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1.
Artigo em Inglês | MEDLINE | ID: mdl-33142077

RESUMO

RATIONALE: Individuals that will develop COPD could be identified at an early age before clinical manifestations appear. OBJECTIVE: We investigated risk of Clinical COPD 10years later in young adults from the general population with and without Early COPD with a focus on smoking exposure. METHODS: We included 14,870 individuals aged 20-100 from the Copenhagen General Population Study with spirometry 10years apart. Early COPD was defined as baseline FEV1/ FVC< LLN in individuals aged<50. Outcomes included Clinical COPD at final examination 10years later (chronic respiratory symptoms with FEV1/FVC<0.70 and FEV1<80% predicted) and acute exacerbation hospitalisations during follow-up. RESULTS: Among 5,497 individuals aged<50 at baseline with FEV1/FVC≥0.70, 104(3%) developed Clinical COPD 10years later; 4% had Early COPD in smokers with ≥10pack-years, 3% in smokers with <10pack-years, and 2% in never-smokers. Among smokers with ≥10pack-years, 24% developed Clinical COPD in those with versus 4% in those without Early COPD. Corresponding numbers were 10% and 1% in smokers with <10pack-years, and 3% and <1% in never-smokers, respectively. Among individuals with Early COPD, odds ratios for Clinical COPD 10years later were 7.77(95%CI:4.10-14.7) in smokers with ≥10pack-years and 8.56(4.92-14.9) in all smokers, while hazard ratios for acute exacerbation hospitalisations were 4.16(95%CI:1.66-10.5) and 4.33(1.89-9.93), respectively. Results were validated in the Copenhagen City Heart Study. CONCLUSIONS: Depending on amount of smoking exposure, less than 24% of young adults in the general population with Early COPD develop Clinical COPD 10 years later. A smoking exposure threshold for Early COPD should be re-considered, as younger individuals are less represented in those with high smoking exposure.

2.
Circulation ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33228395

RESUMO

Background: The high-density lipoprotein (HDL) hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors which failed to show significant reductions in cardiovascular events. Plasma levels of HDL-cholesterol (HDL-C) decline drastically during sepsis and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacologic inhibition of CETP would preserve HDL levels and decrease mortality in clinical cohorts and animal models of sepsis. Methods: We examined the effect of a gain-of-function variant in CETP (rs1800777, p.Arg468Gln) and a genetic score for decreased CETP function on 28-day sepsis survival using Cox proportional hazard models adjusted for age and sex in the UK Biobank (n=5,949), Identification of SNPs Predisposing to Altered Acute Lung Injury Risk (iSPAAR; n=882), Copenhagen General Population Study (n=2,068), Copenhagen City Heart Study (n=493), Early Infection (n=200), St. Paul's Intensive Care Unit 2 (n=203), and Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock studies (n=632). We then studied the effect of the CETP inhibitor anacetrapib in adult, female APOE*3-Leiden mice with or with human CETP expression using the cecal-ligation and puncture model of sepsis. Results: A fixed-effect meta-analysis of all 7 cohorts found that the CETP gain-of-function variant was significantly associated with increased risk of acute sepsis mortality (hazard ratio [95% confidence interval]: 1.44 [1.22-1.70], p<0.0001). In addition, a genetic score for decreased CETP function was associated with significantly decreased sepsis mortality in the UK Biobank (hazard ratio [95% confidence interval]: 0.77 [0.59-1.00] per 1 mmol/L increase in HDL-C) and iSPAAR cohorts (hazard ratio [95% confidence interval]: 0.60 [0.37-0.98] per 1 mmol/L increase HDL-C). APOE*3-Leiden.CETP mice treated with anacetrapib had preserved levels of HDL-C and apolipoprotein-AI and increased survival relative to placebo treatment (70.6% vs 35.3%, Log-rank p=0.03), while there was no effect of anacetrapib on the survival of APOE*3-Leiden mice which do not express CETP (50.0% vs 42.9%, Log-rank p=0.87). Conclusions: Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve HDL levels and improve outcomes for individuals with sepsis.

3.
Cancers (Basel) ; 12(11)2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33158149

RESUMO

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.

