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1.
BMC Med ; 20(1): 122, 2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35443726

RESUMO

BACKGROUND: The global burden of cardiovascular disease and type 2 diabetes could be decreased by improving dietary factors, but identification of groups suitable for interventional approaches can be difficult. Reporting of dietary intake is prone to errors, and measuring of metabolites has shown promise in determining habitual dietary intake. Our aim is to create a metabolic signature that is associated with healthy eating and test if it associates with type 2 diabetes and coronary artery disease risk. METHODS: Using plasma metabolite data consisting of 111 metabolites, partial least square (PLS) regression was used to identify a metabolic signature associated with a health conscious food pattern in the Malmö Offspring Study (MOS, n = 1538). The metabolic signature's association with dietary intake was validated in the Malmö Diet and Cancer study (MDC, n = 2521). The associations between the diet-associated metabolic signature and incident type 2 diabetes and coronary artery disease (CAD) were tested using Cox regression in MDC and logistic regression in Malmö Preventive Project (MPP, n = 1083). Modelling was conducted unadjusted (model 1), adjusted for potential confounders (model 2) and additionally for potential mediators (model 3). RESULTS: The metabolic signature was associated with lower risk for type 2 diabetes in both MDC (hazard ratio: 0.58, 95% CI 0.52-0.66, per 1 SD increment of the metabolic signature) and MPP (odds ratio: 0.54, 95% CI 0.44-0.65 per 1 SD increment of the metabolic signature) in model 2. The results were attenuated but remained significant in model 3 in both MDC (hazard ratio 0.73, 95% CI 0.63-0.83) and MPP (odds ratio 0.70, 95% CI 0.55-0.88). The diet-associated metabolic signature was also inversely associated with lower risk of CAD in both MDC and MPP in model 1, but the association was non-significant in model 3. CONCLUSIONS: In this proof-of-concept study, we identified a healthy diet-associated metabolic signature, which was inversely associated with future risk for type 2 diabetes and coronary artery disease in two different cohorts. The association with diabetes was independent of traditional risk factors and might illustrate an effect of health conscious dietary intake on cardiometabolic health.


Assuntos
Doença da Artéria Coronariana , Diabetes Mellitus Tipo 2 , Biomarcadores , Doença da Artéria Coronariana/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Dieta , Humanos , Estudos Prospectivos , Fatores de Risco
2.
PLoS One ; 17(4): e0267497, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35482727

RESUMO

BACKGROUND: Adrenomedullin is a vasoactive hormone with potentially prognostic and therapeutic value, which mainly has been investigated in intensive care unit (ICU) settings. The triaging in the emergency department (ED) of patients to the right level of care is crucial for patient outcome. OBJECTIVES: The primary aim of this study was to investigate the association of bioactive adrenomedullin (bio-ADM) with mortality among sepsis patients in the ED. Secondary aims were to investigate the association of bio-ADM with multiple organ failure (MOF), ICU admission and ED discharge. METHODS: In this prospective observational cohort study, adult sepsis patients in the ED (2013-2015) had blood samples collected for later batch analysis of bio-ADM. Odds ratios (OR) with 95% confidence interval (CI) for bio-ADM were calculated. RESULTS: Bio-ADM in 594 sepsis patients was analyzed of whom 51 died within 28 days (8.6%), 34 developed severe MOF, 27 were ICU admitted and 67 were discharged from the ED. The median (interquartile range) bio-ADM was 36 (26-56) and 63 (42-132) pg/mL among survivors and non-survivors, respectively, 81 (56-156) pg/mL for patients with severe MOF and 77 (42-133) pg/mL for ICU admitted patients. Each log-2 increment of bio-ADM conferred an OR of 2.30 (95% CI 1.74-3.04) for mortality, the adjusted OR was 2.39 (95% CI 1.69-3.39). The area under the receiver operating characteristic curve of a prognostic mortality model based on demographics and biomarkers increased from 0.80 to 0.86 (p = 0.02) when bio-ADM was added. Increasing bio-ADM was associated with severe MOF, ICU admission and ED discharge with adjusted ORs of 3.30 (95% CI 2.13-5.11), 1.75 (95% CI 1.11-2.77) and 0.46 (95% CI 0.32-0.68), respectively. CONCLUSION: Bio-ADM in sepsis patients in the ED is associated with mortality, severe MOF, ICU admission and ED discharge, and may be of clinical importance for triage of sepsis patients in the ED.


