ABSTRACT
OBJECTIVE: Mechanical restraint (MR) is used to prevent patients from harming themselves or others during inpatient treatment. The objective of this study was to investigate whether incident MR occurring in the first 3 days following admission could be predicted based on analysis of electronic health data available after the first hour of admission. METHODS: The dataset consisted of clinical notes from electronic health records from the Central Denmark Region and data from the Danish Health Registers from patients admitted to a psychiatric department in the period from 2011 to 2015. Supervised machine learning algorithms were trained on a randomly selected subset of the data and validated using an independent test dataset. RESULTS: A total of 5050 patients with 8869 admissions were included in the study. One hundred patients were mechanically restrained in the period between one hour and 3 days after the admission. A Random Forest algorithm predicted MR with an area under the curve of 0.87 (95% CI 0.79-0.93). At 94% specificity, the sensitivity was 56%. Among the ten strongest predictors, nine were derived from the clinical notes. CONCLUSIONS: These findings open for the development of an early warning system that may guide interventions to reduce the use of MR.
Subject(s)
Inpatients/psychology , Machine Learning/standards , Mental Disorders/psychology , Restraint, Physical/adverse effects , Case-Control Studies , Denmark/epidemiology , Early Warning Score , Electronic Health Records , Female , Hospitalization/statistics & numerical data , Humans , Machine Learning/statistics & numerical data , Male , Mental Disorders/epidemiology , Predictive Value of Tests , Restraint, Physical/methods , Restraint, Physical/statistics & numerical data , Self-Injurious Behavior/prevention & control , Sensitivity and Specificity , Time FactorsABSTRACT
BACKGROUND: Besides the important skeletal functions, it has been suggested that vitamin D is involved in the pathogenesis of allergy and asthma and related to lung function. However, previous studies are inconclusive. OBJECTIVE: The purpose of this study was to investigate associations of serum levels of 25-hydroxy vitamin D (25(OH)D) with atopy, asthma, and lung function in a prospective study of Danish adults. METHODS: This study included 4999 adults aged 30-60 years in 1999-2001. Three thousand and thirty-two of those included at baseline also participated at a follow-up examination 5 years later, and 3727 answered a 10-year follow-up questionnaire. Serum levels of (25(OH)D) were measured by high-performance liquid chromatography (HPLC) at baseline. No information on use of vitamin D supplements was available. Specific IgE against four common antigens was measured. Information about doctor-diagnosed asthma was obtained from questionnaires, and lung function (FEV1 and forced vital capacity) was measured by spirometry. RESULTS: We found no significant associations of 25(OH)D with atopy and doctor-diagnosed asthma. However, we found that low levels of 25(OH)D were associated with lower FEV1 percentage predicted (FEV1%pred) in the cross-sectional analyses. The odds ratio (OR) of FEV1%pred < 80% among participants in the highest quartile of 25(OH)D compared with those in the lowest was 0.66 (95% confidence interval (CI): 0.49-0.74). In contrast, prospective analyses indicated an association between high levels of 25(OH)D at baseline and adverse changes in lung function. OR (95%CI) of incident FEV1%pred < 80% was 1.73 (1.06-2.82) in the highest quartile of 25(OH)D compared with the lowest. CONCLUSIONS AND CLINICAL RELEVANCE: Our data indicates that 25(OH)D levels do not influence the development of asthma and allergy among adults. Further, the results did not consistently support that 25(OH)D levels associate with lung function. Randomized controlled trials are needed to further address this issue.
Subject(s)
Asthma/blood , Asthma/diagnosis , Asthma/physiopathology , Calcifediol/blood , Adult , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prospective Studies , Respiratory Function TestsABSTRACT
OBJECTIVES: Soluble urokinase plasminogen activator receptor (suPAR) is a marker of inflammation and endothelial dysfunction. We investigated the associations between suPAR and diabetes, including diabetes duration and complications, in patients with type 1 diabetes. DESIGN, SETTING AND SUBJECTS: From 2009 to 2011, 667 patients with type 1 diabetes and 51 nondiabetic control subjects were included in a cross-sectional study at Steno Diabetes Center, Gentofte, Denmark. suPAR levels were measured with an enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES: The investigated diabetic complications were cardiovascular disease (CVD: previous myocardial infarction, revascularisation, peripheral arterial disease and stroke), autonomic dysfunction (heart rate variability during deep breathing <11 beats min(-1) ), albuminuria [urinary albumin excretion rate (UAER) ≥30 mg/24 h] or a high degree of arterial stiffness (pulse wave velocity ≥10 m s(-1) ). Analyses were adjusted for gender, age, systolic blood pressure, estimated glomerular filtration rate, UAER, glycated haemoglobin (HbA1c ), total cholesterol, body mass index, C-reactive protein, antihypertensive treatment and smoking. RESULTS: Soluble urokinase plasminogen activator receptor levels were lower in control subjects versus all patients, in control subjects versus normoalbuminuric patients (UAER <30 mg/24 h), in normoalbuminuric patients with short (<10 years) versus long diabetes duration and were increased with degree of albuminuria (adjusted P < 0.001 for all). Furthermore, suPAR levels were higher in patients with versus without CVD (n = 144; 21.3%), autonomic dysfunction (n = 369; 59.2%), albuminuria (n = 357; 53.1%) and a high degree of arterial stiffness (n = 298; 47.2%) (adjusted P ≤ 0.024). The adjusted odds ratio (95% confidence interval) values per 1 ln unit increase in suPAR were as follows: 2.5 (1.1-5.7) for CVD: 2.7 (1.2-6.2) for autonomic dysfunction; 3.8 (1.3-10.9) for albuminuria and 2.5 (1.1-6.1) for a high degree of arterial stiffness (P ≤ 0.039). CONCLUSION: The suPAR level is higher in patients with type 1 diabetes and is associated with diabetes duration and complications independent of other risk factors. suPAR is a potential novel risk marker for the management of diabetes.