4.
Eur Heart J ; 41(41): 4024-4033, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33022702

RESUMO

AIMS: Dementia is a major global challenge for health and social care in aging populations. A third of all dementia may be preventable due to cardiovascular risk factors. Intensive multi-domain intervention trials targeting primarily cardiovascular risk factors show improved cognitive function in people at risk. Such interventions will, however, be expensive to implement in all individuals at risk and will represent unrealistic economic tasks for most societies. Therefore, a risk score identifying high-risk individuals is warranted. METHODS AND RESULTS: In 61 664 individuals from two prospective cohorts of the Danish general population, we generated 10-year absolute risk scores for all-cause dementia from cardiovascular risk factors and genetics. In both sexes, 10-year absolute risk of all-cause dementia increased with increasing age, number of apolipoprotein E (APOE) ɛ4 alleles, number of genome-wide association studies (GWAS) risk alleles, and cardiovascular risk factors. The highest 10-year absolute risks of all-cause dementia seen in smoking women with diabetes, low education, APOE ɛ44 genotype, and 22-31 GWAS risk alleles were 6%, 23%, 48%, and 66% in those aged 50-59, 60-69, 70-79, and 80-100, respectively. Corresponding values for men were 5%, 19%, 42%, and 60%, respectively. CONCLUSION: Ten-year absolute risk of all-cause dementia increased with age, APOE ɛ4 alleles, GWAS risk alleles, diabetes, low education, and smoking in both women and men. Ten-year absolute risk charts for dementia will facilitate identification of high-risk individuals, those who likely will benefit the most from an early intervention against cardiovascular risk factors.

5.
Thorax ; 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33109689

RESUMO

BACKGROUND: Vitamin D may regulate the innate immune system, and randomised controlled trials suggest a beneficial effect of vitamin D supplementation against acute respiratory tract infections. By using a Mendelian randomisation approach, we tested the hypothesis that low 25-hydroxyvitamin D is associated with increased risk of bacterial pneumonia in observational and genetic analyses. METHODS: We genotyped 116 335 randomly chosen white Danes aged 20 to 100 from the Copenhagen City Heart Study and Copenhagen General Population Study for plasma 25-hydroxyvitamin D decreasing genetic variants around CYP2R1 (rs117913124, rs12794714 and rs10741657), DHCR7 (rs7944926 and rs11234027), GEMIN2 (rs2277458) and HAL (rs3819817). Information on plasma 25-hydroxyvitamin D was available on 35 833 individuals. Individuals were followed from 1981 through 2018 for hospital diagnoses of bacterial pneumonias. RESULTS: During up to 38 years follow-up, we observed 6342 bacterial pneumonias in observational analyses and 13 916 in genetic analyses. In observational analyses, multivariable adjusted HR for bacterial pneumonias was 1.27 (95% CI: 1.16 to 1.40) for individuals with 25-hydroxyvitamin D<25 nmol/L compared with those with ≥25 nmol/L. In genetic analyses, the OR for bacterial pneumonia per 10 nmol/L lower plasma 25-hydroxyvitamin D was 1.12 (95% CI: 1.02 to 1.23) in Wald's ratio, 1.12 (95% CI: 1.04 to 1.20) in inverse-variance weighted, 1.63 (95% CI: 0.96 to 2.78) in MR-Egger and 1.15 (95% CI: 1.05 to 1.26) in weighted median instrumental variable analysis. This association was strongest for genetic variants around CYP2R1. There was no observational or genetic evidence to support that 25-hydroxyvitamin D is associated with risk of urinary tract infections, skin infections, sepsis or gastroenteritis, which were used as negative control outcomes. CONCLUSIONS: Low vitamin D is associated observationally and genetically with increased risk of bacterial pneumonias.