Assuntos
Adrenomedulina , Sepse , Adulto , Cuidados Críticos , Serviço Hospitalar de Emergência , Humanos , Insuficiência de Múltiplos Órgãos , Estudos Prospectivos
3.
Front Oncol ; 12: 860446, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35425699

RESUMO

Prostate apoptosis response-4 (Par-4) is a tumor suppressor that induces apoptosis in cancer cells. However, the physiological function of Par-4 remains unknown. Here we show that conventional Par-4 knockout (Par-4-/-) mice and adipocyte-specific Par-4 knockout (AKO) mice, but not hepatocyte-specific Par-4 knockout mice, are obese with standard chow diet. Par-4-/- and AKO mice exhibit increased absorption and storage of fat in adipocytes. Mechanistically, Par-4 loss is associated with mdm2 downregulation and activation of p53. We identified complement factor c3 as a p53-regulated gene linked to fat storage in adipocytes. Par-4 re-expression in adipocytes or c3 deletion reversed the obese mouse phenotype. Moreover, obese human subjects showed lower expression of Par-4 relative to lean subjects, and in longitudinal studies, low baseline Par-4 levels denoted an increased risk of developing obesity later in life. These findings indicate that Par-4 suppresses p53 and its target c3 to regulate obesity.

4.
NPJ Precis Oncol ; 6(1): 25, 2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35396534

RESUMO

Polygenic risk scores (PRS) for prostate cancer incidence have been proposed to optimize prostate cancer screening. Prediction of lethal prostate cancer is key to any stratified screening program to avoid excessive overdiagnosis. Herein, PRS for incident prostate cancer was evaluated in two population-based cohorts of unscreened middle-aged men linked to cancer and death registries: the Västerbotten Intervention Project (VIP) and the Malmö Diet and Cancer study (MDC). SNP genotypes were measured by genome-wide SNP genotyping by array followed by imputation or genotyping of selected SNPs using mass spectrometry. The ability of PRS to predict lethal prostate cancer was compared to PSA and a commercialized pre-specified model based on four kallikrein markers. The PRS was associated with incident prostate cancer, replicating previously reported relative risks, and was also associated with prostate cancer death. However, unlike PSA, the PRS did not show stronger association with lethal disease: the hazard ratio for prostate cancer incidence vs. prostate cancer metastasis and death was 1.69 vs. 1.65 in VIP and 1.25 vs. 1.25 in MDC. PSA was a much stronger predictor of prostate cancer metastasis or death with an area-under-the-curve of 0.78 versus 0.63 for the PRS. Importantly, addition of PRS to PSA did not contribute additional risk stratification for lethal prostate cancer. We have shown that a PRS that predicts prostate cancer incidence does not have utility above and beyond that of PSA measured at baseline when applied to the clinically relevant endpoint of prostate cancer death. These findings have implications for public health policies for delivery of prostate cancer screening. Focusing polygenic risk scores on clinically significant endpoints such as prostate cancer metastasis or death would likely improve clinical utility.

5.
Eur J Prev Cardiol ; 2022 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-35403197

RESUMO

AIMS: This study aimed to evaluate the association between physical activity and the incidence of coronary heart disease (CHD) in individuals with and without CHD risk factors. METHODS AND RESULTS: EPIC-CVD is a case-cohort study of 29 333 participants that included 13 582 incident CHD cases and a randomly selected sub-cohort nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Self-reported physical activity was summarized using the Cambridge physical activity index (inactive, moderately inactive, moderately active, and active). Participants were categorized into sub-groups based on the presence or the absence of the following risk factors: obesity (body mass index ≥30 kg/m2), hypercholesterolaemia (total cholesterol ≥6.2 mmol/L), history of diabetes, hypertension (self-reported or ≥140/90 mmHg), and current smoking. Prentice-weighted Cox regression was used to assess the association between physical activity and incident CHD events (non-fatal and fatal).Compared to inactive participants without the respective CHD risk factor (referent), excess CHD risk was highest in physically inactive and lowest in moderately active participants with CHD risk factors. Corresponding excess CHD risk estimates amongst those with obesity were 47% [95% confidence interval (CI) 32-64%] and 21% (95%CI 2-44%), with hypercholesterolaemia were 80% (95%CI 55-108%) and 48% (95%CI 22-81%), with hypertension were 80% (95%CI 65-96%) and 49% (95%CI 28-74%), with diabetes were 142% (95%CI 63-260%), and 100% (95%CI 32-204%), and amongst smokers were 152% (95%CI 122-186%) and 109% (95%CI 74-150%). CONCLUSIONS: In people with CHD risk factors, moderate physical activity, equivalent to 40 mins of walking per day, attenuates but does not completely offset CHD risk.

