| 1. |
- Ganesh, Santhi K., et al.
(författare)
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Loci influencing blood pressure identified using a cardiovascular gene-centric array
- 2013
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 22:8, s. 1663-1678
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Tidskriftsartikel (refereegranskat)abstract
- Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped 50 000 single-nucleotide polymorphisms (SNPs) that capture variation in 2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P 2.4 10(6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
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| 2. |
- Eijkemans, Marianne, et al.
(författare)
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Physical activity, sedentary behaviour, and childhood asthma: a European collaborative analysis
- 2024
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Ingår i: BMJ Open Respiratory Research. - : BMJ PUBLISHING GROUP. - 2052-4439. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To investigate the associations of physical activity (PA) and sedentary behaviour in early childhood with asthma and reduced lung function in later childhood within a large collaborative study.Design Pooling of longitudinal data from collaborating birth cohorts using meta-analysis of separate cohort-specific estimates and analysis of individual participant data of all cohorts combined.Setting Children aged 0-18 years from 26 European birth cohorts.Participants 136 071 individual children from 26 cohorts, with information on PA and/or sedentary behaviour in early childhood and asthma assessment in later childhood.Main outcome measure Questionnaire-based current asthma and lung function measured by spirometry (forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity) at age 6-18 years.Results Questionnaire-based and accelerometry-based PA and sedentary behaviour at age 3-5 years was not associated with asthma at age 6-18 years (PA in hours/day adjusted OR 1.01, 95% CI 0.98 to 1.04; sedentary behaviour in hours/day adjusted OR 1.03, 95% CI 0.99 to 1.07). PA was not associated with lung function at any age. Analyses of sedentary behaviour and lung function showed inconsistent results.Conclusions Reduced PA and increased sedentary behaviour before 6 years of age were not associated with the presence of asthma later in childhood.
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| 3. |
- Manzoni, Claudia, et al.
(författare)
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Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia
- 2024
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Ingår i: American Journal of Human Genetics. - 0002-9297. ; 111:7, s. 1316-1329
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Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10−12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10−12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10−8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.
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| 4. |
- Ostergaard, Anna, et al.
(författare)
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The Prognostic Effect of IKZF1 Deletions in ETV6:: RUNX1 and High Hyperdiploid Childhood Acute Lymphoblastic Leukemia
- 2023
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Ingår i: HemaSphere. - 2572-9241. ; 7:5, s. 875-875
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Tidskriftsartikel (refereegranskat)abstract
- IKZF1 deletions are an established prognostic factor in childhood acute lymphoblastic leukemia (ALL). However, their relevance in patients with good risk genetics, namely ETV6::RUNX1 and high hyperdiploid (HeH), ALL remains unclear. We assessed the prognostic impact of IKZF1 deletions in 939 ETV6::RUNX1 and 968 HeH ALL patients by evaluating data from 16 trials from 9 study groups. Only 3% of ETV6::RUNX1 cases (n = 26) were IKZF1-deleted; this adversely affected survival combining all trials (5-year event-free survival [EFS], 79% versus 92%; P = 0.02). No relapses occurred among the 14 patients with an IKZF1 deletion treated on a minimal residual disease (MRD)-guided protocols. Nine percent of HeH cases (n = 85) had an IKZF1 deletion; this adversely affected survival in all trials (5-year EFS, 76% versus 89%; P = 0.006) and in MRD-guided protocols (73% versus 88%; P = 0.004). HeH cases with an IKZF1 deletion had significantly higher end of induction MRD values (P = 0.03). Multivariate Cox regression showed that IKZF1 deletions negatively affected survival independent of sex, age, and white blood cell count at diagnosis in HeH ALL (hazard ratio of relapse rate [95% confidence interval]: 2.48 [1.32-4.66]). There was no evidence to suggest that IKZF1 deletions affected outcome in the small number of ETV6::RUNX1 cases in MRD-guided protocols but that they are related to higher MRD values, higher relapse, and lower survival rates in HeH ALL. Future trials are needed to study whether stratifying by MRD is adequate for HeH patients or additional risk stratification is necessary.
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| 5. |
- van Schie, Rianne M F, et al.
(författare)
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Loading and maintenance dose algorithms for phenprocoumon and acenocoumarol using patient characteristics and pharmacogenetic data
- 2011
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 32:15, s. 1909-1917
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Polymorphisms in CYP2C9 and VKORC1 influence patients' phenprocoumon (PHE) and acenocoumarol (ACE) dose requirements. To provide physicians with tools to estimate the patient's individual dose, we aimed to develop algorithms for PHE and ACE. METHODS AND RESULTS: In two Dutch anticoagulation clinics, data on age, sex, height, weight, co-medication, coumarin derivative doses, and international normalized ratio values were obtained from 624 patients taking PHE and 471 taking ACE. Single nucleotide polymorphisms relevant to coumarin derivative dosing on the CYP2C9 and VKORC1 genes were determined. Using multiple linear regression, we developed genotype-guided and non-genotype-guided algorithms to predict the maintenance dose with patient characteristics and genetic information. In addition, loading doses were derived from the calculated maintenance doses. We performed external validation in an independent data set with 229 PHE and 168 ACE users. CYP2C9 and VKORC1 genotype, weight, height, sex, age, and amiodarone use contributed to the maintenance dose of PHE and ACE. The genotype-guided algorithms explained 55.9% (PHE) and 52.6% (ACE) of the variance of the maintenance dose, the non-genetic algorithms 17.3% (PHE) and 23.7% (ACE). Validation in an independent data set resulted in an explained variation of 59.4% (PHE) and 49.0% (ACE) for the genotype-guided algorithms and for 23.5% (PHE) and 17.8% (ACE) for the non-genotype-guided algorithms, without height and weight as parameters. CONCLUSION: To our knowledge, these are the first genotype-guided loading and maintenance dose algorithms for PHE and ACE using large cohorts. The utility of these algorithms will be tested in randomized controlled trials.
