Uiterwaal, C.S.P.M.

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk (Article)

2011-10-06T00:00:00Z

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140mmg Hg systolic blood pressure ≥90mmg Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3 GUCY1B3, NPR3 C5orf23, ADM, FURIN FES, GOSR2, GNAS EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption (Article)

2011-04-26T00:00:00Z

Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 x 10-8to P = 4 x 10-9). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Downregulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.

The emerging burden of hospital admissions of adults with congenital heart disease (Article)

2010-06-01T00:00:00Z

Objective: To assess the extent and the characteristics of hospital admissions in registered adult patients with congenital heart disease. Design: Observational cohort study. Setting: The Netherlands. Patients: 5798 adult patients with congenital heart disease from the Dutch CONCOR national registry linked to the Dutch National Medical Registration (Prismant). Main outcome measures: All hospital admissions from the years 2001 up until 2006. Results: During 28 990 patient-years, 2908 patients (50%) were admitted to hospital. Median age at admission was 39 years (range 18-86 years); 46% were male. Admission rate in CONCOR patients was high among all ages (range 11-68%) and exceeded that of the general Dutch population two to three times; this difference was most pronounced in the older age groups. Altogether there were 8916 admissions, 5411 (61%) of which were for cardiovascular indications. Among cardiovascular admissions, referrals for arrhythmias were most common (31%). Of 4926 interventions, 2459 (50%) were cardiovascular, most often reparative interventions or cardioversion (53%). Most non-cardiovascular admissions were obstetric. Among defects, univentricular heart and tricuspid atresia had the highest incidence and duration of admission. Conclusions: Healthcare utilisation in registered and medically supervised adult patients with congenital heart disease is high and increases with age. Admission rates are at least two times higher than in the general population, and most marked in the older age groups. With the ageing of this population, a major increase in healthcare utilisation is imminent in the near future. Timely preparation of healthcare resources is crucial to sustain optimal care.

Mortality in adult congenital heart disease (Article)

2010-05-01T00:00:00Z

AimsMortality in adults with congenital heart disease is known to be increased, yet its extent and the major mortality risks are unclear.Methods and resultsThe Dutch CONCOR national registry for adult congenital heart disease was linked to the national mortality registry. Cox's regression was used to assess mortality predictors. Of 6933 patients, 197 (2.8) died during a follow-up of 24 865 patient-years. Compared with the general national population, there was excess mortality, particularly in the young. Median age at death was 48.8 years. Of all deaths, 77 had a cardiovascular origin; 45 were due to chronic heart failure (26, age 51.0 years) or sudden death (19, age 39.1 years). Age predicted mortality, as did gender, severity of defect, number of interventions, and number of complications [hazard ratio (HR) range 1.1-5.9, P < 0.05]. Several complications predicted all-cause mortality beyond the effects of age, gender, and congenital heart disease severity, i.e. endocarditis, supraventricular arrhythmias, ventricular arrhythmias, conduction disturbances, myocardial infarction, and pulmonary hypertension (HR range 1.4-3.1, P < 0.05). These risks were similar in patients above and below 40 years of age. Almost all complications predicted death due to heart failure (HR range 2.0-5.1, P < 0.05); conduction disturbances and pulmonary hypertension predicted sudden death (HR range 2.0-4.7, P < 0.05). Conclusion Mortality is increased in adults with congenital heart disease, particularly in the young. The vast majority die from cardiovascular causes. Mortality risk, particularly by heart failure, is increased by virtually all complications. Complications are equally hazardous in younger as in older patients.

Non-right-handedness and mental health problems among adolescents from the general population: The trails study (Article)

2010-05-01T00:00:00Z

To determine whether the association between non-right-handedness and mental problems among adolescents is specific for psychotic symptoms, we included a group of 2096 adolescents with a mean age of 14 years from the general population. Mental health problems were assessed using the parent, self-report, and teacher versions of the Child Behavior Checklist. Internalising problems comprised anxious and depressed, withdrawn and depressed, and somatic complaints. Externalising problems consisted of delinquent behaviour and aggressive behaviour. The remaining problems consisted of social problems, attention problems, and thought problems. The latter were divided into psychotic and non-psychotic items. A total of 14.3% of the adolescents were non-right-handed. We observed positive associations of non-right-handedness with thought problems, social problems, and being withdrawn and depressed. Externalising problems showed no associations with handedness. Within the thought problems subscale, the effect sizes associated with non-right-handedness for psychotic and non-psychotic items were 0.18 (p.005) and 0.04 (p.459), respectively. In conclusion, non-right-handedness is predominantly associated with psychosis-related mental problems as early as in adolescence. Handedness could be taken into account when identifying adolescents at risk for psychosis.

Adjustment of treatment increases quality of life in patients with epilepsy: A randomized controlled pragmatic trial (Article)

2009-11-01T00:00:00Z

Background and purpose: Complaints about side-effects of antiepileptic drugs (AEDs) may be overlooked in clinical practice. We assessed the value and risks of an active intervention policy for reported complaints in a randomized controlled pragmatic trial. Methods: This randomized controlled pragmatic trial included 111 adults treated for epilepsy in seven general hospitals. They were considered well-managed by their treating physician, but reported moderate to severe complaints on a questionnaire (SIDAED, assessing SIDe effects in AED treatment). The intervention was adjustment of AED treatment (53 patients), either reduction of dose or switch of AED, versus continuation of treatment unchanged (58 control patients) during 7 months. Primary outcomes were quality of life (Qolie-10) and complaints score. Secondary outcome measures were the occurrence of seizures or adverse events. Results: After 7 months, the relative risk (RR) for improvement in quality of life was 1.80 (1.04-3.12) for the intervention group compared to control and the RR of decrease in complaints was 1.34 (0.88-2.05). In 58% of patients randomized to adjustment, the medication had indeed been changed. Discussion: In conclusion, despite a possible risk of seizure recurrence, adjustment of drug treatment in well-managed patients with epilepsy, who report considerable complaints, improves the quality of life.

Maternal smoking in pregnancy is associated with cholesterol development in the offspring: A 27-years follow-up study (Article)

2008-01-01T00:00:00Z

Objective: To examine the associations of maternal smoking in pregnancy with development of cholesterol levels from childhood to adulthood. Methods: Total cholesterol, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol were measured annually from 1975 to 1993 and in 2002 in 350 subjects aged 5-19 years at baseline who participate in a prospective cohort study. Pregnancy and birth data were obtained through questionnaires sent to the parents. Results: Children of mothers who smoked in pregnancy showed a higher annual change in total cholesterol of 0.12 mmol/l per 10 years (95% confidence interval (CI): 0, 0.23) compared to children whose mothers did not smoke in pregnancy. Larger effect estimates were found in children with moderate overweight (0.39 mmol/l per 10 years (95% CI: 0.14, 0.63). HDL-cholesterol and LDL-cholesterol showed tendencies towards a decrease and increase, respectively, in children of mothers who smoked in pregnancy compared to children whose mothers did not smoke in pregnancy. Adjustment for potential confounders did not materially change the effect estimates. Conclusion: This study suggests for the first time that maternal smoking in pregnancy is associated with an increased rise in total cholesterol levels and a tendency towards an adverse lipoprotein profile in the offspring.

Lipids and atherosclerosis in families (Doctoral Thesis)

1995-06-07T00:00:00Z