6.
Atherosclerosis ; 314: 10-17, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33129081

RESUMO

BACKGROUND AND AIMS: Children with a growth trajectory of overweight have higher levels of cardiovascular disease (CVD) risk factors than children with a normal-weight trajectory. However, less is known about how trajectories of body mass index (BMI) across the rest of the BMI spectrum relate to CVD risk factors and whether adult BMI affects these associations. Our aim was to examine associations between childhood BMI trajectories and adult CVD risk factors. METHODS: We included 2466 individuals with childhood weights and heights (ages 6-14) from the Copenhagen School Health Records Register and adult CVD risk factors (ages 20-81) from the Copenhagen City Heart Study. Associations between childhood BMI trajectories identified by latent class modelling and CVD risk factors were examined using generalized linear regression analyses with and without adjustment for adult BMI. Normal-weight and overweight were defined by growth references from the Centers for Disease Control and Prevention. RESULTS: We identified four childhood trajectories within the normal-weight spectrum and one trajectory of overweight. Compared to the trajectory with the lowest BMI level, several higher BMI trajectories were associated with worse circumference, HDL and glucose homeostasis in adulthood. The highest trajectory was additionally associated with higher total cholesterol and triglycerides. When adjusting for adult BMI, the higher BMI trajectories had lower waist circumference, blood pressure and triglycerides. CONCLUSIONS: Trajectories of BMI within the normal-weight range and in the overweight range are associated with a worse CVD risk profile than in the lowest BMI trajectory, and these associations are modifiable by growth after childhood.

7.
Atherosclerosis ; 312: 8-15, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32947224

RESUMO

BACKGROUND AND AIMS: Smoking causes cardiovascular disease. AHRR hypomethylation at the cg05575921 site is associated with active and former smoking status at baseline, and cumulative amount of tobacco smoked. We tested the hypothesis that AHRR cg05575921 hypomethylation as an epigenetic marker of smoking history predicts the risk of myocardial infarction in former smokers. METHODS: We included 10,510 individuals with methylation extent measurements and information on smoking status from the Copenhagen City Heart Study (CCHS), a prospective, cohort study of the general population carried out from 1991 to 2003. The endpoint myocardial infarction was retrieved from the national Danish Patient Registry and the national Danish Causes of Death Registry. RESULTS: For individuals in the 1st (lowest) quartile of AHRR cg05575921 methylation (≤49% methylation extent), 99% were ever smokers at baseline (active and former smokers combined) compared to 42% in the 4th (highest) quartile (>62% methylation extent). For former smokers, the cumulative incidence of myocardial infarction was higher in the lowest methylation extent (1st-50th percentile) compared to the highest methylation extent (51st-100th percentile). Compared to never smokers, the multivariable adjusted subhazard ratio for myocardial infarction was 1.09 (95%CI:0.88-1.35) for former smokers with the highest methylation degree, 1.38 (1.06-1.80) for active smokers with the highest methylation extent, 1.39 (1.08-1.78) for former smokers with the lowest methylation extent, and 1.61 (1.35-1.92) for active smokers with the lowest methylation extent. CONCLUSIONS: AHRR cg05575921 hypomethylation as an epigenetic marker of smoking history predicts risk of myocardial infarction, particularly in former smokers. Further, AHRR hypomethylation, regardless of smoking status, was associated with increased risk of myocardial infarction.

8.
Alzheimers Dement ; 2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32808727

RESUMO

INTRODUCTION: The mechanism behind the strong association between the ɛ2/ɛ3/ɛ4 apolipoprotein E gene (APOE) polymorphism and Alzheimer's disease is not well-characterized. Because low plasma levels of apoE associate with risk of dementia, genetic variants altering apoE levels in general may also associate with dementia. METHODS: The APOE gene was sequenced in 10,369 individuals, and nine amino acid-changing variants with frequencies ≥2/10,000 were further genotyped in 95,228 individuals. Plasma apoE levels were measured directly. RESULTS: Risk of all dementia and Alzheimer's disease (AD) increased with decreasing genetically determined apoE levels (P = 5 × 10-4 and P = 1 × 10-4 after APOE ɛ2/ɛ3/ɛ4 adjustment). Hazard ratios (95% confidence intervals) for all dementia and AD were 2.76 (1.39 to 5.47) and 4.92 (2.36 to 10.29) for the group with the genetically lowest apoE versus ɛ33. DISCUSSION: We found that genetically low apoE levels increase and genetically high levels decrease risk, beyond ɛ2/ɛ3/ɛ4. This underscores that dementia risk more likely relates to variants affecting levels of apoE.

