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1.
Pharmacogenomics J ; 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34616002

RESUMO

Digoxin is characterized by a small therapeutic window and a QT-interval shortening effect. Moreover, it has been shown that the genetic variants of the nitric oxide synthase-1 adaptor protein (NOS1AP) gene are associated with QT-interval prolongation. We investigated whether the rs10494366 variant of the NOS1AP gene decreases the QT-interval shortening effect of digoxin in patients using this drug. We included 10,057 individuals from the prospective population-based cohort of the Rotterdam Study during a median of 12.2 (interquartile range (IQR) 6.7-18.1) years of follow-up. At study entry, the mean age was 64 years and almost 59% of participants were women. A total of 23,179 ECGs were longitudinally recorded, of which 334 ECGs were from 249 individuals on digoxin therapy. The linear mixed model analysis was used to estimate the effect of the rs10494366 variant on the association between digoxin use and QT-interval duration, adjusted for age, sex, RR interval, diabetes, heart failure, and history of myocardial infarction. In non-users of digoxin, the GG genotype was associated with a significant 6.5 ms [95% confidence interval (CI) 5.5; 7.5] longer QT-interval duration than the TT variant. In current digoxin users, however, the GG variant was associated with a significantly -23.9 [95%CI -29.5; -18.5] ms shorter mean QT-interval duration than in those with the TT variant with -15.9 [95%CI -18.7; -13.1]. This reduction was strongest in the high digoxin dose category [≥0.250 mg/day] with the GG genotype group, with -40.8 [95%CI -52.5; -29.2] ms changes compared to non-users. Our study suggests that the minor homozygous GG genotype group of the NOS1AP gene rs10494366 variant is associated with a paradoxical increase of the QT-interval shortening effect of digoxin in a population of European ancestry.

2.
Ned Tijdschr Geneeskd ; 1652021 07 08.
Artigo em Holandês | MEDLINE | ID: mdl-34346594

RESUMO

In this Commentary on a British study of congenital malformations after use of macrolide antibiotics by pregnant women with data from general practitioners, the importance of high-quality healthcare databases for pharmacovigilance is emphasized. The authors of the British study compared three groups during the study period January 1990 through June 2016: 104,605 children from mothers treated during pregnancy with a macrolide or penicillin, a group of 53,735 siblings, and 82,314 children whose mothers were treated with a macrolide before conception. A significantly increased risk of 55% of congenital malformations was seen for use of macrolides during the first semester in comparison to use of penicillins, especially cardiovascular malformations. Although this well-performed study is the largest up till now, some potential limitations are discussed such as potential exposure and outcome misclassification, as well as confounding by indication.


Assuntos
Macrolídeos , Gestantes , Antibacterianos/efeitos adversos , Criança , Atenção à Saúde , Feminino , Humanos , Macrolídeos/efeitos adversos , Penicilinas , Gravidez
3.
Ann Rheum Dis ; 80(5): 598-604, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34412027

RESUMO

OBJECTIVES: Vitamin K is hypothesised to play a role in osteoarthritis (OA) pathogenesis through effects on vitamin K-dependent bone and cartilage proteins, and therefore may represent a modifiable risk factor. A genetic variant in a vitamin K-dependent protein that is an essential inhibitor for cartilage calcification, matrix Gla protein (MGP), was associated with an increased risk for OA. Vitamin K antagonist anticoagulants (VKAs), such as warfarin and acenocoumarol, act as anticoagulants through inhibition of vitamin K-dependent blood coagulation proteins. VKAs likely also affect the functioning of other vitamin K-dependent proteins such as MGP. METHODS: We investigated the effect of acenocoumarol usage on progression and incidence of radiographic OA in 3494 participants of the Rotterdam Study cohort. We also examined the effect of MGP and VKORC1 single nucleotide variants on this association. RESULTS: Acenocoumarol usage was associated with an increased risk of OA incidence and progression (OR=2.50, 95% CI=1.94-3.20), both for knee (OR=2.34, 95% CI=1.67-3.22) and hip OA (OR=2.74, 95% CI=1.82-4.11). Among acenocoumarol users, carriers of the high VKORC1(BB) expression haplotype together with the MGP OA risk allele (rs1800801-T) had an increased risk of OA incidence and progression (OR=4.18, 95% CI=2.69-6.50), while this relationship was not present in non-users of that group (OR=1.01, 95% CI=0.78-1.33). CONCLUSIONS: These findings support the importance of vitamin K and vitamin K-dependent proteins, as MGP, in the pathogenesis of OA. Additionally, these results may have direct implications for the clinical prevention of OA, supporting the consideration of direct oral anticoagulants in favour of VKAs.


