The Gly82Ser polymorphism in the receptor for advanced glycation endproducts increases the risk for coronary events in the general population.

The receptor for advanced glycation endproducts (RAGE) has pro-inflammatory and pro-atherogenic effects. Low plasma levels of soluble RAGE (sRAGE), a decoy receptor for RAGE ligands, have been associated with increased risk for major adverse coronary events (MACE) in the general population. We performed a genome-wide association study to identify genetic determinants of plasma sRAGE in 4338 individuals from the cardiovascular arm of the Malmö Diet and Cancer study (MDC-CV). Further, we explored the associations between these genetic variants, incident first-time MACE and mortality in 24,640 unrelated individuals of European ancestry from the MDC cohort. The minor alleles of four single nucleotide polymorphisms (SNPs): rs2070600, rs204993, rs116653040, and rs7306778 were independently associated with lower plasma sRAGE. The minor T (vs. C) allele of rs2070600 was associated with increased risk for MACE [HR 1.13 95% CI (1.02-1.25), P = 0.016]. Neither SNP was associated with mortality. This is the largest study to demonstrate a link between a genetic sRAGE determinant and CV risk. Only rs2070600, which enhances RAGE function by inducing a Gly82Ser polymorphism in the ligand-binding domain, was associated with MACE. The lack of associations with incident MACE for the other sRAGE-lowering SNPs suggests that this functional RAGE modification is central for the observed relationship.

Plasma Metabolome Predicts Aortic Stiffness and Future Risk of Coronary Artery Disease and Mortality After 23 Years of Follow-Up in the General Population.

BACKGROUND: Increased aortic stiffness (arteriosclerosis) is associated with early vascular aging independent of age and sex. The underlying mechanisms of early vascular aging remain largely unexplored in the general population. We aimed to investigate the plasma metabolomic profile in aortic stiffness (vascular aging) and associated risk of incident cardiovascular disease and mortality. METHODS AND RESULTS: We included 6865 individuals from 2 Swedish population-based cohorts. Untargeted plasma metabolomics was performed by liquid-chromatography mass spectrometry. Aortic stiffness was assessed directly by carotid-femoral pulse wave velocity (PWV) and indirectly by augmentation index (AIx@75). A least absolute shrinkage and selection operator (LASSO) regression model was created on plasma metabolites in order to predict aortic stiffness. Associations between metabolite-predicted aortic stiffness and risk of new-onset cardiovascular disease, cardiovascular mortality, and all-cause mortality were calculated. Metabolite-predicted aortic stiffness (PWV and AIx@75) was positively associated particularly with acylcarnitines, dimethylguanidino valeric acid, glutamate, and cystine. The plasma metabolome predicted aortic stiffness (PWV and AIx@75) with good accuracy (R2=0.27 and R2=0.39, respectively). Metabolite-predicted aortic stiffness (PWV and AIx@75) was significantly correlated with age, sex, systolic blood pressure, body mass index, and low-density lipoprotein. After 23 years of follow-up, metabolite-predicted aortic stiffness (PWV and AIx@75) was significantly associated with increased risk of new-onset coronary artery disease, cardiovascular mortality, and all-cause mortality. CONCLUSIONS: Aortic stiffness is associated particularly with altered metabolism of acylcarnitines, cystine, and dimethylguanidino valeric acid. These metabolic disturbances predict increased risk of new-onset coronary artery disease, cardiovascular mortality, and all-cause mortality after more than 23 years of follow-up in the general population.

The possible role of the vasopressin system in hematopoiesis.