6.
J Clin Med ; 11(7)2022 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-35407427

RESUMO

OBJECTIVE: Implantable cardiac monitors (ILR) have an important role in diagnosing unexplained syncope. However, outcomes of primary vs. delayed ILR implantation after initial syncope evaluation have not been explored. METHODS: A total of 1705 patients with unexplained syncope were prospectively enrolled in the SYSTEMA (Syncope Study of Unselected Population in Malmö) cohort. Patients who underwent cardiovascular autonomic testing (CAT) and ILR were grouped into those referred to CAT after ILR implantation (primary ILR) and those in whom ILR was indicated after CAT (post-CAT ILR). RESULTS: One-hundred-and-fifteen patients (6.7%) received ILRs. ILR recipients were older (58 vs. 52 years; p = 0.002), had more syncope recurrences (6 vs. 4; p < 0.001), more traumatic falls (72% vs. 53%; p < 0.001), and less prodrome (40% vs. 55%; p = 0.005) than patients without ILRs. During follow-up ≥16 months after ILR, 67 (58%) had normal sinus rhythm, 10 (8.7%) had sinus arrest, 10 (8.7%) AV-block, 13 (11.3%) atrial fibrillation, 9 (7.8%) supraventricular tachycardia, 4 (3.5%) sinus tachycardia and 2 (1.7%) ventricular tachycardia with clinical symptom reproduction. There were 52 patients (45%) in the primary-ILR group and 63 (55%) in the post-CAT ILR group. Proportions of negative ILR monitoring (17/52 vs. 25/63; p = 0.56) and pacemaker implantations (7/52 vs. 15/63; p = 0.23) did not differ between groups. Baseline ECG conduction disorders predicted pacemaker implantation (n = 11/17; odds ratio:10.6; 95%CI: 3.15-35.3; p < 0.001). CAT was more often positive (73% vs. 40%; p < 0.001) in primary-ILR group. CONCLUSIONS: Primary ILR implantation was associated with more positive CAT compared with delayed ILR implantation, but negative monitoring and pacemaker implantations were not different between groups. ECG conduction disorders predicted subsequent pacemaker implantation.

7.
Int J Epidemiol ; 2022 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-35312764

RESUMO

BACKGROUND: The relation between blood pressure and kidney cancer risk is well established but complex and different study designs have reported discrepant findings on the relative importance of diastolic blood pressure (DBP) and systolic blood pressure (SBP). In this study, we sought to describe the temporal relation between diastolic and SBP with renal cell carcinoma (RCC) risk in detail. METHODS: Our study involved two prospective cohorts: the European Prospective Investigation into Cancer and Nutrition study and UK Biobank, including >700 000 participants and 1692 incident RCC cases. Risk analyses were conducted using flexible parametric survival models for DBP and SBP both separately as well as with mutuality adjustment and then adjustment for extended risk factors. We also carried out univariable and multivariable Mendelian randomization (MR) analyses (DBP: ninstruments = 251, SBP: ninstruments = 213) to complement the analyses of measured DBP and SBP. RESULTS: In the univariable analysis, we observed clear positive associations with RCC risk for both diastolic and SBP when measured ≥5 years before diagnosis and suggestive evidence for a stronger risk association in the year leading up to diagnosis. In mutually adjusted analysis, the long-term risk association of DBP remained, with a hazard ratio (HR) per standard deviation increment 10 years before diagnosis (HR10y) of 1.20 (95% CI: 1.10-1.30), whereas the association of SBP was attenuated (HR10y: 1.00, 95% CI: 0.91-1.10). In the complementary multivariable MR analysis, we observed an odds ratio for a 1-SD increment (ORsd) of 1.34 (95% CI: 1.08-1.67) for genetically predicted DBP and 0.70 (95% CI: 0.56-0.88) for genetically predicted SBP. CONCLUSION: The results of this observational and MR study are consistent with an important role of DBP in RCC aetiology. The relation between SBP and RCC risk was less clear but does not appear to be independent of DBP.