Assuntos
4-Hidroxicumarinas/efeitos adversos , Acenocumarol/efeitos adversos , Anticoagulantes/efeitos adversos , Indenos/efeitos adversos , Osteoartrite/epidemiologia , Vitamina K/antagonistas & inibidores , Idoso , Alelos , Proteínas de Ligação ao Cálcio/efeitos dos fármacos , Progressão da Doença , Proteínas da Matriz Extracelular/efeitos dos fármacos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Osteoartrite/induzido quimicamente , Osteoartrite/patologia , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Vitamina K/efeitos adversos , Vitamina K Epóxido Redutases/efeitos dos fármacos
4.
J Antimicrob Chemother ; 76(10): 2708-2716, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34312676

RESUMO

BACKGROUND: Macrolides are widely prescribed antibiotics for many different indications. However, there are concerns about adverse effects such as ototoxicity. OBJECTIVES: To investigate whether macrolide use is associated with tinnitus and hearing loss in the general population. METHODS: Cross-sectional (n = 4286) and longitudinal (n = 636) analyses were performed within the population-based Rotterdam Study. We investigated with multivariable logistic regression models the association between macrolides and tinnitus, and with multivariable linear regression models the association between macrolides and two different hearing thresholds (both ears, averaged over 0.25, 0.5, 1, 2, 4 and 8 kHz and 2, 4 and 8 kHz). Both regression models were adjusted for age, sex, systolic blood pressure, alcohol, smoking, BMI, diabetes, education level, estimated glomerular filtration rate and other ototoxic or tinnitus-generating drugs. Cumulative exposure to macrolides was categorized according to the number of dispensed DDDs and duration of action. RESULTS: In the fully adjusted model, ever use of macrolides was associated with a 25% higher likelihood of prevalent tinnitus (OR = 1.25; 95% CI 1.07-1.46). This association was more prominent in participants with a cumulative dose of more than 14 DDDs and among users of intermediate- or long-acting macrolides. Macrolide use in between both assessments was associated with more than a 2-fold increased risk on incident tinnitus. No general association between macrolides and hearing loss was observed. A borderline significant higher hearing threshold in very recent users (≤3 weeks) was found. CONCLUSIONS: Macrolide use was significantly associated with both prevalent and incident tinnitus. Macrolide-associated tinnitus was likely cumulative dose-dependent.

5.
J Endocr Soc ; 5(8): bvab092, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34195528

RESUMO

Context: Recent studies have shown that ß-blocker (BB) users have a decreased risk of fracture and higher bone mineral density (BMD) compared to nonusers, likely due to the suppression of adrenergic signaling in osteoblasts, leading to increased BMD. There is also variability in the effect size of BB use on BMD in humans, which may be due to pharmacogenomic effects. Objective: To investigate potential single-nucleotide variations (SNVs) associated with the effect of BB use on femoral neck BMD, we performed a cross-sectional analysis using clinical data, dual-energy x-ray absorptiometry, and genetic data from the Framingham Heart Study's (FHS) Offspring Cohort. We then sought to validate our top 4 genetic findings using data from the Rotterdam Study, the BPROOF Study, the Malta Osteoporosis Fracture Study (MOFS), and the Hertfordshire Cohort Study. Methods: We used sex-stratified linear mixed models to determine SNVs that had a significant interaction effect with BB use on femoral neck (FN) BMD across 11 gene regions. We also evaluated the association of our top SNVs from the FHS with microRNA (miRNA) expression in blood and identified potential miRNA-mediated mechanisms by which these SNVs may affect FN BMD. Results: One variation (rs11124190 in HDAC4) was validated in females using data from the Rotterdam Study, while another (rs12414657 in ADRB1) was validated in females using data from the MOFS. We performed an exploratory meta-analysis of all 5 studies for these variations, which further validated our findings. Conclusion: This analysis provides a starting point for investigating the pharmacogenomic effects of BB use on BMD measures.