Vasopressin is a pleiotropic hormone that controls body fluid homeostasis. Vasopressin has also been proposed to be involved in erythropoiesis, thrombocyte activity and inflammation. However, whether increasing vasopressin is associated with changes in hematopoietic markers is not known. To evaluate this gap of knowledge we measured the vasopressin marker copeptin and markers of erythropoiesis (erythrocyte count, hemoglobin (Hb), red blood cell distribution width (RDW), mean corpuscular volume (MCV), erythrocyte volume fraction (EVF)), leukocyte count (total count, lymphocytes, neutrophils) and thrombocyte count in 5312 participants from the Swedish CArdioPulmonary bioImage Study (SCAPIS). The associations between increasing copeptin tertile and the hematopoietic markers were analyzed in multivariate linear regression analyses. We found that increasing copeptin tertile was significantly (p < 0.001) associated with increasing erythrocytes, RDW, EVF, Hb, leukocytes and neutrophils after adjustment for age, sex, current smoking, prevalent diabetes, hypertension, creatinine, body mass index and physical activity. Increasing copeptin tertile was, however, not associated with change in MCV, lymphocyte or thrombocyte count. In conclusion, we found that increasing copeptin levels are positively associated with markers of erythropoiesis and leukocyte count in the general population. These results warrant further research on possible mechanistic effects of vasopressin on hematopoiesis.

The effects of Calorie restriction and Bariatric surgery on Circulating Proneurotensin levels.

CONTEXT: Proneurotensin (pNT) is associated with obesity and T2D, but the effects of Roux-en-Y gastric bypass (RYGB) on postprandial pNT levels are not well studied. OBJECTIVE: Assess effects of RYGB versus very low-energy diet (VLED) on pNT levels in response to mixed-meal tests (MMT), and long-term effects of RYGB on fasting pNT.Study participants: Cohort 1: Nine normoglycemic (NG) and ten T2D patients underwent MMT before and after VLED, immediately post-RYGB and six weeks post-RYGB. Cohort 2: Ten controls with normal weight and ten patients with obesity and T2D, who underwent RYGB or vertical sleeve gastrectomy (VSG), were subjected to MMTs and GIP infusions pre-surgery and three months post-surgery. GLP-1 infusions were performed in normal weight participants. Cohort 3: Fasting pNT was assessed pre-RYGB (n=161), two months post-RYGB (n=92) and 1-year post-RYGB (n=118) in NG and T2D patients. pNT levels were measured using ELISA. RESULTS: Reduced fasting and postprandial pNT were evident after VLED and immediately following RYGB. Reintroduction of solid food post-RYGB increased fasting and postprandial pNT. Prior to RYGB, all patients lacked a meal response in pNT, but this was evident post-RYGB/VSG. GIP- or GLP-1 infusion had no effect on pNT levels. Fasting pNT were higher 1-year post-RYGB regardless of glycemic status. CONCLUSION: RYGB causes a transient reduction in pNT as a consequence of caloric restriction. The RYGB/VSG-induced rise in postprandial pNT is independent of GIP and GLP-1 and higher fasting pNT are maintained one year post-surgically.

Neurotensin accelerates atherosclerosis and increases circulating levels of short-chain and saturated triglycerides.

BACKGROUND AND AIMS: Obesity and type 2 diabetes are significant risk factors for atherosclerotic cardiovascular disease (CVD) worldwide, but the underlying pathophysiological links are poorly understood. Neurotensin (NT), a 13-amino-acid hormone peptide, facilitates intestinal fat absorption and contributes to obesity in mice fed a high-fat diet. Elevated levels of pro-NT (a stable NT precursor produced in equimolar amounts relative to NT) are associated with obesity, type 2 diabetes, and CVD in humans. Whether NT is a causative factor in CVD is unknown. METHODS: Nt+/+ and Nt-/- mice were either injected with adeno-associated virus encoding PCSK9 mutants or crossed with Ldlr-/- mice and fed a Western diet. Atherosclerotic plaques were analyzed by en face analysis, Oil Red O and CD68 staining. In humans, we evaluated the association between baseline pro-NT and growth of carotid bulb thickness after 16.4 years. Lipidomic profiles were analyzed. RESULTS: Atherosclerotic plaque formation is attenuated in Nt-deficient mice through mechanisms that are independent of reductions in circulating cholesterol and triglycerides but associated with remodeling of the plasma triglyceride pool. An increasing plasma concentration of pro-NT predicts atherosclerotic events in coronary and cerebral arteries independent of all major traditional risk factors, indicating a strong link between NT and atherosclerosis. This plasma lipid profile analysis confirms the association of pro-NT with remodeling of the plasma triglyceride pool in atherosclerotic events. CONCLUSIONS: Our findings are the first to directly link NT to increased atherosclerosis and indicate the potential role for NT in preventive and therapeutic strategies for CVD.