8.
Artigo em Inglês | MEDLINE | ID: mdl-35306566

RESUMO

BACKGROUND: Accelerated reproductive aging, in women indicated by early natural menopause, is associated with increased coronary heart disease (CHD) risk in observational studies. Conversely, an adverse CHD risk profile has been suggested to accelerate menopause. OBJECTIVES: To study the direction and evidence for causality of the relationship between reproductive aging and (non-)fatal CHD and CHD risk factors in a bidirectional Mendelian Randomization (MR) approach, using age at natural menopause (ANM) genetic variants as a measure for genetically determined reproductive aging in women. We also studied the association of these variants with CHD risk (factors) in men. DESIGN: Two-sample MR, using both cohort data as well as summary statistics, with four methods: simple and weighted median-based, standard inverse-variance weighted (IVW) regression, and MR-Egger regression. PARTICIPANTS: Data from EPIC-CVD and summary statistics from UK Biobank and publicly available GWAS were pooled for the different analyses. MAIN OUTCOME MEASURES: CHD, CHD risk factors and ANM. RESULTS: Across different methods of MR no association was found between genetically determined reproductive aging and CHD risk in women (Relative Risk Estimate (RRE)IVW=0.99, 95% confidence interval (CI):0.97;1.01), or any of the CHD risk factors. Similarly, no associations were found in men. Neither did the reversed analyses show evidence for an association between CHD (risk factors) and reproductive aging. CONCLUSION: Genetically determined reproductive aging is not causally associated with CHD risk (factors) in women, nor were the genetic variants associated in men. We found no evidence for a reverse association in a combined sample of women and men.

9.
Cerebrovasc Dis ; : 1-7, 2022 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-35340013

RESUMO

BACKGROUND: Subjects exposed to risk factors such as age, gender, hypertension, diabetes mellitus, and smoking are prone to atherosclerotic events. AIMS: The main aim of this longitudinal cohort study was to determine whether the role of novel plasma biomarkers for atherosclerotic carotid artery disease is different in subjects developing symptomatic carotid artery stenosis (CAS), as opposed to those with incident asymptomatic CAS. METHODS: The following biomarkers were measured in 5,550 middle-aged subjects in a population-based cohort study: C-reactive protein (CRP), lipoprotein-associated phospholipase A2 mass and activity, proneurotensin, midregional proadrenomedullin (MR-proADM), midregional proatrial natriuretic peptide (MR-proANP), N-terminal pro-B-type natriuretic peptide (NT pro-BNP), copeptin, and cystatin C. After exclusion of those with prevalent CAS, subjects were thereafter followed in national patient registers for 23.4 (interquartile range 19.5-24.3) years regarding incident symptomatic and asymptomatic CAS. RESULTS: Among 110 patients with confirmed incident CAS, 56 were symptomatic and 54 were asymptomatic. When including conventional risk markers in a Cox regression analysis, NT pro-BNP (hazard ratio [HR] 1.59; 95% confidence interval [CI]: 1.20-2.11), MR-proADM (HR 1.40; CI: 1.13-1.73), cystatin C (HR 1.21; CI: 1.02-1.43), and CRP (HR 1.53; CI: 1.13-1.73) were independently associated with incident symptomatic CAS, whereas no plasma biomarker was associated with incident asymptomatic CAS. CONCLUSION: Plasma biomarkers NT pro-BNP, MR-proADM, cystatin C, and CRP were independently associated with incident symptomatic CAS, whereas no such association could be demonstrated with incident asymptomatic CAS. As these biomarkers indicate future development of clinically relevant atherosclerotic CAS, their potential utility in relation to intensified preventive measures and selection of potential candidates for carotid surgery should be further evaluated.