6.
ERJ Open Res ; 7(2)2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34195251

RESUMO

Observational studies report a reduction of COPD exacerbations in patients treated with ß-blockers. In contrast, the Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease (BLOCK COPD) randomised controlled trial which excluded COPD patients with cardiovascular conditions showed an increase in COPD exacerbations. It is unclear whether this discrepancy could be explained by underlying cardiovascular comorbidity. We examined whether the association between use of ß-blockers and risk of COPD exacerbations differed between patients with and without a cardiovascular indication for ß-blockers use. Within the Rotterdam Study, we followed COPD subjects until the first COPD exacerbation, or end of follow-up. Cardiovascular indication for ß-blockers use was defined as a history of hypertension, coronary heart disease, atrial fibrillation and/or heart failure at baseline. The association between ß-blockers use and COPD exacerbations was assessed using Cox proportional hazards models adjusted for age, sex, smoking, incident cardiovascular disease (i.e. heart failure, hypertension, atrial fibrillation and/or coronary heart disease during follow-up), respiratory drugs and nitrates. In total, 1312 COPD patients with a mean age of 69.7±9.2 years were included. In patients with a cardiovascular indication (n=755, mean age of 70.4±8.8 years), current use of cardioselective ß-blockers was significantly associated with a reduced risk of COPD exacerbations (HR 0.69, 95% CI 0.57-0.85). In contrast, in subjects without a cardiovascular indication (n=557, mean age of 68.8±9.7 years), current use of cardioselective ß-blockers was not associated with an altered risk of COPD exacerbations (HR 0.94, 95% CI 0.55-1.62). Use of cardioselective ß-blockers reduced the risk of exacerbations in COPD patients with concomitant cardiovascular disease. Therefore, the potential benefits of ß-blockers might be confined to COPD patients with cardiovascular disease.

7.
ERJ Open Res ; 7(3)2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34262968

RESUMO

Aim: The aim of this study was to investigate occurrence and determinants of asthma exacerbations in an ageing general population. Methods: Subjects aged 45 years or above with physician-diagnosed asthma in the Rotterdam Study, a population-based prospective cohort from January 1991 to May 2018, were assessed for asthma exacerbations. Exacerbations were defined as acute episodes of worsening asthma treated with oral corticosteroids. Cox proportional hazards analysis was used to investigate risk factors for a future exacerbation. Results: Out of 763 participants with asthma (mean age 61.3 years, 69.2% female), 427 (56.0%) experienced at least one exacerbation, in a mean follow-up time of 13.9 years. The mean annual exacerbation rate was 0.22. Most exacerbations occurred during winter months. Risk factors for exacerbations were a history of previous exacerbations (HR 4.25; 95% CI 3.07-5.90, p<0.001)), respiratory complaints (HR 2.18; 95% CI 1.48-3.21, p<0.001), airflow obstruction (HR 1.52; 95% CI 1.07-2.15, p=0.019), obesity (HR 1.38; 95% CI 1.01-1.87, p=0.040) and depressive symptoms (HR 1.55; 95% CI 1.05-2.29, p=0.027). Compared to those not using respiratory medication, we observed higher hazard ratios for those on short-acting ß2-agonists (SABA, i.e. rescue medication) only (HR 3.08, 95% CI 1.61-5.90, p=0.001) than those on controller medication (HR 2.50, 95% CI 1.59-3.92, p<0.001). Conclusion: Many older adults with asthma suffer from at least one severe exacerbation. Previous exacerbations, use of SABA without concomitant controller medication, respiratory complaints, obesity, airway obstruction and depression are independent risk factors for exacerbations.