The association between water intake and future cardiometabolic disease outcomes in the Malmö Diet and Cancer cardiovascular cohort.

The aim of this study was to explore the longitudinal association between reported baseline water intake and incidence of coronary artery disease (CAD) and type 2 diabetes in the Malmö Diet and Cancer Cohort (n = 25,369). Using cox proportional hazards models, we separately modelled the effect of plain and total (all water, including from food) water on CAD and type 2 diabetes risk, whilst adjusting for age, sex, diet collection method, season, smoking status, alcohol intake, physical activity, education level, energy intake, energy misreporting, body mass index, hypertension, lipid lowering medication, apolipoprotein A, apolipoprotein B, and dietary variables. Sensitivity analyses were run to assess validity. After adjustment, no association was found between tertiles of plain or total water intake and type 2 diabetes risk. For CAD, no association was found comparing moderate to low intake tertiles from plain or total water, however, risk of CAD increased by 12% (95% CI 1.03, 1.21) when comparing high to low intake tertiles of plain water, and by 17% (95% CI 1.07, 1.27) for high versus low tertiles of total water. Sensitivity analyses were largely in agreement. Overall, baseline water intake was not associated with future type 2 diabetes risk, whilst CAD risk was higher with higher water intakes. Our findings are discordant with prevailing literature suggesting higher water intakes should reduce cardiometabolic risk. These findings may be an artefact of limitations within the study, but future research is needed to understand if there is a causal underpinning.

Relationships between Charlson comorbidity index associated biomarkers and outcomes among participants in the Malmö diet and cancer study.

INTRODUCTION: The aim was to evaluate two biomarker scores trained to identify comorbidity burden in the prediction of specified chronic morbidities, and mortality in the general population. METHODS: Cardiovascular biomarkers were measured in the cardiovascular cohort of the Malmö Diet and Cancer Study. A score of 19 biomarkers associated with Charlson Comorbidity Index (CCI) was created (BSMDC). Individuals with CCI diagnoses and other major comorbidities were excluded. Another score of 11 biomarkers associated with comorbidity burden from a previous study of acute dyspnea was also created (BSADYS). The scores were prospectively evaluated for prediction of mortality, and some chronic diseases, using Cox Proportional Hazards Model. RESULTS: Fully adjusted models showed that BSMDC was significantly associated per 1 SD increment of the score with incident COPD, 55%, and congestive heart failure, 32%; and with mortality, 33% cardiovascular, 91% respiratory, 30% cancer, and 45% with all-cause mortality. The BSADYS showed no association with these outcomes, after simultaneous inclusion of both biomarker scores to all the clinical covariates. CONCLUSION: BSMDC shows strong prediction of morbidity and mortality in individuals free from comorbidities at baseline, and the results suggest that healthy individuals with high level of BSMDC would benefit from intense preventive actions.

A score of 19 biomarkers associated with Charlson Comorbidity Index was created, the Biomarker Score of Malmö Diet and Cancer study (BSMDC).The created BSMDC index was associated with both incident COPD, and incident CHF.BSMDC was also associated with cardiovascular mortality, respiratory mortality, cancer mortality and with all-cause mortality.

Elevated soluble LOX-1 predicts risk of first-time myocardial infarction.

BACKGROUND: There is an unmet clinical need for novel therapies addressing the residual risk in patients receiving guideline preventive therapy for coronary heart disease. Experimental studies have identified a pro-atherogenic role of the oxidized LDL receptor LOX-1. We investigated the association between circulating soluble LOX-1 (sLOX-1) and the risk for development of myocardial infarction. METHODS: The study subjects (n = 4658) were part of the Malmö Diet and Cancer study. The baseline investigation was carried out 1991-1994 and the incidence of cardiovascular events monitored through national registers during a of 19.5 ± 4.9 years follow-up. sLOX-1 and other biomarkers were analyzed by proximity extension assay and ELISA in baseline plasma. RESULTS: Subjects in the highest tertile of sLOX-1 had an increased risk of myocardial infarction (hazard ratio (95% CI) 1.76 (1.40-2.21) as compared with those in the lowest tertile. The presence of cardiovascular risk factors was related to elevated sLOX-1, but the association between sLOX-1 and risk of myocardial infarction remained significant when adjusting for risk factors. CONCLUSIONS: In this prospective population study we found an association between elevated sLOX-1, the presence of carotid disease and the risk for first-time myocardial infarction. Taken together with previous experimental findings of a pro-atherogenic role of LOX-1, this observation supports LOX-1 inhibition as a possible target for prevention of myocardial infarction.