Subject(s)
Diabetes Complications/blood , Diabetes Mellitus, Type 1/blood , Receptors, Urokinase Plasminogen Activator/metabolism , Albuminuria/blood , Albuminuria/etiology , Biomarkers/metabolism , C-Reactive Protein/metabolism , Cross-Sectional Studies , Diabetes Complications/etiology , Diabetes Mellitus, Type 1/complications , Diabetic Angiopathies/blood , Diabetic Angiopathies/etiology , Diabetic Nephropathies/blood , Diabetic Nephropathies/etiology , Epidemiologic Methods , Female , Humans , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/etiology , Male , Middle AgedABSTRACT
BACKGROUND/OBJECTIVES: The aim was to examine the causal effect of vitamin D on serum adiponectin using a multiple instrument Mendelian randomization approach. SUBJECTS/METHODS: Serum 25-hydroxy vitamin D (25(OH)D) and serum total or high molecular weight (HMW) adiponectin were measured in two Danish population-based studies: the Inter99 study (6405 adults, 30-60 years) conducted in 1999-2001, and the MONICA10 study (2656 adults, 41-71 years) conducted in 1993-1994. RESULTS: In the Inter99 study, serum 25(OH)D was positively associated with total adiponectin (the effect estimate in % per doubling of 25(OH)D was 4.78, 95% CI: 1.96, 7.68, P<0.001). Using variations in the vitamin D-binding protein gene and the filaggrin gene as instrumental variables, the causal effect in % was estimated to 61.46, 95% CI: 17.51, 120.28, P=0.003 higher adiponectin per doubling of 25(OH)D. In the MONICA10 cohort, no significant association was observed between the serum concentrations of 25(OH)D and HMW adiponectin (the effect estimate in % per doubling of 25(OH)D was -1.51, 95% CI: -5.80, 2.98, P=0.50), although the instrumental variables analysis to some extent supported a positive causal association (the effect estimate in % per doubling of 25(OH)D was 37.13, 95% CI: -3.67, 95.20, P=0.080). CONCLUSIONS: The results indicate a possible causal association between serum 25(OH)D and total adiponectin. However, the association was not replicated for HMW adiponectin. Thus, further studies are needed to confirm a causal relationship.
Subject(s)
Adiponectin/blood , Genetic Variation , Mendelian Randomization Analysis , Vitamin D/analogs & derivatives , Adult , Aged , Anthropometry , Denmark , Female , Filaggrin Proteins , Genotype , Humans , Iceland , Intermediate Filament Proteins/genetics , Male , Middle Aged , Molecular Weight , Norway , Sweden , Vitamin D/blood , Vitamin D/genetics , Vitamin D-Binding Protein/geneticsABSTRACT
BACKGROUND AND AIMS: Danish legislation regarding food fortification has been very restrictive and vitamin D deficiency is thought to be common in Denmark due to inadequate dietary intakes and the fact that in Denmark (latitude 56°N) vitamin D is only synthesized in the skin after exposure to solar radiation during summertime (April-September). The purpose of this study was to evaluate the vitamin D status of a general adult population in Denmark and, in addition, associations between vitamin D status and distinct lifestyle factors were studied. METHODS: A random sample of 6784 persons from a general population aged 30-60 years participated in a health examination in 1999-2001. Serum samples from all participants were stored and levels of 25-hydroxyvitamin D (25(OH)D) were measured by HPLC in 2009. The method was compared to another HPLC method. Information on dietary intake of vitamin D and other lifestyle factors were obtained by questionnaires. A total of 6146 persons defined as ethnic Danes and with successful measurements of 25(OH)D were included in the analyses. RESULTS: The overall prevalence of vitamin D deficiency (25(OH)D<25 nmol/l) and insufficiency (25(OH)D<50 nmol/l) were 13.8% and 52.2%, respectively. A marked seasonal fluctuation was seen in serum levels of 25(OH)D - median values of 25(OH)D were lowest in February and highest in August. In multiple logistic regression models (n=5506), low vitamin D status was significantly associated with obesity (BMI≥30), daily smoking and a sedentary lifestyle. However, measurements of 25(OH)D were not associated with the estimated dietary intake of vitamin D. Comparison of two HPLC methods demonstrated considerable differences in accuracy. DISCUSSION AND CONCLUSIONS: Our results suggest that poor vitamin D status is common among adults in a Northern European country without food fortification with vitamin D. Methodological issues are, however, of great importance when using cut-off values to define poor vitamin D status. In addition, we demonstrated that low serum levels of 25(OH)D were associated with several lifestyle factors.