8.
Psychooncology ; 30(10): 1699-1710, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34004035

RESUMO

OBJECTIVE: Clinical studies showing that non-central nervous system cancer patients can develop cognitive impairment have primarily focused on patients with specific cancer types and intensive treatments. To better understand the course of cognitive function in the general population of cancer patients, we assessed cognitive trajectories of patients before and after cancer diagnosis in a population-based setting. METHODS: Between 1989 and 2014, 2211 participants from the population-based Rotterdam study had been diagnosed with cancer of whom 718 (32.5%) had undergone ≥1 cognitive assessment before and after diagnosis. Cognition was measured every 3 to 6 years using a neuropsychological battery. Linear mixed models were used to compare cognitive trajectories of patients before and after diagnosis with those of age-matched cancer-free controls (1:3). RESULTS: Median age at cancer diagnosis was 70.3 years and 47.1% were women. Most patients (68.1%) had received local treatment only. Cognitive trajectories of patients before and after cancer diagnosis were largely similar to those of controls. After diagnosis, the largest difference was found on a memory test (patients declined with 0.14 units per year on the Word Learning Test: delayed recall [95% CI = -0.35; 0.07] and controls with 0.09 units [95% CI = -0.18;-0.00], p for difference = .59). CONCLUSIONS: In this longitudinal cohort, cancer did not appear to alter the trajectory of change in cognitive test results over time from that seen in similar individuals without cancer, although most cancer patients did not receive systemic therapies. Future studies should focus on identifying subgroups of patients who are at high risk for developing cognitive impairment.

9.
Thorax ; 76(11): 1150-1153, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33859051

RESUMO

Patients with advanced non-small-cell lung cancer who are treated with pemetrexed display a wide variation in clinical response and toxicity. In this prospective, multicentre cohort study, we investigated the association with treatment effectiveness and toxicity of 10 polymorphisms in nine candidate genes, covering the folate pathway (MTHFR), cell transport (SLC19A1/ABCC2/ABCC4), intracellular metabolism (FPGS/GGH) and target enzymes (TYMS/DHFR/ATIC) of pemetrexed. Adjusted for sex, ECOG performance score and disease stage, the association between ATIC (rs12995526) and overall survival (HR 1.59, 95% CI 1.06 to 2.39) was significant. Regarding toxicity, this ATIC polymorphism was significantly associated with severe laboratory (p=0.014) and clinical (p=0.016) chemotherapy-related adverse events, severe neutropenia (p=0.007) and all-grade diarrhoea (p=0.034) in multivariable analyses.

10.
Front Pharmacol ; 12: 618208, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33854433

RESUMO

Background: Whether liraglutide use improves cardiometabolic risk factors in different subsets of subjects with coronary artery disease (CAD) remains unclear. In a systematic review and meta-analysis, we quantified the effects of liraglutide on cardiometabolic risk profile in subjects with CAD with or without type 2 diabetes mellitus (T2D). Methods: Online database searches were conducted in PubMed, Scopus, EMBASE, Web of Science, Cochrane library, and Google Scholar from incept up to 15th January 2021. We identified randomized controlled trials (RCTs) assessing the effects of liraglutide compared to placebo on cardiometabolic risk profile. We used the random- or fixed-effect models to pool the weighted mean differences (WMDs) and 95% confidence intervals (CIs). Results: Out of a total of 7,320 citations, six articles (seven RCTs) with 294 subjects with CAD (mean age, 61.21 years; 19% women) were included. Our findings presented as WMD and 95% CI showed a statistical significant decrease in hemoglobin A1c (HbA1c) [-0.36%; -0.47; -0.26, p < 0.001; I 2 = 0.0% (with 6 RCTs)], body mass index (BMI) [-0.61 kg/m2; -1.21; -0.01, p = 0.047; I 2 = 72.2% (with five RCTs)], and waist circumference [-2.41 cm; -3.47; -1.36, p < 0.001; I 2 = 0.0% (with three RCTs)]. Through a set of subgroup analyses, we found a significant reduction in BMI in CAD patients with T2D [WMD = -1.06; 95% CI, -1.42, -0.70, p < 0.001; I 2 = 0.0% (with three RCTs)] compared to CAD only patients [WMD = -0.08; 95% CI, -0.45, 0.29, p = 0.66; I 2 = 0.0% (with two RCTs)] in the liraglutide group compared with the placebo group. No significant changes in heart rate, blood pressure, and lipid profiles were observed. Conclusions: Among people with established CAD, liraglutide significantly improved HbA1c, BMI, and waist circumference values. The effect of liraglutide on BMI was more robust in individuals with T2D compared to those without.