9.
Eur Respir J ; 2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32817007

RESUMO

Complement C3 plays a role in asthma development and severity. We tested the hypothesis that high plasma complement C3 concentration was associated with high risk of asthma hospitalisations and exacerbations.We prospectively assessed the risk of asthma hospitalisations in 101 029 individuals from the Copenhagen General Population Study with baseline measurements of plasma complement C3, and genotyped for rs1065489, rs429608, and rs448260 determining levels of complement C3. Risk of asthma exacerbations was further assessed in 2248 individuals with allergic asthma.The multivariable adjusted hazard ratio of asthma hospitalisations was 1.23(95% confidence interval 1.04-1.45) for individuals in the highest tertile(>1.19 g·L-1) of plasma complement C3 compared with those in the lowest tertile(<1.03 g·L-1). The C3 rs448260 genotype was associated with risk of asthma hospitalisations with an observed hazard ratio of 1.17(1.06-1.28) for the CC genotype compared with the AA genotype. High plasma complement C3 was associated with high levels of blood eosinophils and IgE(p for trends ≤6·10-9), but only the SKIV2L rs429608 genotype was positively associated with blood eosinophil count(p=3·10-4) and level of IgE(p=3·10-4). In allergic asthma, the multivariable adjusted incidence rate ratio for risk of exacerbations was 1.69(1.06-2.72) for individuals in the highest plasma complement C3 tertile(>1.24 g·L-1) versus the lowest(<1.06 g·L-1).In conclusion, high concentration of plasma complement C3 was associated with high risk of asthma hospitalisations in the general population and with high risk of asthma exacerbations in individuals with allergic asthma. Our findings support a causal role of the complement system in asthma severity.

10.
Thorax ; 75(11): 944-954, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32820083

RESUMO

BACKGROUND: Different airflow limitation criteria are often used to diagnose COPD. We investigated head-to-head whether Global Initiative for Chronic Obstructive Lung Disease (GOLD) (FEV1/FVC <0.70) and four lower limit of normal (LLN) (FEV1/FVC

11.
Artigo em Inglês | MEDLINE | ID: mdl-32801009

RESUMO

BACKGROUND & AIMS: Almost one third of adults in the West have increased plasma levels of triglycerides. Even mild to moderate hypertriglyceridemia (2-10 mmol/L or 177-886 mg/dL) is associated with an increased risk of acute pancreatitis. However, it is not clear whether hypertriglyceridemia is a cause or result of acute pancreatitis. Lipoprotein lipase degrades plasma triglycerides. Variants in LPL, APOA5, APOC3, ANGPTL3, and ANGPTL4, which regulate the lipoprotein lipase pathway, result in increased or reduced plasma triglyceride levels. We investigated associations between these variants and acute pancreatitis in a study of the general population. METHODS: In a prospective cohort study, men and women randomly selected from the area of Copenhagen were invited to complete a questionnaire, undergo a physical examination, and provide blood samples for biochemical and genetic analyses, from 2003 through 2015. We obtained triglyceride measurements from 117,427 participants. We examined for 15 genetic variants that are associated with lipoprotein lipase function in DNA samples from 102,888 participants and analyzed data from 117,427 participants in observational analyses. Diagnoses of acute pancreatitis (970 diagnoses among participants in the genetic analysis and 527 among participants in the observational study) were obtained from Danish registries. We performed a 1-sample Mendelian randomization analysis in which specific variants were used as markers of the plasma level of triglycerides to determine the association between the plasma level of triglyceride and acute pancreatitis. We calculated unweighted, internally weighted, and externally weighted allele scores for each participant by adding numbers of triglyceride-increasing alleles. RESULTS: The highest genetic allele score correlated with a higher plasma level of triglycerides of 0.54 mmol/L (48 mg/dL). Among participants with the highest vs the lowest genetic allele score, the odds ratio for acute pancreatitis was 1.55 (95% CI, 1.08-2.23). Using instrumental variable analysis, integrating the effect of genotype on both triglycerides levels and risk of acute pancreatitis, we associated higher unweighted allele scores with an increased risk of acute pancreatitis (odds ratio [OR], 1.76; 95% CI, 1.16-2.65), as well as internally weighted higher allele scores (OR, 1.41; 95% CI, 1.01-1.97) and externally weighted higher allele scores (OR, 1.44; 95% CI, 1.01-2.04). Every 1 mmol/L (89 mg/dL) increase in triglycerides was observationally associated with an increase in OR of 1.09 (95% CI, 1.05-1.14) after multivariable adjustment. CONCLUSIONS: Based on an analysis of individuals with genetic variants associated with an increased level of triglycerides, via their effects on the lipoprotein lipase pathway, we associated an increased plasma levels of triglycerides with an increased risk of acute pancreatitis. Strategies to reduce plasma levels of triglycerides, by increasing lipoprotein lipase function, might be developed for prevention of acute pancreatitis.