Subject(s)
Vitamin D Deficiency/diagnosis , Vitamin D Deficiency/epidemiology , Vitamin D/blood , Adult , Denmark/epidemiology , Female , Humans , Life Style , Male , Mass Screening , Middle Aged , Obesity/blood , Obesity/diagnosis , Prevalence , Seasons , Smoking , Sunlight , Vitamin D Deficiency/bloodABSTRACT
Twenty-five per cent of individuals infected with hepatitis C virus (HCV) are able to clear HCV spontaneously. Differences in host genetics are believed to affect the outcome of HCV infection. We analysed an exonic, a promoter and an intronic single nucleotide polymorphism (SNP) of the interferon-λ3 coding interleukin (IL)-28B gene to study the relationship between IL28B SNPs and outcome of HCV infection. Among 206 HIV-1-infected Europeans with evidence of HCV infection, 47 (23%) individuals had cleared HCV and 159 (77%) had developed chronic infection. The exonic rs8103142 CT, the promoter rs12979860 CT and the intronic rs11881222 AG genotypes were associated with a decreased HCV clearance rate with adjusted odds ratios (aOR) of 0.3 (95% CI, 0.1-0.7), 0.4 (95% CI, 0.2-0.8) and 0.4 (95% CI, 0.2-0.8), respectively. The haplotype block TCG CTA was associated with a decreased HCV clearance rate (aOR 0.4, 95% CI, 0.2-0.8). Further, we found significant differences in HCV RNA levels among individuals chronically infected with HCV genotype 1 for rs8103142 and rs12979860 (P ≤ 0.05). Chronically infected individuals with HCV genotype 3 and with the favourable haplotype block CTA CTA had higher median HCV RNA levels than individuals with unfavourable haplotype blocks (P ≤ 0.05). Our findings suggest that IL28B may account for some differences in HCV outcome but that other factors including the viral genotype, host genetics and the host-virus interaction are likely to influence the outcome of HCV infection.
Subject(s)
Hepacivirus/immunology , Hepacivirus/isolation & purification , Hepatitis C/immunology , Hepatitis C/virology , Interleukins/genetics , Polymorphism, Single Nucleotide , Viral Load , Adult , Female , Gene Frequency , HIV Infections/complications , Haplotypes , Humans , Interferons , Male , Treatment OutcomeABSTRACT
BACKGROUND: Low-grade inflammation is thought to contribute to the development of cardiovascular disease (CVD), type-2 diabetes mellitus (T2D), cancer and mortality. Biomarkers of inflammation may aid in risk prediction and enable early intervention and prevention of disease. OBJECTIVE: The aim of this study was to investigate whether plasma levels of the inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) are predictive of disease and mortality in the general population. DESIGN: This was an observational prospective cohort study. Cohort participants were included from June 1993 to December 1994 and followed until the end of 2006. SETTING: General adult Caucasian population. PARTICIPANTS: The MONICA10 study, a population-based cohort recruited from Copenhagen, Denmark, included 2602 individuals aged 41, 51, 61 or 71 years. MEASUREMENTS: Blood samples were analysed for suPAR levels using a commercially available enzyme-linked immunosorbent assay. Risk of cancer (n = 308), CVD (n = 301), T2D (n = 59) and mortality (n = 411) was assessed with a multivariate proportional hazards model using Cox regression. RESULTS: Elevated baseline suPAR level was associated with an increased risk of cancer, CVD, T2D and mortality during follow-up. suPAR was more strongly associated with cancer, CVD and mortality in men than in women, and in younger compared with older individuals. suPAR remained significantly associated with the risk of negative outcome after adjustment for a number of relevant risk factors including C-reactive protein levels. LIMITATION: Further validation in ethnic populations other than Caucasians is needed. CONCLUSION: The stable plasma protein suPAR may be a promising biomarker because of its independent association with incident cancer, CVD, T2D and mortality in the general population.
