic BP and BC risk in Cox-regression survival analysis in the Swedish cohorts, (hazard ratio [HR] per standard deviation [SD]: 1.14 [95% confidence interval 1.05–1.22]) and MR analysis (odds ratio per SD: 2-stage least-square regression, 7.70 [1.92–30.9]; inverse-variance weighted estimate, 3.43 [1.12–10.5]), and no associations in the UK-biobank (HR systolic BP: 0.93 [0.85–1.02]; MR OR: 1.24 [0.35–4.40] and 1.37 [0.43–4.37], respectively). BP levels were positively associated with muscle-invasive BC (MIBC) (HRs: systolic BP, 1.32 [1.09–1.59]; diastolic BP, 1.27 [1.04–1.55]), but not with non-muscle invasive BC, which could be analyzed in the Swedish cohorts only. There was no interaction between BP and NAT2 in relation to BC on the additive or multiplicative scale. These results suggest that BP might be related to BC, more particularly MIBC. There was no evidence to support interaction between BP and NAT2 in relation to BC in our study.

Novel methods to characterize the plasma proteome has made it possible to examine a wide range of proteins in large longitudinal cohort studies, but the complexity of the human proteome makes it difficult to identify robust protein-disease associations. Nevertheless, identification of individuals at high risk of early mortality is a central issue in clinical decision making and novel biomarkers may be useful to improve risk stratification. With adjustment for established risk factors, we examined the associations between 138 plasma proteins measured using two proximity extension assays and long-term risk of all-cause mortality in 3,918 participants of the population-based Malmö Diet and Cancer Study. To examine the reproducibility of protein-mortality associations we used a two-step random-split approach to simulate a discovery and replication cohort and conducted analyses using four different methods: Cox regression, stepwise Cox regression, Lasso-Cox regression, and random survival forest (RSF). In the total study population, we identified eight proteins that associated with all-cause mortality after adjustment for established risk factors and with Bonferroni correction for multiple testing. In the two-step analyses, the number of proteins selected for model inclusion in both random samples ranged from 6 to 21 depending on the method used. However, only three proteins were consistently included in both samples across all four methods (growth/differentiation factor-15 (GDF-15), N-terminal pro-B-type natriuretic peptide, and epididymal secretory protein E4). Using the total study population, the C-statistic for a model including established risk factors was 0.7222 and increased to 0.7284 with inclusion of the most predictive protein (GDF-15; P < 0.0001). All multiple protein models showed additional improvement in the C-statistic compared to the single protein model (all P < 0.0001). We identified several plasma proteins associated with increased risk of all-cause mortality independently of established risk factors. Further investigation into the putatively causal role of these proteins for longevity is needed. In addition, the examined methods for identifying multiple proteins showed tendencies for overfitting by including several putatively false positive findings. Thus, the reproducibility of findings using such approaches may be limited.

Background Both lifestyle and genetic predisposition determine the development of type 2 diabetes (T2D), and studies have indicated interactions between specific dietary components and individual genetic variants. However, it is unclear whether the importance of overall dietary habits, including T2D-related food intakes, differs depending on genetic predisposition to T2D. We examined interaction between a genetic risk score for T2D, constructed from 48 single nucleotide polymorphisms identified in genome-wide association studies, and a diet risk score of four foods consistently associated with T2D in epidemiological studies (processed meat, sugar-sweetened beverages, whole grain and coffee). In total, 25,069 individuals aged 45–74 years with genotype information and without prevalent diabetes from the Malmö Diet and Cancer cohort (1991–1996) were included. Diet data were collected with a modified diet history method. Results During 17-year follow-up, 3588 incident T2D cases were identified. Both the diet risk score (HR in the highest risk category 1.40; 95% CI 1.26, 1.58; P trend = 6 × 10 −10 ) and the genetic risk score (HR in the highest tertile of the genetic risk score 1.67; 95% CI 1.54, 1.81; P trend = 7 × 10 −35 ) were associated with increased incidence of T2D. No significant interaction between the genetic risk score and the diet risk score ( P  = 0.83) or its food components was observed. The highest risk was seen among the 6% of the individuals with both high genetic and dietary risk scores (HR 2.49; 95% CI 2.06, 3.01). Conclusions The findings thus show that both genetic heredity and dietary habits previously associated with T2D add to the risk of T2D, but they seem to act in an independent fashion, with the consequence that all individuals, whether at high or low genetic risk, would benefit from favourable food choices.

It is still unclear whether carbohydrate consumption is associated with cardiovascular disease (CVD) risk. Genetic susceptibility might modify the associations between dietary intakes and disease risk. The aim was to examine the association between the consumption of carbohydrate-rich foods (vegetables, fruits and berries, juice, potatoes, whole grains, refined grains, cookies and cakes, sugar and sweets, and sugar-sweetened beverages) and the risk of incident ischemic CVD (iCVD; coronary events and ischemic stroke), and whether these associations differ depending on genetic susceptibility to dyslipidemia. Among 26,445 individuals (44-74 years; 62% females) from the Malmö Diet and Cancer Study cohort, 2,921 experienced an iCVD event during a mean follow-up time of 14 years. At baseline, dietary data were collected using a modified diet history method, and clinical risk factors were measured in 4,535 subjects. We combined 80 validated genetic variants associated with triglycerides and HDL-C or LDL-C, into genetic risk scores and examined the interactions between dietary intakes and genetic risk scores on the incidence of iCVD. Subjects in the highest intake quintile for whole grains had a 13% (95% CI: 3-23%; p-trend: 0.002) lower risk for iCVD compared to the lowest quintile. A higher consumption of foods rich in added sugar (sugar and sweets, and sugar-sweetened beverages) had a significant cross-sectional association with higher triglyceride concentrations and lower HDL-C concentrations. A stronger positive association between a high consumption of sugar and sweets on iCVD risk was observed among those with low genetic risk score for triglycerides (p-interaction=0.05). In this prospective cohort study that examined food sources of carbohydrates, individuals with a high consumption of whole grains had a decreased risk of iCVD. No convincing evidence of an interaction between genetic susceptibility for dyslipidemia, measured as genetic risk scores of dyslipidemia-associated variants, and the consumption of carbohydrate-rich foods on iCVD risk was observed.