10.
Diabetes Care ; 2022 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-35287165

RESUMO

OBJECTIVE: Obesity is a key risk factor for type 2 diabetes; however, up to 20% of patients are normal weight. Our aim was to identify metabolite patterns reproducibly predictive of BMI and subsequently to test whether lean individuals who carry an obese metabolome are at hidden high risk of obesity-related diseases, such as type 2 diabetes. RESEARCH DESIGN AND METHODS: Levels of 108 metabolites were measured in plasma samples of 7,663 individuals from two Swedish and one Italian population-based cohort. Ridge regression was used to predict BMI using the metabolites. Individuals with a predicted BMI either >5 kg/m2 higher (overestimated) or lower (underestimated) than their actual BMI were characterized as outliers and further investigated for obesity-related risk factors and future risk of type 2 diabetes and mortality. RESULTS: The metabolome could predict BMI in all cohorts (r2 = 0.48, 0.26, and 0.19). The overestimated group had a BMI similar to individuals correctly predicted as normal weight, had a similar waist circumference, were not more likely to change weight over time, but had a two times higher risk of future type 2 diabetes and an 80% increased risk of all-cause mortality. These associations remained after adjustments for obesity-related risk factors and lifestyle parameters. CONCLUSIONS: We found that lean individuals with an obesity-related metabolome have an increased risk for type 2 diabetes and all-cause mortality compared with lean individuals with a healthy metabolome. Metabolomics may be used to identify hidden high-risk individuals to initiate lifestyle and pharmacological interventions.

11.
Cancers (Basel) ; 14(5)2022 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-35267617

RESUMO

Cardiovascular comorbidity is common in small cell lung cancer (SCLC) and may significantly affect treatment tolerability and patient outcome. Still, there are no established biomarkers for objective and dynamic assessment as a tool for improved treatment decisions. We have investigated circulating levels of midregional-pro-adrenomedullin (MR-proADM), midregional-pro-atrial-natriuretic peptide (MR-proANP), copeptin (surrogate for vasopressin) and suppression-of-tumorigenicity-2 (ST2), all known to correlate with various aspects of cardiovascular function, in a SCLC cohort (N = 252) from a randomized, controlled trial (RASTEN). For all measured biomarkers, protein levels were inversely associated with survival, particularly with ST2 and MR-proADM, where the top versus bottom quartile was associated with an adjusted hazard ratio of 2.40 (95% CI 1.44-3.98; p = 0.001) and 2.18 (95% CI 1.35-3.51; p = 0.001), respectively, in the entire cohort, and 3.43 (95% CI 1.73-6.79; p < 0.001) and 3.49 (95% CI 1.84-6.60; p < 0.001), respectively, in extensive disease patients. A high combined score of MR-proADM and ST2 was associated with a significantly reduced median OS of 7.0 months vs. 14.9 months for patients with a low combined score. We conclude that the cardiovascular biomarkers MR-proADM and ST2 strongly correlate with survival in SCLC, warranting prospective studies on the clinical utility of MR-proADM and ST2 for improved, individualized treatment decisions.

12.
Artigo em Inglês | MEDLINE | ID: mdl-35294966

RESUMO

CONTEXT: It is unclear to what extent the plasma proteome of abdominal fat distribution differs from that of body mass index, and whether the differences have clinical implications. OBJECTIVE: To evaluate the difference between the plasma proteomic profiles of body mass index (BMI) and waist-to-hip ratio (WHR), and then examine the identified BMI- or WHR- specific proteins in relation to incidence of diabetes. DESIGN: the Malmö Diet and Cancer-Cardiovascular Cohort study. SETTING: general community. PARTICIPANTS: 4,203 participants with no previous diabetes (aged 57.2±6.0 years, 37.8% men). INTERVENTION(S): Plasma proteins (n=136) were measured by the Proseek proximity extension method. BMI- and WHR-specific proteins were identified at baseline using a two-step iterative resampling approach to optimize internal replicability followed by ß coefficients comparisons. The identified proteins were considered internally replicated and were then studied in relation to incident diabetes by Cox proportional hazards regression analysis. MAIN OUTCOME MEASURE(S): Incident diabetes over a mean follow-up of 20.3±5.9 years. RESULTS: After excluding 21 overlapping proteins and proteins that did not show significantly different associations with BMI versus WHR, ten internally replicated proteins were found to be specific to BMI, and 22 were found to be specific to WHR (false discovery rate-adjusted p<0.05). Of the WHR-specific proteins, eighteen remained associated with diabetes risk after multivariate adjustments, whereas none of the BMI-specific proteins showed associations with diabetes risk. CONCLUSIONS: Abdominal fat distribution was associated with some unique characteristics of the plasma proteome that potentially could be related to its additional risk of diabetes beyond general obesity.