Activation of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) represents a possible target for treatment of the residual inflammatory risk in cardiovascular patients on guideline therapy.Having high levels of soluble LOX-1, a marker of cellular LOX-1 activation, is associated with an increased risk for development of myocardial infarction and heart failure.sLOX-1 levels correlated with major cardiovascular risk factors and biomarkers reflecting LDL oxidation.

Global Effect of Modifiable Risk Factors on Cardiovascular Disease and Mortality.

BACKGROUND: Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking. METHODS: We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality. RESULTS: Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6). CONCLUSIONS: Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the German Center for Cardiovascular Research (DZHK); ClinicalTrials.gov number, NCT05466825.).

Metabolite Profiling in a Diet-Induced Obesity Mouse Model and Individuals with Diabetes: A Combined Mass Spectrometry and Proton Nuclear Magnetic Resonance Spectroscopy Study.

Mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy techniques have been used extensively for metabolite profiling. Although combining these two analytical modalities has the potential of enhancing metabolite coverage, such studies are sparse. In this study we test the hypothesis that combining the metabolic information obtained using liquid chromatography (LC) MS and 1H NMR spectroscopy improves the discrimination of metabolic disease development. We induced metabolic syndrome in male mice using a high-fat diet (HFD) exposure and performed LC-MS and NMR spectroscopy on plasma samples collected after 1 and 8 weeks of dietary intervention. In an orthogonal projection to latent structures (OPLS) analysis, we observed that combining MS and NMR was stronger than each analytical method alone at determining effects of both HFD feeding and time-on-diet. We then tested our metabolomics approach on plasma from 56 individuals from the Malmö Diet and Cancer Study (MDCS) cohort. All metabolic pathways impacted by HFD feeding in mice were confirmed to be affected by diabetes in the MDCS cohort, and most prominent HFD-induced metabolite concentration changes in mice were also associated with metabolic syndrome parameters in humans. The main drivers of metabolic disease discrimination emanating from the present study included plasma levels of xanthine, hippurate, 2-hydroxyisovalerate, S-adenosylhomocysteine and dimethylguanidino valeric acid. In conclusion, our combined NMR-MS approach provided a snapshot of metabolic imbalances in humans and a mouse model, which was improved over employment of each analytical method alone.

Insulin resistance probability score and incident cardiovascular disease.

BACKGROUND: Insulin resistance (IR) is associated with cardiovascular disease (CVD). However, insulin immunoassay variability and scarce research of the elderly have hindered the adoption of IR assessment for CVD prevention. We asked whether the probability of having IR [p(IR)]-derived from insulin and C-peptide mass-spectrometry assays-was associated with CVD in the elderly. METHODS: A random cohort was drawn from MPP, a population-based study of the elderly. After excluding those with missing data, CVD, or diabetes, 3645 participants (median age = 68) remained. RESULTS: During follow-up (13.3 years), 794 incident CVD events were observed. p(IR) > 80% (n = 152) compared with p(IR) ≤ 80% was associated with incident CVD (HR = 1.51, 95% CI 1.12-2.05, p = 0.007) and CVD or all-cause mortality (HR = 1.43, 95% CI 1.16-1.77, p = 0.0009) after adjusting for age, sex, hypertension, smoking, HDL-cholesterol, total cholesterol, triglycerides, BMI, and prediabetes. CONCLUSION: High p(IR) was associated with >50% greater risk of incident CVD. IR assessment in the elderly may be warranted.

Biochemical activity induced by a germline variation in KLK3 (PSA) associates with cellular function and clinical outcome in prostate cancer.

Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility. The non-synonymous KLK3 SNP, rs17632542 (c.536T>C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity as a previously undescribed function mediating prostate cancer pathogenesis. The 'Thr' PSA variant led to small subcutaneous tumours, supporting reduced prostate cancer risk. However, 'Thr' PSA also displayed higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterization of this PSA variant demonstrated markedly reduced proteolytic activity that correlated with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele had reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes.