Subject(s)
Cardiovascular Diseases/diagnosis , Diabetes Mellitus, Type 2/diagnosis , Neoplasms/diagnosis , Receptors, Urokinase Plasminogen Activator/blood , Adult , Age Distribution , Aged , Biomarkers/blood , Biomarkers, Tumor/blood , C-Reactive Protein/metabolism , Cardiovascular Diseases/epidemiology , Denmark/epidemiology , Diabetes Mellitus, Type 2/epidemiology , Epidemiologic Methods , Female , Humans , Male , Middle Aged , Neoplasms/epidemiology , Prognosis , Sex DistributionABSTRACT
BACKGROUND: Recent studies suggested low serum folate and impaired folate metabolism as potential risk factors for development of asthma and atopic disease, but the results are inconsistent. The aim of this study was to investigate the relations of markers of folate and vitamin B12 (B12) deficiency with different phenotypes of asthma and atopy. METHODS: A random sample of 6784 persons from a general population aged 30-60 years participated in a health examination in 1999-2001, and 4516 (66.6%) of those also participated in a follow-up examination 5 years later. The examinations included spirometry, measurements of serum folate and B12, specific IgE to inhalant allergens, total IgE, and genotyping of the MTHFR-C677T polymorphism - a genetic marker of impaired folate metabolism. Information about dietary intake of folate and B12, asthma diagnosis, and airway symptoms was obtained by questionnaires. RESULTS: Low serum folate levels and the TT genotype of the MTHFR-C677T polymorphism were associated with increased prevalence of self-reported doctor-diagnosed asthma [odds ratio (OR) 1.37, 95% confidence interval (CI) 1.05-1.79 and OR 1.52; 95% CI 1.12-2.06, respectively] and attacks of shortness of breath (OR 1.43, 95% CI 1.14-1.79 and OR 1.47; 95% CI: 1.14-1.91, respectively). We found no significant associations with lung function or atopic outcomes. Serum levels of B12 and dietary intake of folate and B12 were not associated with asthma or atopy. CONCLUSIONS: We found that two objective markers of folate deficiency were associated with self-reported doctor-diagnosed asthma and attacks of shortness of breath, but not with lung function or atopy.
Subject(s)
Asthma/metabolism , Folic Acid/blood , Hypersensitivity, Immediate/metabolism , Vitamin B 12/blood , Adult , Asthma/genetics , Asthma/physiopathology , Cross-Sectional Studies , Diet , Enzyme-Linked Immunosorbent Assay , Female , Genetic Predisposition to Disease , Genotype , Humans , Hypersensitivity, Immediate/genetics , Hypersensitivity, Immediate/physiopathology , Male , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Middle Aged , Polymorphism, Single Nucleotide , Respiratory Function TestsABSTRACT
BACKGROUND: Although hypersensitivity reactions following intake of alcoholic drinks are common in Caucasians, the underlying mechanisms and clinical significance are not known. In contrast, in Asians, alcohol-induced asthma and flushing have been shown to be because of a single nucleotide polymorphism (SNP), the acetaldehyde dehydrogenase 2 (ALDH2) 487lys, causing decreased acetaldehyde (the metabolite of ethanol) metabolism and high levels of histamine. However, the ALDH2 487lys is absent in Caucasians. OBJECTIVES: To investigate the genetic determinants of self-reported alcohol-induced hypersensitivity reactions in Caucasians. METHODS: The study included two population-based studies of 1216 and 6784 adults living in Copenhagen. Assessment of alcohol consumption and hypersensitivity reactions (in a subgroup) was performed by a questionnaire and was related to common SNPs of genes encoding alcohol dehydrogenases (ADHs) and ALDHs. RESULTS: In both populations, alcohol drinkers with a genetically determined fast metabolism of ethanol (the A allele of the ADH1b rs1229984) had an increased risk of alcohol-induced hypersensitivity reactions (odds ratio AA/AG vs. GG in combined populations: 1.82, 95% CI 1.04-3.17). In both populations, a common SNP encoding ALDH1b1 (rs2228093) was found to be significantly associated with alcohol-induced hypersensitivity (odds ratio TT vs. CC in combined populations: 2.53, 95% CI 1.31-4.90). CONCLUSIONS: Our data support that alcohol sensitivity in Caucasians is genetically determined and suggest that a histamine-releasing effect of acetaldehyde represents a plausible biological mechanism. Furthermore, we present the first report of a clinically significant SNP within the acetaldehyde-metabolizing system in a Caucasian population.