13.
J Intern Med ; 2022 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-35340071

RESUMO

BACKGROUND: Vasopressin concentration is typically higher at night, during stress, and in males, but readily lowered by water intake. Vasopressin is also a causal candidate for cardiometabolic disease, which shows seasonal variation. OBJECTIVE: To study whether vasopressin concentration varies by season in a temperate climate. METHODS: The vasopressin surrogate marker copeptin was analyzed in fasting plasma samples from five population-based cohorts in Malmö, Sweden (n = 25,907, 50.4% women, age 18-86 years). We investigated seasonal variation of copeptin concentration and adjusted for confounders in sinusoidal models. RESULTS: The predicted median copeptin level was 5.81 pmol/L (7.18 pmol/L for men and 4.44 pmol/L for women). Copeptin exhibited a distinct seasonal pattern with a peak in winter (mid-February to mid-March) and nadir in late summer (mid-August to mid-September). The adjusted absolute seasonal variation in median copeptin was 0.62 pmol/L (95% confidence interval [CI] 0.50; 0.74, 0.98 pmol/L [95% CI 0.73; 1.23] for men and 0.46 pmol/L [95% CI 0.33; 0.59] for women). The adjusted relative seasonal variation in mean log copeptin z-score was 0.20 (95% CI 0.17; 0.24, 0.18 [95% CI 0.14; 0.23] in men and 0.24 [95% CI 0.19; 0.29] in women). The observed seasonal variation of copeptin corresponded to a risk increase of 4% for incident diabetes mellitus and 2% for incident coronary artery disease. CONCLUSION: The seasonal variation of the vasopressin marker copeptin corresponds to increased disease risk and mirrors the known variation in cardiometabolic status across the year. Moderately increased water intake might mitigate the winter peak of cardiometabolic disease.

14.
J Thromb Haemost ; 2022 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-35263815

RESUMO

BACKGROUND: Severe alpha-1-antitrypsin deficiency (AATD), phenotype PiZZ, was associated with venous thromboembolism (VTE) in a case-control study. OBJECTIVES: This study aimed to determine the genetic variation in the SERPINA1 gene and a possible thrombotic risk of these variants in a population-based cohort study. PATIENTS/METHODS: The coding sequence of SERPINA1 was analyzed for the Z (rs28929474), S (rs17580), and other qualifying variants in 28,794 subjects without previous VTE (born 1923-1950, 60% women), who participated in the Malmö Diet and Cancer study (1991-1996). Individuals were followed from baseline until the first event of VTE, death, or 2018. RESULTS: Resequencing the coding sequence of SERPINA1 identified 84 variants in the total study population, 21 synonymous, 62 missense, and 1 loss-of-function variant. Kaplan-Meier analysis showed that homozygosity for the Z allele increased the risk of VTE whereas heterozygosity showed no effect. The S (rs17580) variant was not associated with VTE. Thirty-one rare variants were qualifying and included in collapsing analysis using the following selection criteria, loss of function, in frame deletion or non-benign (PolyPhen-2) missense variants with minor allele frequency (MAF) <0.1%. Combining the rare qualifying variants with the Z variant showed that carrying two alleles (ZZ or compound heterozygotes) showed increased risk. Cox regression analysis revealed an adjusted hazard ratio of 4.5 (95% confidence interval 2.0-10.0) for combinations of the Z variant and rare qualifying variants. One other variant (rs141620200; MAF = 0.002) showed an increased risk of VTE. CONCLUSIONS: The SERPINA1 ZZ genotype and compound heterozygotes for severe AATD are rare but associated with VTE in a population-based Swedish study.