11.
ERJ Open Res ; 7(1)2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33718493

RESUMO

Sarcopenia is a heterogeneous skeletal muscle disorder involving the loss of muscle mass and function. However, the prevalence of sarcopenia based on the most recent definition remains to be determined in older people with chronic airway diseases. The aim was to evaluate sarcopenia prevalence and association with chronic airway diseases and its lung function in an older population, using the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) criteria. We performed a cross-sectional analysis in 5082 participants (mean age 69.0±8.8 years, 56% females) from the Rotterdam Study. Participants with interpretable spirometry and an available assessment of sarcopenia were included. The appendicular skeletal muscle mass index (ASMI) and handgrip strength (HGS) were assessed using dual-energy X-ray absorptiometry (DXA) and a hydraulic hand dynamometer, respectively. We analysed the association between sarcopenia and chronic airway diseases by using regression models adjusted for age, sex, smoking status, total fat percentage and other relevant confounders. Participants with chronic airway diseases had higher prevalence of probable sarcopenia (12.0%, 95% CI 10.2-13.8) and confirmed sarcopenia (3.0%, 95% CI 2.1-3.9) than without. Chronic airway diseases were associated with "probable sarcopenia" (OR 1.28, 95% CI 1.02-1.60), "confirmed sarcopenia" (OR 2.13, 95% CI 1.33-3.43), reduced HGS (ß -0.51 (-0.90--0.11)) and reduced ASMI (ß -0.19 (-0.25--0.14)). Forced expiratory volume in 1 s <80% was associated with lower HGS (ß -1.03 (-1.75--0.31)) and lower ASMI (ß -0.25 (-0.36--0.15)) than forced expiratory volume in 1 s ≥80%. Sarcopenia was prevalent and associated with chronic airway diseases among older population. These results suggest the need for early diagnosis of sarcopenia in older people with chronic airway diseases by applying EWGSOP2 recommendations.

12.
ERJ Open Res ; 7(1)2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33748261

RESUMO

Background: Epigenetics may play an important role in the pathogenesis of lung diseases. However, little is known about the epigenetic factors that influence impaired gas exchange at the lung. Aim: To identify the epigenetic signatures of the diffusing capacity of the lung measured by carbon monoxide uptake (the diffusing capacity of the lung for carbon monoxide (D LCO)). Methods: An epigenome-wide association study (EWAS) was performed on diffusing capacity, measured by carbon monoxide uptake (D LCO) and per alveolar volume (V A) (as D LCO/V A), using the single-breath technique in 2674 individuals from two population-based cohort studies. These were the Rotterdam Study (RS, the "discovery panel") and the Framingham Heart Study (FHS, the "replication panel"). We assessed the clinical relevance of our findings by investigating the identified sites in whole blood and by lung tissue specific gene expression. Results: We identified and replicated two CpG sites (cg05575921 and cg05951221) that were significantly associated with D LCO/V A and one (cg05575921) suggestively associated with D LCO. Furthermore, we found a positive association between aryl hydrocarbon receptor repressor (AHRR) gene (cg05575921) hypomethylation and gene expression of exocyst complex component 3 (EXOC3) in whole blood. We confirmed that the expression of EXOC3 in lung tissue is positively associated with D LCO/V A and D LCO. Conclusions: We report on epigenome-wide associations with diffusing capacity in the general population. Our results suggest EXOC3 to be an excellent candidate, through which smoking-induced hypomethylation of AHRR might affect pulmonary gas exchange.