Subject(s)
Acetaldehyde/metabolism , Alcoholic Beverages/adverse effects , Alcoholism/enzymology , Aldehyde Dehydrogenase/genetics , Drug Hypersensitivity/genetics , Ethanol/adverse effects , Adolescent , Adult , Aged , Aldehyde Dehydrogenase 1 Family , Aldehyde Dehydrogenase, Mitochondrial , Alleles , Denmark , Ethanol/metabolism , Ethanol/pharmacology , Genetic Predisposition to Disease , Genotype , Humans , Middle Aged , White PeopleABSTRACT
BACKGROUND/OBJECTIVES: Total homocysteine (tHcy) has been associated with increased risk of several diseases in the general population. It is not clear whether these associations are causal. A less healthy lifestyle as well as a less favorable biological risk factor profile have been related to increased tHcy in cross-sectional studies. In addition, the methylenetetrahydrofolate reductase (MTHFR) C677T gene variant is an important determinant of elevated tHcy. The main objective of the study was to examine the effect of changes in biological risk factors and lifestyle on tHcy in relation to MTHFR C677T genotype. SUBJECTS/METHODS: The study is a population-based study including 1805 men and women aged 30-60 years participating in a health examination at baseline (1999-2001) and at a 5-year follow-up examination. RESULTS: Changes in tHcy were not associated with changes in dietary habits, physical activity, smoking status, coffee, tea, total alcohol or wine consumption. An inverse relationship was observed between changes in tHcy and changes in the intake of beer in TT individuals but not in CC/CT individuals (P (interaction)=0.01). In addition, changes in tHcy were positively associated with changes in several biological risk factors, such as waist circumference, diastolic blood pressure, total cholesterol and LDL cholesterol (P<0.01). The association between waist circumference and MTHFR genotype seemed stronger in TT individuals than in CC/CT individuals (P (interaction)=0.03). CONCLUSIONS: tHcy was not influenced by lifestyle changes except for the inverse association between beer consumption and tHcy observed in TT individuals. This suggests that tHcy is not a mediator in the causal pathway between lifestyle and lifestyle-related diseases such as cardiovascular disease in accordance with results of recent randomized trials. However, tHcy was related to changes in several biological risk factors, suggesting that tHcy may be a good predictor or marker of disease.
Subject(s)
Beer , Homocysteine/blood , Life Style , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Adult , Alcohol Drinking , Biomarkers/blood , Blood Pressure/physiology , Cardiovascular Diseases/blood , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/genetics , Cholesterol/blood , Coffee , Cross-Sectional Studies , Denmark , Feeding Behavior , Female , Follow-Up Studies , Genetic Predisposition to Disease , Genotype , Humans , Male , Middle Aged , Risk Factors , Smoking , Tea , Waist CircumferenceABSTRACT
AIM: To study the relative contribution of genetic and environmental factors to the correlation between exhaled nitric oxide (FeNO), airway responsiveness, airway obstruction, and serum total immunoglobulin E (IgE). METHODS: Within a sampling frame of 21,162 twin subjects, 20-49 years of age, from the Danish Twin Registry, a total of 575 subjects (256 intact pairs and 63 single twins) who either themselves and/or their co-twins reported a history of asthma at a nationwide questionnaire survey, were clinically examined. Traits were measured using standard techniques. Latent factor models were fitted to the observed data using maximum likelihood methods. RESULTS: Additive genetic factors explained 67% of the variation in FeNO, 43% in airway responsiveness, 22% in airway obstruction, and 81% in serum total IgE. In general, traits had genetically and environmentally distinct variance structures. The most substantial genetic similarity was observed between FeNO and serum total IgE, genetic correlation (rhoA) = 0.37, whereas the strongest environmental resemblance was observed between airway responsiveness and airway obstruction, specific environmental correlation (rhoE) = -0.46, and between FeNO and airway responsiveness, rhoE = 0.34. CONCLUSIONS: Asthma is a complex disease characterized by a set of etiologically heterogeneous biomarkers, which likely constitute diverse targets of intervention.
Subject(s)
Asthma/genetics , Asthma/physiopathology , Environmental Exposure , Adult , Asthma/blood , Female , Humans , Immunoglobulin E/blood , Male , Phenotype , Respiratory Function Tests , Surveys and QuestionnairesABSTRACT
OBJECTIVE: To investigate the impact of HIV co-infection on mortality in patients infected with hepatitis C virus (HCV). METHODS: From a nationwide Danish database of HCV-infected patients, we identified individuals diagnosed with HCV subsequent to an HIV diagnosis. For each co-infected patient, four control HCV patients without HIV were matched on age, gender and year of HCV diagnosis. Data on comorbidity, drug abuse, alcoholism and date of death were extracted from two healthcare databases. We constructed Kaplan-Meier curves and used Cox regression analyses to estimate mortality rate ratios (MRRs), controlling for comorbidity. RESULTS: We identified 483 HCV-HIV co-infected and 1932 HCV mono-infected patients, yielding 2192 and 9894 person-years of observation with 129 and 271 deaths, respectively. The 5-year probability of survival was 0.74 [95% confidence interval (CI) 0.69-0.80] for HCV-HIV co-infected patients and 0.87 (95% CI 0.85-0.89) for HCV mono-infected patients. Co-infection was associated with substantially increased mortality (MRR 2.1, 95% CI 1.7-2.6). However, prior to the first observed decrease in CD4 counts to below 300 cells/muL, HIV infection did not increase mortality in HCV-infected patients (MRR 0.9, 95% CI 0.5-1.50). CONCLUSIONS: HIV infection has a substantial impact on mortality among HCV-infected individuals, mainly because of HIV-induced immunodeficiency.