15.
PLoS Biol ; 20(3): e3001561, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35239643

RESUMO

Type 2 diabetes (T2D) and cardiovascular disease (CVD) represent significant disease burdens for most societies and susceptibility to these diseases is strongly influenced by diet and lifestyle. Physiological changes associated with T2D or CVD, such has high blood pressure and cholesterol and glucose levels in the blood, are often apparent prior to disease incidence. Here we integrated genetics, lipidomics, and standard clinical diagnostics to assess future T2D and CVD risk for 4,067 participants from a large prospective population-based cohort, the Malmö Diet and Cancer-Cardiovascular Cohort. By training Ridge regression-based machine learning models on the measurements obtained at baseline when the individuals were healthy, we computed several risk scores for T2D and CVD incidence during up to 23 years of follow-up. We used these scores to stratify the participants into risk groups and found that a lipidomics risk score based on the quantification of 184 plasma lipid concentrations resulted in a 168% and 84% increase of the incidence rate in the highest risk group and a 77% and 53% decrease of the incidence rate in lowest risk group for T2D and CVD, respectively, compared to the average case rates of 13.8% and 22.0%. Notably, lipidomic risk correlated only marginally with polygenic risk, indicating that the lipidome and genetic variants may constitute largely independent risk factors for T2D and CVD. Risk stratification was further improved by adding standard clinical variables to the model, resulting in a case rate of 51.0% and 53.3% in the highest risk group for T2D and CVD, respectively. The participants in the highest risk group showed significantly altered lipidome compositions affecting 167 and 157 lipid species for T2D and CVD, respectively. Our results demonstrated that a subset of individuals at high risk for developing T2D or CVD can be identified years before disease incidence. The lipidomic risk, which is derived from only one single mass spectrometric measurement that is cheap and fast, is informative and could extend traditional risk assessment based on clinical assays.


Assuntos
Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 2/genética , Lipidômica/métodos , Herança Multifatorial/genética , Medição de Risco/estatística & dados numéricos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/metabolismo , Estudos de Coortes , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Genômica/métodos , Humanos , Incidência , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Medição de Risco/métodos , Fatores de Risco , Suécia/epidemiologia
16.
J Clin Periodontol ; 49(4): 353-361, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35132662

RESUMO

AIM: The metabolite 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF) is a fatty fish-intake biomarker. We investigated the association between plasma levels of CMPF in relation to gingival inflammation and periodontitis case definition, as well as the extent and severity variables. MATERIALS AND METHODS: The Malmö Offspring Study is a population-based study, and the Malmö Offspring Dental Study (MODS) is its dental arm, including periodontal charting. Plasma CMPF was measured using liquid chromatography-mass spectrometry and studied in relation to periodontal diagnosis and parameters using multivariable linear or logistic regression modelling adjusting for age, sex, education, body mass index, fasting glucose, and smoking. RESULTS: Metabolite data were available for 922 MODS participants. Higher CMPF levels were associated with less gingival inflammation (ß = -2.12, p = .002) and lower odds of severe periodontitis (odds ratio [OR] = 0.74, 95% confidence interval [CI]: 0.56 to 0.98). Higher CMPF levels were also associated with more teeth (ß = 0.19, p = .001), lower number of periodontal pockets (≥4 mm) (ß = -1.07, p = .007), and lower odds of having two or more periodontal pockets of ≥6 mm (OR = 0.80, 95% CI: 0.65 to 0.98) in fully adjusted models. CONCLUSIONS: CMPF, a validated biomarker of fatty fish consumption, is associated with less periodontal inflammation and periodontitis. Residual confounding cannot be ruled out, and future studies are warranted.


Assuntos
Gengivite , Periodontite , Animais , Biomarcadores , Humanos , Inflamação , Insuficiência de Múltiplos Órgãos , Bolsa Periodontal , Periodontite/diagnóstico , Periodontite/epidemiologia
17.
J Am Heart Assoc ; 11(4): e023018, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35112923

RESUMO

Background Five classic thrombophilias have been recognized: factor V Leiden (rs6025), the prothrombin G20210A variant (rs1799963), and protein C, protein S, and antithrombin deficiencies. This study aimed to determine the thrombotic risk of classic thrombophilias in a cohort of middle-aged and older adults. Methods and Results Factor V Leiden, prothrombin G20210A and protein-coding variants in the PROC (protein C), PROS1 (protein S), and SERPINC1 (antithrombin) anticoagulant genes were determined in 29 387 subjects (born 1923-1950, 60% women) who participated in the Malmö Diet and Cancer study (1991-1996). The Human Gene Mutation Database was used to define 68 disease-causing mutations. Patients were followed up from baseline until the first event of venous thromboembolism (VTE), death, or Dec 31, 2018. Carriership (n=908, 3.1%) for disease-causing mutations in the PROC, PROS1, and SERPINC1 genes was associated with incident VTE: Hazard ratio (HR) was 1.6 (95% CI, 1.3-1.9). Variants not in Human Gene Mutation Database were not linked to VTE (HR, 1.1; 95% CI, 0.8-1.5). Heterozygosity for rs6025 and rs1799963 was associated with incident VTE: HR, 1.8 (95% CI, 1.6-2.0) and HR, 1.6 (95% CI, 1.3-2.0), respectively. The HR for carrying 1 classical thrombophilia variant was 1.7 (95% CI, 1.6-1.9). HR was 3.9 (95% CI, 3.1-5.0) for carriers of ≥2 thrombophilia variants. Conclusions The 5 classic thrombophilias are associated with a dose-graded risk of VTE in middle-aged and older adults. Disease-causing variants in the PROC, PROS1, and SERPINC1 genes were more common than the rs1799963 variant but the conferred genetic risk was comparable with the rs6025 and rs1799963 variants.