Genetic Susceptibility to Mood Disorders and Risk of Stroke: A Polygenic Risk Score and Mendelian Randomization Study.

BACKGROUND: Mood disorders and strokes are often comorbid, and their health toll worldwide is huge. This study characterizes prognostic and causal roles of mood disorders in stroke. METHODS: We tested if genetic susceptibilities for mood disorders were associated with all strokes, ischemic strokes in the Malmö Diet and Cancer cohort (24 631 individuals with a median follow-up of 21.3 (interquartile range: 16.6-23.2) years. We further examined the causal effects for mood disorders on all strokes and ischemic strokes using summary statistics from large genome-wide association studies of mood disorders (up to 609 424 individuals, Psychiatric Genomics Consortium), all strokes and ischemic strokes (up to 446 696 individuals, MEGASTROKE Consortium). RESULTS: Among 24 366 stroke-free participants at baseline, 2632 individuals developed strokes, 2172 of them ischemic, during follow-up. After properly adjusting for well-known risk factors, participants in the highest quintile of polygenic risk scores for mood disorders had 1.45× (95% CI, 1.21-1.74) higher risk of strokes and 1.44× (95% CI, 1.18-1.76) higher risk of ischemic strokes compared with the lowest quintile in women. Mendelian randomization analyses suggested that mood disorders had a causal effect on strokes (odds ratio, 1.07 [95% CI, 1.03-1.11]) and ischemic strokes (odds ratio, 1.09 [95% CI, 1.04-1.13]). CONCLUSIONS: Our results suggest a causal role of mood disorders in the risk of stroke. High-risk women could be identified early in life using polygenic risk scores to ultimately prevent mood disorders and strokes.

Sex-Specific Risk Factors for Deep Venous Thrombosis and Pulmonary Embolism in a Population-Based Historical Cohort Study of Middle-Aged and Older Individuals.

Background Whether sex-specific differences exist for risk factors for pulmonary embolism (PE) and deep venous thrombosis (DVT), with the exception of pregnancy and estrogen therapy, has been sparsely studied. We aimed to study whether sex-specific differences of risk factors exist for noncancer-related DVT and PE in middle-aged and older individuals without cardiovascular history or previous diagnosis in a population-based historical (retrospective) cohort. Methods and Results Potential venous thromboembolism (VTE) risk factors were registered at baseline in 15 807 women and 9996 men aged 44 to 74 years, who participated in the Malmö Diet and Cancer study (1991-1996). We excluded subjects with a previous history of VTE, cancer, a diagnosis of cardiovascular disease, or a diagnosis of cancer-associated VTE during follow-up. Patients were followed up from baseline until the first event of PE or DVT, death, or December 31, 2018. During the follow-up period, 365 (2.3%) women and 168 (1.7%) men were affected by first DVT, and 309 (2.0%) women and 154 (1.5%) men were affected by first PE. In the multivariable Cox regression models, the anthropometric obesity markers of weight, body mass index, waist and hip circumference, fat percentage, and muscle weight were in a dose-dependent way associated with DVT and PE among women but not men. In an analysis that included patients with cardiovascular disease and cancer-related VTE, the results were similar for women. For men, several obesity measures became significantly associated with PE or DVT but were weaker than in women, especially for DVT. Conclusions Anthropometric obesity measures are more important risk factors for both DVT and PE among women than men, especially for individuals without cardiovascular history or previous diagnosis or cancer-related VTE.

Endogenous incretin levels and risk of first incident cancer: a prospective cohort study.