Subject(s)
AIDS-Related Opportunistic Infections/mortality , HIV-1 , Hepatitis C, Chronic/mortality , Adult , Cohort Studies , Female , Humans , Male , Prognosis , Survival AnalysisABSTRACT
AIMS/HYPOTHESIS: The cluster of obesity, insulin resistance, dyslipidaemia and hypertension, called the metabolic syndrome, has been suggested as a risk factor for cardiovascular disease and type 2 diabetes. The aim of the present study was to evaluate whether there are common genetic and environmental factors influencing this cluster in a general population of twin pairs. MATERIALS AND METHODS: A multivariate genetic analysis was performed on nine endophenotypes associated with the metabolic syndrome from 625 adult twin pairs of the GEMINAKAR study of the Danish Twin Registry. RESULTS: All endophenotypes showed moderate to high heritability (0.31-0.69) and small common environmental variance (0.05-0.21). In general, genetic and phenotypic correlations between the endophenotypes were strong only within sets of physiologically similar endophenotypes, but weak to moderate for other pairs of endophenotypes. However, moderate correlations between insulin resistance indices and either obesity-related endophenotypes or triacylglycerol levels indicated that some common genetic backgrounds are shared between those components. CONCLUSIONS/INTERPRETATION: We demonstrated that, in a general population, the endophenotypes associated with the metabolic syndrome apparently do not share a substantial common genetic or familial environmental background.
Subject(s)
Metabolic Syndrome/genetics , Adult , Aged , Blood Pressure , Body Mass Index , Environment , Female , Humans , Insulin Resistance/genetics , Insulin Resistance/physiology , Lipids/blood , Lipoproteins/blood , Male , Metabolic Syndrome/etiology , Middle Aged , Obesity/genetics , Obesity/physiopathology , Phenotype , Twins, Dizygotic , Twins, MonozygoticABSTRACT
Surfactant protein D (SP-D) is a key regulator of pathogen-induced inflammation. SP-D is further involved in lipid homeostasis in mouse lung and circulation and recent data have demonstrated that the body mass index (BMI; in kg/m(2)) is influenced by genes in common with SP-D. The objective of the present study was to describe the association between serum SP-D and weight, waist circumference or BMI, and furthermore to observe body weight development in SP-D-deficient (Spd-/-) mice. As a part of the Danish population-based twin study (GEMINAKAR) on the metabolic syndrome, we analysed 1476 Danish twins for serum SP-D and investigated associations with weight, waist circumference and BMI by multiple regression analysis. Serum SP-D was significantly and inversely associated with weight (P = 0.001) and waist circumference in men (P < 0.001) and to BMI in both genders (P = 0.039 women, P < 0.001 men). The age-dependent increase in serum SP-D was most prominent in lean persons (BMI < 20). Spd-/- mice and wild-type mice were subjected to a feeding study and body weights were recorded in a time course over 24 weeks. Spd-/- mouse weight gain was significantly increased, with 90 mg/week (P < 0.0001) in males on normal chow. Fat percentage was significantly increased by 17% in the Spd-/- male mice (P = 0.003). We conclude, that there is an association between low levels or absent SP-D and obesity.
Subject(s)
Immunity, Innate/genetics , Obesity/immunology , Pulmonary Surfactant-Associated Protein D/deficiency , Weight Gain/immunology , Adolescent , Adult , Aged , Animals , Body Mass Index , Female , Humans , Male , Mice , Mice, Mutant Strains , Middle Aged , Obesity/genetics , Pulmonary Surfactant-Associated Protein D/genetics , Weight Gain/geneticsABSTRACT
Accumulating evidence implicates deficiencies in apolipoprotein D (ApoD) function and arachidonic acid signaling in schizophrenic disorders. We addressed two hypotheses in relation to ApoD: first, polymorphisms in the ApoD gene confer susceptibility to or are markers of disease, and, second, genetic variation in the ApoD is associated with long-term clinical outcome to antipsychotic treatment. We genotyped two single-nucleotide polymorphisms in the ApoD gene in 343 chronic patients with schizophrenia spectrum disorders (ICD-10) and 346 control subjects of Danish origin. We did not find ApoD alleles, genotypes or haplotypes to be associated with disease. However, we did find that long-term clinical outcome was associated with the ApoD polymorphism rs7659 (P = 0.041) following adjustment for lifetime clinical global impression, age at first admission and gender.