13.
Pharmacoepidemiol Drug Saf ; 30(7): 952-959, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33675258

RESUMO

PURPOSE: Current guidelines have no sex-specific dosage advice for metoprolol. To evaluate whether women and men are prescribed the same dose a cohort analysis was performed in the population-based Rotterdam Study (RS). Results were replicated in the Integrated Primary Care Information (IPCI) database of automated general practice data. METHODS: The mean daily starting doses of metoprolol in both sexes were compared with independent-samples t-tests and a linear regression analysis was used to adjust in the RS for co-variables, notably, cardiovascular comorbidity, migraine, age, SBP, DBP, BMI, socioeconomic status, use of other antihypertensive drugs, smoking, and alcohol. In the IPCI-database, adjustment was for age only. RESULTS: The mean daily starting dose was statistically significantly lower in women than in men in both the RS and IPCI database, with a mean difference of 4.8 mg (95%CI -7.8, -1.8) and 4.6 mg (95%CI -5.3,-4.0), respectively. Statistical significance remained after adjustment in both databases. CONCLUSIONS: Women received lower starting doses of metoprolol than men in two independent data collections despite non-sex specific cardiovascular guideline recommendations. This example of real-life pharmacotherapy can lead to a form of confounding by contraindication in pharmacoepidemiology.

14.
Sci Rep ; 11(1): 2794, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33531528

RESUMO

Underlying genetic determinants contribute to developing type 2 diabetes (T2D) future diseases. The present study aimed to identify which genetic variants are associated with the incident of the major T2D co-morbid disease. First, we conducted a discovery study by investigating the genetic associations of comorbid diseases within the framework of the Utrecht Cardiovascular Pharmacogenetic studies by turning information of > 25 years follow-up data of 1237 subjects whom were genotyped and included in the discovery study. We performed Cox proportional-hazards regression to examine associations between genetic variants and comorbid diseases including cardiovascular diseases (CVD), chronic eye disease, cancer, neurologic diseases and chronic kidney disease. Secondly, we replicated our findings in two independent cohorts consisting of 1041 subjects. Finally, we performed a meta-analysis by combining the discovery and two replication cohorts. We ascertained 390 (39.7%) incident cases of CVD, 182 (16.2%) of chronic eye disease, 155 (13.8%) of cancer, 31 (2.7%) of neurologic disease and 13 (1.1%) of chronic kidney disease during a median follow-up of 10.2 years. In the discovery study, we identified a total of 39 Single Nucleotide Polymorphisms (SNPs) associated with comorbid diseases. The replication study, confirmed that rs1870849 and rs8051326 may play a role in the incidence of chronic eye disease in T2D patients. Half of patients developed at least one comorbid disease, with CVD occurring most often and earliest followed by chronic eye disease. Further research is needed to confirm the associations of two associated SNPs with chronic eye disease in T2D.

15.
Clin Exp Allergy ; 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33428814

RESUMO

BACKGROUND: Inhaled corticosteroids (ICS) are a cornerstone of asthma treatment. However, their efficacy is characterized by wide variability in individual responses. OBJECTIVE: We investigated the association between genetic variants and risk of exacerbations in adults with asthma and how this association is affected by ICS treatment. METHODS: We investigated the pharmacogenetic effect of 10 single nucleotide polymorphisms (SNPs) selected from the literature, including SNPs previously associated with response to ICS (assessed by change in lung function or exacerbations) and novel asthma risk alleles involved in inflammatory pathways, within all adults with asthma from the Dutch population-based Rotterdam study with replication in the American GERA cohort. The interaction effects of the SNPs with ICS on the incidence of asthma exacerbations were assessed using hurdle models adjusting for age, sex, BMI, smoking and treatment step according to the GINA guidelines. Haplotype analyses were also conducted for the SNPs located on the same chromosome. RESULTS: rs242941 (CRHR1) homozygotes for the minor allele (A) showed a significant, replicated increased risk for frequent exacerbations (RR = 6.11, P < 0.005). In contrast, rs1134481 T allele within TBXT (chromosome 6, member of a family associated with embryonic lung development) showed better response with ICS. rs37973 G allele (GLCCI1) showed a significantly poorer response on ICS within the discovery cohort, which was also significant but in the opposite direction in the replication cohort. CONCLUSION: rs242941 in CRHR1 was associated with poor ICS response. Conversely, TBXT variants were associated with improved ICS response. These associations may reveal specific endotypes, potentially allowing prediction of exacerbation risk and ICS response.