Concerns have been raised regarding a potentially increased risk of cancer associated with treatment with glucagon-like peptide-1 (GLP-1) receptor agonists. Here, we explored whether fasting and oral glucose tolerance test post-challenge glucose-dependent insulinotropic peptide (GIP) and GLP-1 levels were associated with incident first cancer. Within the cardiovascular re-examination arm of the population-based Malmö Diet Cancer study (n = 3734), 685 participants with a previous cancer diagnosis were excluded, resulting in 3049 participants (mean age 72.2 ± 5.6 years, 59.5% women), of whom 485 were diagnosed with incident first cancer (median follow-up time 9.9 years). Multivariable Cox-regression and competing risk regression (death as competing risk) were used to explore associations between incretin levels and incident first cancer. Higher levels of fasting GLP-1 (462 incident first cancer cases/2417 controls) showed lower risk of incident first cancer in competing risk regression (sub-hazard ratio 0.90; 95% confidence interval 0.82-0.99; p = 0.022). No association was seen for fasting GIP, post-challenge GIP, or post-challenge GLP-1 and incident first cancer. In this prospective study, none of the fasting and post-challenge levels of GIP and GLP-1 were associated with higher risk of incident first cancer; by contrast, higher levels of fasting GLP-1 were associated with lower risk of incident first cancer.

Association Between Dietary Habits in Midlife With Dementia Incidence Over a 20-Year Period.

BACKGROUND AND OBJECTIVES: Dementia cases are expected to triple during the next 30 years, highlighting the importance of finding modifiable risk factors for dementia. The aim of this study was to investigate whether adherence to conventional dietary recommendations or to a modified Mediterranean diet are associated with a subsequent lower risk of developing all-cause dementia, Alzheimer disease (AD), vascular dementia (VaD), or with future accumulation of AD-related ß-amyloid (Aß) pathology. METHODS: Baseline examination in the prospective Swedish population-based Malmö Diet and Cancer Study took place in 1991-1996 with a follow-up for incident dementia until 2014. Nondemented individuals born 1923-1950 and living in Malmö were invited to participate. Thirty thousand four hundred forty-six were recruited (41% of all eligible). Twenty-eight thousand twenty-five had dietary data and were included in this study. Dietary habits were assessed with a 7-day food diary, detailed food frequency questionnaire, and 1-hour interview. Main outcomes were incident all-cause dementia, AD, or VaD determined by memory clinic physicians. Secondary outcome was Aß-accumulation measured using CSF Aß42 (n = 738). Cox proportional hazard models were used to examine associations between diet and risk of developing dementia (adjusted for demographics, comorbidities, smoking, physical activity, and alcohol). RESULTS: Sixty-one percent were women, and the mean (SD) age was 58.1 (7.6) years. One thousand nine hundred forty-three (6.9%) were diagnosed with dementia (median follow-up, 19.8 years). Individuals adhering to conventional dietary recommendations did not have lower risk of developing all-cause dementia (hazard ratio [HR] comparing worst with best adherence, 0.93, 95% CI 0.81-1.08), AD (HR 1.03, 0.85-1.23), or VaD (HR 0.93, 0.69-1.26). Neither did adherence to the modified Mediterranean diet lower the risk of developing all-cause dementia (HR 0.93 0.75-1.15), AD (HR 0.90, 0.68-1.19), or VaD (HR 1.00, 0.65-1.55). The results were similar when excluding participants developing dementia within 5 years or those with diabetes. No significant associations were found between diet and abnormal Aß accumulation, conventional recommendations (OR 1.28, 0.74-2.24) or modified Mediterranean diet (OR 0.85, 0.39-1.84). DISCUSSION: In this 20-year follow-up study, neither adherence to conventional dietary recommendations nor to modified Mediterranean diet were significantly associated with subsequent reduced risk for developing all-cause dementia, AD dementia, VaD, or AD pathology.

Interaction between blood pressure and genetic risk score for bladder cancer, and risk of urothelial carcinoma in men.

There is substantial genetic predisposition to bladder cancer (BC). Recently, blood pressure (BP) was positively associated with BC risk in men, but the potential interaction with genetic susceptibility for BC is unknown. We investigated a weighted genetic risk score (wGRS) of 18 BC genetic variants, BP, and their interaction, in relation to incident urothelial cancer (UC, n = 385) risk in 10,576 men. We used Cox regression, the likelihood ratio test, and the relative excess risk for interaction to calculate hazard ratios (HR) of UC, multiplicative interaction and additive interaction respectively. There was evidence of a positive additive interaction between SBP and the wGRS in relation to aggressive (P = 0.02) but not non-aggressive (P = 0.60) UC. The HR of aggressive UC was for SBP ≥ 140 mmHg and the upper 50% of the wGRS combined 1.72 (95% CI 1.03-2.87) compared to the counterpart group. Additionally, the 20-year risk of aggressive UC in 60 year-old men was 0.78% in the low SBP/low wGRS group and 1.33% in the high SBP/high wGRS group. Our findings support a potential additive interaction between the wGRS and SBP on aggressive UC among men. If replicated, the findings on interaction may provide biological and public health insight to prevent aggressive UC.