12.
Eur J Prev Cardiol ; : 2047487320937491, 2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32646303

RESUMO

AIMS: The relevance of adherence to established dietary guidelines is repeatedly challenged. We hypothesised that non-adherence to established dietary guidelines is associated with an excess risk of cardiovascular, non-cardiovascular and all-cause mortality. METHODS: We studied 100,191 white adult Danes aged 20-100 years recruited in 2003-2015 and followed up until December 2018. During follow-up equalling 865,600 person-years, 9273 individuals died. Participants' diets were assessed at baseline by a food frequency questionnaire focusing on key foods defining a healthy diet according to Danish dietary guidelines. Individuals were divided into five categories ranging from very high to very low adherence to dietary guidelines and studied with Cox and Fine-Gray regression models. At study inclusion, we collected demographic and lifestyle characteristics by questionnaire, made a physical examination and took a blood sample. RESULTS: Cardiovascular, non-cardiovascular and all-cause mortality increased gradually with increasing non-adherence to dietary guidelines. Cardiovascular mortality was 30% higher (95% confidence interval 7-57%), non-cardiovascular mortality 54% higher (32-79%) and all-cause mortality 43% higher (29-59%) in individuals with very low adherence to dietary guidelines compared with those with very high adherence after adjustments for age, sex, education, income, smoking, leisure time physical activity and alcohol intake. Mortality risk estimates were similar in all strata of adjusted variables. CONCLUSION: Non-adherence to Danish food-based dietary guidelines is associated with up to 43% increased all-cause mortality in a dose-response manner. The mortality excess was seen for both cardiovascular and non-cardiovascular causes. The public has good reasons to have confidence in and to adhere to established dietary guidelines.

14.
Eur J Hum Genet ; 28(10): 1467-1475, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32514134

RESUMO

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR98/50 (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR98/50 of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR98/50 of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.

16.
Eur Respir J ; 56(3)2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32398304

RESUMO

Cystic fibrosis (CF) is caused by autosomal-recessive inheritance of a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR), up to 90% due to Phe508del mutation in the CFTR gene. We tested the hypothesis that CFTR Phe508del carriers have increased morbidity and mortality versus non-carriers in the general population.We genotyped 108 035 randomly selected white Danish individuals from the Copenhagen General Population Study (aged from 20-100 years) for CFTR Phe508del mutation (rs113993960). Risk of chronic bronchitis and airflow limitation was assessed cross-sectionally. Overall survival and risk of bronchiectasis, lung cancer, pneumonia, chronic rhinosinusitis, airway bleeding, spontaneous pneumothorax, respiratory failure, acute and chronic pancreatitis, liver cirrhosis, ileus, gastric and colorectal cancer, and male infertility were assessed prospectively during up to 15 years of follow-up (median: 9 years). A single individual was excluded due to homozygosity for CFTR Phe508del and known CF. No other individuals had diagnosed CF at baseline examination or during follow-up.Among the resulting 108 034 individuals, 105 176 (97%) were non-carriers and 2858 (3%) were carriers (i.e. were heterozygous for CFTR Phe508del). Overall survival was similar between carriers and non-carriers. Compared to non-carriers and with multivariable adjustment, carriers had an odds ratio (OR) of 1.31 (95% CI 1.16-1.48) for chronic bronchitis, a hazard ratio (HR) of 1.88 (95% CI 1.03-3.45) for bronchiectasis and 1.52 (95% CI 1.12-2.08) for lung cancer. Carriers did not differ from non-carriers concerning lung function or any other morbidity outcomes as mentioned above.In the general population, carriers of CFTR Phe508del have a normal lifespan but an increased risk of chronic bronchitis (1.3-fold), bronchiectasis (1.9-fold) and lung cancer (1.5-fold).