16.
J Child Adolesc Psychopharmacol ; 31(3): 205-213, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33470894

RESUMO

Objectives: Numerous studies have examined determinants contributing to methylphenidate adherence and persistence, but these were mainly conducted in adults. These determinants are likely to be different in children as they usually rely on their parents to provide them with the care they need. The objective was to study child and family characteristics as determinants of methylphenidate adherence and persistence in children. Methods: The study population consists of 307 children from the Generation R Study in the Netherlands, who had at least one dispensing record of methylphenidate until the age of 16 years. Adherence was defined as a medication possession ratio ≥0.80 up to 2 years after treatment initiation. Persistence was defined as the duration of treatment until a discontinuation period of ≥6 months. Family and child characteristics were tested as determinants of adherence with multivariable logistic regression analysis. Persistence was evaluated using a Kaplan-Meier analysis. Results: Children of mothers with one child (adjusted odds ratio [OR]: 2.31, 95% confidence interval [CI]: 1.17-4.54) or of mothers with an average household income (compared to high) were more likely to be adherent (adjusted OR: 3.45, 95% CI: 1.43-8.31). Children who started treatment at the age of 12-16 years (compared to <12 years) (adjusted hazard ratio [HR]: 3.55, 95% CI: 2.54-4.98) and girls (adjusted HR: 1.44, 95% CI: 1.07-1.95) were more often nonpersistent. Conclusion: Both child and family characteristics may play a role in methylphenidate treatment adherence. Furthermore, gender and the start age of treatment were found to be associated with nonpersistence. These findings may be important for health care professionals when initiating methylphenidate treatment in children.

17.
Clin Nutr ; 40(3): 1199-1206, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32800386

RESUMO

BACKGROUND & AIMS: In the initial B-proof, we found inconsistent results of B vitamin supplementation. However, the debate regarding the effects of B vitamins on age-related diseases continues. Therefore, our aim was to investigate the long-term effects (5-7 years follow-up) of an intervention with folic acid and vitamin-B12 supplementation on fracture and cardiovascular disease risk. METHODS: Extended follow-up of the B-PROOF trial, a multi-center, double-blind randomized placebo-controlled trial designed to assess the effect of 2-3 years daily supplementation with folic acid (400 µg) and vitamin-B12 (500 µg) versus placebo (n = 2,919). Primary outcome was verified self-reported fracture incidence and secondary outcomes were self-reported cardiovascular endpoints, which were collected through a follow-up questionnaires Proportional hazard analyses was used for the effect of the intervention on risk of fracture(s) and logistic regression for the effect of the intervention on risk of cardiovascular disease. RESULTS: A total of 1,298 individuals (44.5%) participated in the second follow-up round with median of 54 months [51-58], (n = 662 and n = 636, treatment versus placebo group). Median age at baseline was 71.0 years [68.0-76.0] for both groups. No effect was observed of the intervention on osteoporotic fracture or any fracture risk after a follow-up (HR: 0.99, 95% CI: 0.62-1.59 and HR: 0.77; 95% CI: 0.50-1.19, respectively), nor on cardiovascular or cerebrovascular disease risk (OR: 1.05; 95%CI: 0.80-1.44 and OR: 0.85; 95%CI: 0.50-1.45, respectively). Potential interaction by baseline homocysteine concentration was observed for osteoporotic- and any fracture (p = 0.10 and 0.06 respectively), which indicated a significantly lower risk of any fracture in the treatment group with higher total homocysteine concentrations (>15.1 µmol/l). No age-dependent effects were present. CONCLUSIONS: This study supports and extends previous null-findings of the B-PROOF trial and shows that supplementation of folic acid and vitamin-B12 has no effect on fracture risk, nor on cardiovascular disease in older individuals over a longer follow-up period. However, B-vitamin supplementation may be beneficial in reducing fractures in individuals with high total homocysteine concentrations, a finding which needs to be replicated.