Assuntos
Trombofilia , Trombose , Tromboembolia Venosa , Idoso , Anticoagulantes , Antitrombinas , Estudos de Coortes , Fator V/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteína C/genética , Proteína S/genética , Protrombina , Fatores de Risco , Trombofilia/complicações , Trombose/complicações , Trombose/epidemiologia , Trombose/genética , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/genética
18.
Hum Mol Genet ; 2022 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-35138370

RESUMO

Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene-sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 (OR = 0.71, p = 4.29x10-8); rs79942605 (OR = 2.17, p = 2.81x10-8); and rs208908 (OR = 0.70, p = 4.54x10-8), were identified with different risk effect of lung cancer between men and women. Further eQTL and functional annotation analysis suggested rs208908 affects lung cancer risk through differential regulation of CXADR (Coxsackie Virus And Adenovirus Receptor) gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.

19.
Nutrients ; 14(4)2022 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-35215475

RESUMO

Selenium has been suggested to be protective regarding breast cancer risk but no overall effect has been established. Genetics may modify the effect. This study compares the effect of selenium exposure on breast cancer risk between women with different alleles in single-nucleotide polymorphisms (SNPs). The Malmö Cancer and Diet Study, a cohort including 17,035 women and >25 years of follow-up on breast cancer diagnosis, was used. Five promising SNPs regarding interaction with selenium exposure were selected from the literature: rs1050450, rs4880, rs3877899, rs7579, and rs71304. Selenium exposure was assessed in three ways: genetically elevated (n = 16,429), dietary intake (n = 15,891) and serum levels (n = 2037) at baseline. Cox regression and logistic regression analyses evaluated breast cancer risk from selenium exposure, stratified for the SNPs and adjusted for risk factors. A total of 1946 women were diagnosed with breast cancer. Women with T/T alleles in rs1050450 had lower breast cancer risk compared with C/C, HR 0.81 (0.68-0.96). Interaction by rs1050450 limited a protective effect of higher selenium intake to T/T carriers, HR 0.68 (0.43-1.08) for intermediate intake and HR 0.63 (0.40-1.00) for high intake. No interactions or risk differences were seen for other SNPs or for serum selenium or genetically elevated selenium. The results indicate that genetic variation in rs1050450 might affect breast cancer risk and that selenium exposure could be a possible modifiable risk factor for breast cancer among women with that variation.


Assuntos
Neoplasias da Mama , Selênio , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Ingestão de Alimentos , Feminino , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco
20.
Int J Mol Sci ; 23(4)2022 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-35216326

RESUMO

Neurotensin (NT) is a small peptide with pleiotropic functions, exerting its primary actions by controlling food intake and energy balance. The first evidence of an involvement of NT in metabolism came from studies on the central nervous system and brain circuits, where NT acts as a neurotransmitter, producing different effects in relation to the specific region involved. Moreover, newer interesting chapters on peripheral NT and metabolism have emerged since the first studies on the NT-mediated regulation of gut lipid absorption and fat homeostasis. Intriguingly, NT enhances fat absorption from the gut lumen in the presence of food with a high fat content, and this action may explain the strong association between high circulating levels of pro-NT, the NT stable precursor, and the increased incidence of metabolic disorders, cardiovascular diseases, and cancer observed in large population studies. This review aims to provide a synthetic overview of the main regulatory effects of NT on several biological pathways, particularly those involving energy balance, and will focus on new evidence on the role of NT in controlling fat homeostasis, thus influencing the risk of unfavorable cardio-metabolic outcomes and overall mortality in humans.


Assuntos
Gorduras/metabolismo , Homeostase/fisiologia , Neurotensina/metabolismo , Animais , Biomarcadores/metabolismo , Humanos , Doenças Metabólicas/metabolismo
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