17.
J Infect Dis ; 222(8): 1353-1362, 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32417886

RESUMO

BACKGROUND: People with human immunodeficiency virus (PWH) may be at risk of nonalcoholic fatty liver disease. We compared the prevalence of moderate-to-severe hepatic steatosis (M-HS) in PWH with human immunodeficiency virus (HIV)-uninfected controls and determined risk factors for M-HS in PWH. METHODS: The Copenhagen Co-Morbidity in HIV Infection study included 453 participants, and the Copenhagen General Population Study included 765 participants. None had prior or current viral hepatitis or excessive alcohol intake. Moderate-to-severe hepatic steatosis was assessed by unenhanced computed tomography liver scan defined by liver attenuation ≤48 Hounsfield units. Adjusted odds ratios (aORs) were computed by adjusted logistic regression. RESULTS: The prevalence of M-HS was lower in PWH compared with uninfected controls (8.6% vs 14.2%, P < .01). In multivariable analyses, HIV (aOR, 0.44; P < .01), female sex (aOR, 0.08; P = .03), physical activity level (aOR, 0.09; very active vs inactive; P < .01), and alcohol (aOR, 0.89 per unit/week; P = .02) were protective factors, whereas body mass index (BMI) (aOR, 1.58 per 1 kg/m2; P < .01), alanine transaminase (ALT) (aOR, 1.76 per 10 U/L; P < .01), and exposure to integrase inhibitors (aOR, 1.28 per year; P = .02) were associated with higher odds of M-HS. CONCLUSIONS: Moderate-to-severe hepatic steatosis is less common in PWH compared with demographically comparable uninfected controls. Besides BMI and ALT, integrase inhibitor exposure was associated with higher prevalence of steatosis in PWH.

18.
Artigo em Inglês | MEDLINE | ID: mdl-32386205

RESUMO

AIMS : Prominent left ventricular trabeculations is a phenotypic trait observed in cardiovascular diseases. In the general population, the extent of left ventricular trabeculations is highly variable, yet it is unknown whether increased trabeculation is associated with adverse outcome. METHODS AND RESULTS : Left ventricular trabeculated mass (g/m2) was measured with contrast-enhanced cardiac computed tomography in 10 097 individuals from the Copenhagen General Population Study. The primary endpoint was a composite of major adverse cardiovascular events and defined as death, heart failure, myocardial infarction, or stroke. The secondary endpoints were the individual components of the primary endpoint. Cox regression models were adjusted for clinical parameters, medical history, electrocardiographic parameters, and cardiac chamber sizes. The mean trabeculated mass was 19.1 g/m2 (standard deviation 4.9 g/m2). During a median follow-up of 4.0 years (interquartile range 1.5-6.7), 710 major adverse cardiovascular events occurred in 619 individuals. Individuals with a left ventricular trabeculated mass in the highest quartile had a hazard ratio for major adverse cardiovascular events of 1.64 [95% confidence interval (CI) 1.30-2.08; P < 0.001] compared to those in the lowest quartile. Corresponding hazard ratios were 2.08 (95% CI 1.38-3.14; P < 0.001) for death, 2.63 (95% CI 1.61-4.31; P < 0.001) for heart failure, 1.08 (95% CI 0.56-2.08; P = 0.82) for myocardial infarction, and 1.07 (95% CI 0.72-1.57; P = 0.74) for stroke. CONCLUSION : Increased left ventricular trabeculation is independently associated with an increased rate of major adverse cardiovascular events in the general population.