18.
Eur J Cancer Prev ; 30(5): 364-372, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-33369946

RESUMO

OBJECTIVES: Previous studies showed that high calcium intake may be associated with the reduced colorectal cancer (CRC) risk, but results were inconclusive. In this study, we evaluated whether calcium intake from diet and supplements, as well as the calcium levels itself, were associated with the CRC risk in middle-aged and older individuals. Also, we evaluated whether these associations were modified by genetic variation of calcium homeostasis. DESIGN: This study was embedded in the Rotterdam study, a prospective cohort study among adults aged 55 years and older without CRC at baseline, from the Ommoord district of Rotterdam, The Netherlands (N = 10 941). Effect modification by a predefined polygenetic risk score (PRS) from seven loci known to be associated with calcium concentrations, was evaluated. RESULTS: The incidence rate of CRC in the study population was 2.9 per 1000 person-years. Relative to the recommended dietary calcium intake, only higher than the recommended dietary calcium intake (≥1485 mg/day) was associated with a reduced risk of CRC [hazard ratio (HR), 0.66; 95% confidence interval (CI), 0.44-1.00]. No significant associations were found for calcium supplementation and only in the subgroup analysis, albumin-adjusted calcium levels were associated with an increased risk of CRC (HR = 1.11; 95% CI, 1.00-1.23). PRS showed effect modification in the association between calcium intake and CRC (P for interaction = 0.08). After stratification of PRS into low, intermediate and high, we found a lower CRC risk for low-weighted PRS per increase in calcium intake. CONCLUSION: There is no consistent association between calcium indices on CRC. However, the association between calcium intake and CRC may be modified by genetic variation associated with serum calcium concentrations that deserves further replication in other studies with different population.

19.
Front Oncol ; 10: 1700, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042813

RESUMO

Background: Atherosclerosis and cancer share multiple disease pathways. Yet, it is unclear if atherosclerosis is associated with a subsequent higher cancer risk. We determined the association of atherosclerotic calcification in the aortic arch, as proxy for systemic atherosclerosis, with the risk of cancer. Methods: Between 2003 and 2006, 2,404 participants (mean age: 69.5 years, 52.5% women) from the prospective population-based Rotterdam Study underwent computed tomography to quantify calcification in the aortic arch. Participants were followed for the onset of cancer, death, loss to follow-up, or January 1st, 2015, whichever came first. We computed sex-specific tertiles of aortic arch calcification volumes. Next, we examined the association between the volume and severity (i.e., tertiles) of aortic arch calcification and the risk of cancer using Cox proportional hazard models. Results: During a median (interquartile range) follow-up of 9.6 years (8.9-10.5), 348 participants were diagnosed with cancer. Participants with the greatest severity of aortic arch calcification had a higher risk of cancer [hazard ratio for the third tertile compared to the first tertile of aortic arch calcification volume in the total population is 1.39 (95% CI = 1.04-1.86)]. Conclusions: Individuals with the most severe aortic arch calcification had a higher risk of cancer. While this could reflect the impact of long-term exposure to shared risk factors, it might also point toward the co-occurrence of both conditions.

20.
Circ Genom Precis Med ; 13(5): 387-395, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32822252

RESUMO

BACKGROUND: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD. METHODS: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies. RESULTS: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A) were associated with longer PWD but lower AF risk. CONCLUSIONS: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.

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