Genetic variation of the blood coagulation regulator tissue factor pathway inhibitor and venous thromboembolism among middle-aged and older adults: A population-based cohort study.

Background: Tissue factor is the main initiator of blood coagulation, and tissue factor pathway inhibitor (TFPI) is the primary inhibitor of the initiation of blood coagulation.The genetic variation of TFPI and the relation to venous thromboembolism (VTE), that is, venous thrombosis and pulmonary embolism, remains to be clarified. This exome sequencing study aimed to determine the molecular epidemiology of the TFPI gene and the relation to VTE in a large population-based cohort of middle-aged and older adults. Methods: The exomes of TFPI were analyzed for variants in 28,794 subjects without previous VTE (born 1923-1950, 60% women), who participated in the Malmö Diet and Cancer Study (1991-1996). Patients were followed until the first event of VTE, death, or 2018. Qualifying variants were defined as loss-of-function or nonbenign (PolyPhen-2) missense variants with minor allele frequency less than 0.1%. Results: No common variant was associated with VTE. Nine rare variants (two loss-of-function and seven nonbenign missense) were classified as qualifying and included in collapsing analysis. Prevalence of qualifying variants was 0.09%. Five individuals with VTE compared to 17 individuals without VTE carried one qualifying variant. Cox multivariate regression analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking and alcohol consumption, rs6025, rs1799963, and ancestry showed a hazard ratio of 2.9 (95% CI, 1.2-7.1) for rare qualifying variants. Conclusion: Rare qualifying TFPI variants were associated with VTE, suggesting that rare variants in TFPI contribute to the development of VTE. The qualifying TFPI gene variants were very rare, suggesting a constrained gene.

Prevalence and Ascertainment of Dementia Cases in the Malmö Diet and Cancer Study.

Background: Register diagnoses, both hospital-based and from open clinic care, are often used in research studies in Sweden. The validity of such diagnoses has been debated and a validation assessment can improve the diagnostic accuracy for use in research studies. Objective: The aim of this study was to investigate the quality of register-derived dementia diagnoses in the Malmö Diet and Cancer population study (MDCS) and to validate these diagnoses using systematic criteria. Methods: MDCS is a population-based prospective study comprising 30,446 participants. Register diagnoses of dementia for the MDCS population were derived from the Swedish National Patient Register (NPR) and validated through re-evaluation of available medical records by physicians. Results: In the MDCS cohort, 2,206 participants were diagnosed with dementia according to the NPR during a mean follow-up of 18.1 years. The general dementia diagnosis was valid in 96% of the cases, but 40% of the specific dementia diagnoses were changed during the process of reevaluation. The diagnostic validity varied between 25.2% and 82.9% for the different diagnoses. The results from the validity assessment per diagnostic category revealed that the validity of the NPR diagnoses was higher for the more specific diagnoses and lower for unspecified dementia. The major diagnostic shift during the re-evaluation was from unspecified dementia to more specific diagnoses. Conclusion: Validation of dementia diagnoses using medical records results in more precise diagnoses. Dementia diagnoses derived from registers should be validated in order to study associations between influential factors and different dementia diagnoses.

Circulating Hepatocyte Growth Factor Reflects Activation of Vascular Repair in Response to Stress.

Hepatocyte growth factor (HGF) is released by stressed human vascular cells and promotes vascular cell repair responses in both autocrine and paracrine ways. Subjects with a low capacity to express HGF in response to systemic stress have an increased cardiovascular risk. Human atherosclerotic plaques with a low content of HGF have a more unstable phenotype. The present study shows that subjects with a low ability to express HGF in response to metabolic stress have an increased risk to suffer myocardial infarction and stroke.