Subject(s)
Apolipoproteins/genetics , Polymorphism, Single Nucleotide , Schizophrenia/genetics , Adult , Antipsychotic Agents/therapeutic use , Apolipoproteins D , Case-Control Studies , DNA/analysis , Female , Genetic Predisposition to Disease , Humans , Logistic Models , Male , Middle Aged , Multivariate Analysis , Risk Factors , Schizophrenia/drug therapy , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: Reduction in total homocysteine (tHcy) may be clinically relevant in the prevention of cardiovascular disease (CVD) in the general population. OBJECTIVE: To examine the effects of changes in various lifestyle habits and lifestyle related biological CVD risk markers on changes in tHcy in relation to MTHFR(C677T) genotype. DESIGN: A 1 year follow-up study. SETTING: Copenhagen County, Denmark. SUBJECTS: Statistical analyses were based on a population-based sample of 915 men and women aged 30-60 years assessed to be at increased CVD risk at baseline and therefore offered lifestyle intervention and re-examination after one year. RESULTS: None of the studied lifestyle changes-- smoking, physical activity, dietary habits, and coffee, tea, and alcohol consumption-- was significantly associated with changes in tHcy, either overall, or in any of the MTHFR genotype subgroups. In addition, changes in tHcy did not differ between participants randomized to low- and high-intensity lifestyle intervention. However, the MTHFR TT genotype was associated with a significant decrease in tHcy compared with the CC/CT genotype in which an increase was observed. In addition, changes in tHcy were associated with changes in several of the biological CVD risk markers: weight, total cholesterol, HDL cholesterol, LDL cholesterol and systolic blood pressure. CONCLUSIONS: Our results indicate that tHcy may not be reduced by lifestyle changes; additionally, they suggest that tHcy may be related to biological CVD risk markers through a lifestyle independent pathway.
Subject(s)
Carbon-Nitrogen Ligases/genetics , Homocysteine/blood , Life Style , Adult , Alcohol Drinking , Carbon-Nitrogen Ligases/metabolism , Cardiovascular Diseases/blood , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/prevention & control , Coffee , Cross-Sectional Studies , Denmark , Exercise , Feeding Behavior , Female , Follow-Up Studies , Genotype , Humans , Male , Middle Aged , Risk Factors , Smoking , TeaABSTRACT
AIM: Recently, low-frequency polymorphisms in the coding region of the ghrelin gene were suggested to be involved in the aetiology of obesity and to modulate glucose-induced insulin secretion in different ethnic study groups. The objective of the present large study was to investigate whether the Leu72Met polymorphism of the ghrelin gene associates with features of the metabolic syndrome (MS) in the Danish population. METHODS: The variant was examined, using PCR-RFLP, in the DanMONICA cohort, a population-based sample of 2413 subjects. The metabolic syndrome was defined using the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) criteria. RESULTS: The allelic frequency of the Met72 allele was 8.6%[6.3-10.9%] in the MS group and 7.8%[7.0-8.6%] among subjects classified as not having the MS (NS). Similarly, there were no significant differences across the three groups of genotypes with respect to any of the examined variables, including BMI, waist circumference, fasting serum lipids, plasma glucose, serum insulin and HOMA estimates of insulin resistance and insulin secretion. CONCLUSION: In conclusion, the Leu72Met polymorphism of the ghrelin gene is not associated with the metabolic syndrome or related quantitative traits in the Danish population.
Subject(s)
Metabolic Syndrome/genetics , Peptide Hormones/genetics , Polymorphism, Restriction Fragment Length , Adult , Aged , Alleles , Cohort Studies , Denmark/epidemiology , Female , Gene Frequency/genetics , Genotype , Ghrelin , Humans , Leucine/genetics , Male , Metabolic Syndrome/epidemiology , Methionine/genetics , Middle AgedABSTRACT
AIM: The glucokinase regulatory protein gene is a candidate gene for Type 2 diabetes. This study reveals three new polymorphisms and examines the impact of one new and one known polymorphism on insulin secretion and parameters associated with the insulin resistance syndrome in Danish twins with different degrees of glucose tolerance. METHODS: Single nucleotide polymorphism detection was performed in 20 healthy subjects and in 20 subjects with Type 2 diabetes. The effect of the polymorphisms on lipid, glucose and insulin measures was studied in 566 same-sex twins aged 55-74 years. RESULTS: The new nucleotide (nt) 363 polymorphism was found only in subjects with impaired glucose tolerance and Type 2 diabetes. The nt 11216 polymorphism influenced insulin measured at 120 min during an oral glucose tolerance test (OGTT). Subjects with genotype C11216C/T11216C had 21% higher insulin values (P<0.05) than subjects with genotype T11216T. In twins discordant for this genotype, the C-allele was associated with significantly higher plasma insulin levels at all time points during the OGTT, higher beta-cell function and lower plasma glucose levels during the OGTT. CONCLUSION: The C-allele of nt 11216 polymorphism was associated with increased insulin secretion, and may therefore exert a potentially protective effect against Type 2 diabetes. This remains to be shown in a larger study population.
Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 2/genetics , Glucokinase/genetics , Insulin/metabolism , Polymorphism, Single Nucleotide/genetics , Aged , Denmark/epidemiology , Diabetes Mellitus, Type 2/enzymology , Diabetes Mellitus, Type 2/epidemiology , Female , Glucose Tolerance Test , Humans , Insulin/blood , Insulin Secretion , Male , Middle Aged , Polymerase Chain ReactionABSTRACT
OBJECTIVE: To examine the associations between various lifestyle factors--smoking habits, physical activity, dietary habits, coffee, tea, and alcohol consumption--and homocysteine (tHcy) in relation to MTHFR(C677T) genotype. DESIGN: Cross-sectional population-based study. SETTING: Residents of Copenhagen County, Denmark. SUBJECTS: A random sample of 6457 men and women aged 30-60 years drawn from the Civil Registration System and invited to a health examination in 1999-2001. A total of 2788 participants were included in the statistical analysis. MAIN OUTCOME MEASURES: tHcy was measured using a Fluorescent Polarization Immuno Assay. MTHFR-genotype was determined by PCR and RFLP analysis. Information about lifestyle factors was obtained from a self-administered questionnaire. RESULTS: Daily smoking, less healthy dietary habits, and coffee drinking were associated with elevated tHcy concentrations independent of other determinants. Wine consumption was related to tHcy in a J-shaped manner, whereas beer consumption was negatively associated with tHcy after multiple adjustments. Interaction was observed between smoking status and MTHFR-genotype, smoking status and sex, and beer consumption and age. The effect of smoking was more pronounced in persons with the TT genotype and in women. The effect of beer consumption was more pronounced at younger than at older ages. CONCLUSIONS: Smoking status, dietary habits, coffee intake, wine, and beer consumption were major lifestyle determinants of tHcy. Changes in these lifestyle factors may reduce tHcy concentrations, thereby lowering cardiovascular risk in the general population. SPONSORSHIP: Danish Medical Research Council, Danish Centre for Evaluation and Health Technology Assessment, and Danish Heart Foundation.
Subject(s)
Homocysteine/blood , Life Style , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Polymorphism, Restriction Fragment Length , Adult , Alcohol Drinking , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/prevention & control , Coffee , Cross-Sectional Studies , Denmark , Exercise/physiology , Feeding Behavior , Female , Genotype , Health Surveys , Humans , Male , Methylenetetrahydrofolate Reductase (NADPH2)/metabolism , Middle Aged , Risk Factors , Smoking , Surveys and Questionnaires , TeaABSTRACT
A genetic contribution to the development of osteoporosis is well documented. Although the association between the common allelic variation of apolipoprotein E (APOE), fracture risk, bone loss and bone mineral density (BMD) has been examined in several studies, the results of these investigations are contradictory. The aim of this study was to examine the association between polymorphisms of APOE, BMD of the lower forearm, quantitative ultrasound of the calcaneus and osteoporotic fractures in a population of postmenopausal women with hip or lower forearm fractures admitted to a department of orthopaedic surgery and age-matched controls from the population register. The APOE genotypes of 327 women were studied: 73 with lower forearm fractures, 43 with hip fractures and 211 age-matched controls. The participants were not receiving antiosteoporotic treatment. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was used to detect the APOE genotypes. Quantitative ultrasound was measured at the calcaneus. Bone mineral density (BMD) of the lower forearm was measured with dual-energy X-ray absorptiometry. The distributions of genotype frequencies in this study were: E2/E2: 0.3%; E2/E3: 16.5%; E2/E4: 2.5%; E3/E3: 54.7%; E3/E4: 24.2%; E4/E4: 1.8%. All subpopulations were in Hardy-Weinburg equilibrium. There was no association between bone mass parameters and the APOE allele groups. Logistic regression analysis did not show any association between fractures and APOE allele groups. In conclusion, this study showed no association between bone mass parameters (BMD, speed of sound (SOS), broadband ultrasound attenuation (BUA)), hip or lower forearm fracture and APOE genotypes in a population of postmenopausal women and age-matched controls.