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| 6. |
- Enshaei, Amir, et al.
(författare)
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A validated novel continuous prognostic index to deliver stratified medicine in pediatric acute lymphoblastic leukemia
- 2020
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 135:17, s. 1438-1446
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Tidskriftsartikel (refereegranskat)abstract
- Risk stratification is essential for the delivery of optimal treatment in childhood acute lymphoblastic leukemia. However, current risk stratification algorithms dichotomize variables and apply risk factors independently, which may incorrectly assume identical associations across biologically heterogeneous subsets and reduce statistical power. Accordingly, we developed and validated a prognostic index (PIUKALL) that integrates multiple risk factors and uses continuous data. We created discovery (n = 2405) and validation (n = 2313) cohorts using data from 4 recent trials (UKALL2003, COALL-03, DCOG-ALL10, and NOPHO-ALL2008). Using the discovery cohort, multivariate Cox regression modeling defined a minimal model including white cell count at diagnosis, pretreatment cytogenetics, and end-of-induction minimal residual disease. Using this model, we defined PIUKALL as a continuous variable that assigns personalized risk scores. PIUKALL correlated with risk of relapse and was validated in an independent cohort. Using PIUKALL to risk stratify patients improved the concordance index for all end points compared with traditional algorithms. We used PIUKALL to define 4 clinically relevant risk groups that had differential relapse rates at 5 years and were similar between the 2 cohorts (discovery: low, 3% [95% confidence interval (CI), 2%-4%]; standard, 8% [95% CI, 6%-10%]; intermediate, 17% [95% CI, 14%-21%]; and high, 48% [95% CI, 36%-60%; validation: low, 4% [95% CI, 3%-6%]; standard, 9% [95% CI, 6%-12%]; intermediate, 17% [95% CI, 14%-21%]; and high, 35% [95% CI, 24%-48%]). Analysis of the area under the curve confirmed the PIUKALL groups were significantly better at predicting outcome than algorithms employed in each trial. PIUKALL provides an accurate method for predicting outcome and more flexible method for defining risk groups in future studies.
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| 7. |
- Daelman, Bo, et al.
(författare)
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Frailty and cognitive function in middle-aged and older adults with congenital heart disease
- 2024
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Ingår i: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 83:12, s. 1149-1159
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Tidskriftsartikel (refereegranskat)abstract
- Background: Life expectancy of patients with congenital heart disease (CHD) has increased rapidly, resulting in a growing and aging population. Recent studies have shown that older people with CHD have higher morbidity, health care use, and mortality. To maintain longevity and quality of life, understanding their evolving medical and psychosocial challenges is essential.Objectives: The authors describe the frailty and cognitive profile of middle-aged and older adults with CHD to identify predictor variables and to explore the relationship with hospital admissions and outpatient visits.Methods: Using a cross-sectional, multicentric design, we included 814 patients aged ≥40 years from 11 countries. Frailty phenotype was determined using the Fried method. Cognitive function was assessed by the Montreal Cognitive Assessment.Results: In this sample, 52.3% of patients were assessed as robust, 41.9% as prefrail, and 5.8% as frail; 38.8% had cognitive dysfunction. Multinomial regression showed that frailty was associated with older age, female sex, higher physiologic class, and comorbidities. Counterintuitively, patients with mild heart defects were more likely than those with complex lesions to be prefrail. Patients from middle-income countries displayed more prefrailty than those from higher-income countries. Logistic regression demonstrated that cognitive dysfunction was related to older age, comorbidities, and lower country-level income.Conclusions: Approximately one-half of included patients were (pre-)frail, and more than one-third experienced cognitive impairment. Frailty and cognitive dysfunction were identified in patients with mild CHD, indicating that these concerns extend beyond severe CHD. Assessing frailty and cognition routinely could offer valuable insights into this aging population.
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| 9. |
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| 10. |
- Van Bulck, Liesbet, et al.
(författare)
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Rationale, design and methodology of APPROACH-IS II: International study of patient-reported outcomes and frailty phenotyping in adults with congenital heart disease.
- 2022
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Ingår i: International journal of cardiology. - : Elsevier BV. - 1874-1754 .- 0167-5273. ; 363, s. 30-39
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Tidskriftsartikel (refereegranskat)abstract
- In recent years, patient-reported outcomes (PROs) have received increasing prominence in cardiovascular research and clinical care. An understanding of the variability and global experience of PROs in adults with congenital heart disease (CHD), however, is still lacking. Moreover, information on epidemiological characteristics and the frailty phenotype of older adults with CHD is minimal. The APPROACH-IS II study was established to address these knowledge gaps. This paper presents the design and methodology of APPROACH-IS II.APPROACH-IS II is a cross-sectional global multicentric study that includes Part 1 (assessing PROs) and Part 2 (investigating the frailty phenotype of older adults). With 53 participating centers, located in 32 countries across six continents, the aim is to enroll 8000 patients with CHD. In Part 1, self-report surveys are used to collect data on PROs (e.g., quality of life, perceived health, depressive symptoms, autonomy support), and explanatory variables (e.g., social support, stigma, illness identity, empowerment). In Part 2, the cognitive functioning and frailty phenotype of older adults are measured using validated assessments.APPROACH-IS II will generate a rich dataset representing the international experience of individuals in adult CHD care. The results of this project will provide a global view of PROs and the frailty phenotype of adults with CHD and will thereby address important knowledge gaps. Undoubtedly, the project will contribute to the overarching aim of improving optimal living and care provision for adults with CHD.
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