19.
J Am Coll Cardiol ; 75(20): 2553-2566, 2020 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-32439005

RESUMO

BACKGROUND: Despite the greater prevalence of familial hypercholesterolemia (FH) in subjects with ischemic heart disease (IHD), premature IHD, and severe hypercholesterolemia (low-density lipoprotein ≥190 mg/dl), overall prevalence estimates are not available. OBJECTIVES: The aim of this study was to provide worldwide estimates of FH prevalence in subjects with IHD, premature IHD, and severe hypercholesterolemia compared with those in the general population. METHODS: In this systematic review and meta-analyses, Embase, PubMed, and the Web of Science were searched until June 3, 2019, for peer-reviewed papers and conference abstracts reporting heterozygous FH prevalence in nonfounder populations, revealing 104 studies eligible for inclusion. RESULTS: Estimates of FH prevalence were pooled using random-effects meta-analyses and were 0.32% (95% confidence interval [CI]: 0.26% to 0.39% [corresponding to 1:313]) among 10,921,310 unique subjects in the general population (33,036 patients with FH) on the basis of 44 studies, 3.2% (95% CI: 2.2% to 4.3% [1:31]) among 84,479 unique subjects with IHD (2,103 patients with FH) on the basis of 28 studies, 6.7% (95% CI: 4.9% to 8.7% [1:15]) among 31,316 unique subjects with premature IHD (1,471 patients with FH) on the basis of 32 studies, and 7.2% (95% CI: 4.6% to 10.8% [1:14]) among 17,728 unique subjects with severe hypercholesterolemia (920 patients with FH) on the basis of 7 studies. FH prevalence in the general population was similar using genetic versus clinical diagnoses. Seventeen of 195 countries (9%) in the world have reported FH prevalence for the general population, leaving 178 (91%) countries in the world with unknown prevalence. CONCLUSIONS: Compared with 1:313 among subjects in the general population, FH prevalence is 10-fold higher among those with IHD, 20-fold higher among those with premature IHD, and 23-fold higher among those with severe hypercholesterolemia. The prevalence of FH is unknown in 90% of countries in the world.

20.
Clin Chem ; 66(5): 676-685, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32255480

RESUMO

BACKGROUND: Whether low plasma 25-hydroxyvitamin D concentrations cause osteoporotic fractures is unclear. We tested the hypothesis that low plasma 25-hydroxyvitamin D concentrations are associated with increased risk of osteoporotic fractures using a Mendelian randomization analysis. METHODS: We genotyped 116 335 randomly chosen white Danish persons aged 20-100 years in 2 population-based cohort studies for plasma 25-hydroxyvitamin D decreasing genotypes in CYP2R1 (rs117913124 and rs12794714), DHCR7 (rs7944926 and rs11234027), GEMIN2 (rs2277458), and HAL (rs3819817); 35 833 had information on plasma 25-hydroxyvitamin D. We assessed risk of total, osteoporotic, and anatomically localized fractures from 1981 through 2017. Information on fractures and vital status was obtained from nationwide registries. RESULTS: During up to 36 years of follow-up, we observed 17 820 total fractures, 10 861 osteoporotic fractures, and 3472 fractures of hip or femur. Compared with individuals with 25-hydroxyvitamin D ≥ 50nmol/L, multivariable adjusted hazard ratios (95% CIs) for total fractures were 1.03 (0.97-1.09) for individuals with 25-49.9 nmol/L, 1.19 (1.10-1.28) for individuals with 12.5-24.9 nmol/L, and 1.39 (1.21-1.60) for individuals with 25-hydroxyvitamin D < 12.5 nmol/L. Corresponding hazard ratios were 1.07 (1.00-1.15), 1.25 (1.13-1.37), and 1.49 (1.25-1.77) for osteoporotic fractures and 1.09 (0.98-1.22), 1.37 (1.18-1.57), and 1.41 (1.09-1.81) for fractures of hip or femur, respectively. Hazard ratios per 1 increase in vitamin D allele score, corresponding to 3.0% (approximately 1.6 nmol/L) lower 25-hydroxyvitamin D concentrations, were 0.99 (0.98-1.00) for total fractures, 0.99 (0.97-1.00) for osteoporotic fractures, and 0.98 (0.95-1.00) for fractures of hip or femur. CONCLUSIONS: Low plasma 25-hydroxyvitamin D concentrations were associated with osteoporotic fractures; however, Mendelian randomization analysis provided no evidence supporting a causal role for vitamin D in the risk for osteoporotic fractures.


Assuntos
Fraturas por Osteoporose/etiologia , Fatores de Risco , Deficiência de Vitamina D/complicações , Vitamina D/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Variação Genética , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fraturas por Osteoporose/sangue , Fraturas por Osteoporose/genética , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Adulto Jovem
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