Genome-wide profiling of blood pressure in adults and children

Hypertension is an important determinant of cardiovascular morbidity and mortality and has a substantial heritability, which is likely of polygenic origin. The aim of this study was to assess to what extent multiple common genetic variants contribute to blood pressure regulation in both adults and children and to assess overlap in variants between different age groups, using genome-wide profiling. Single nucleotide polymorphism sets were defined based on a meta-analysis of genome-wide association studies on systolic blood pressure and diastolic blood pressure performed by the Cohort for Heart and Aging Research in Genome Epidemiology (n=29 136), using different P value thresholds for selecting single nucleotide polymorphisms. Subsequently, genetic risk scores for systolic blood pressure and diastolic blood pressure were calculated in an independent adult population (n=2072) and a child population (n=1034). The explained variance of the genetic risk scores was evaluated using linear regression models, including sex, age, and body mass index. Genetic risk scores, including also many nongenome-wide significant single nucleotide polymorphisms, explained more of the variance than scores based only on very significant single nucleotide polymorphisms in adults and children. Genetic risk scores significantly explained ≤1.2% (P=9.6*10(-8)) of the variance in adult systolic blood pressure and 0.8% (P=0.004) in children. For diastolic blood pressure, the variance explained was similar in adults and children (1.7% [P=8.9*10(-10)] and 1.4% [P=3.3*10(-5)], respectively). These findings suggest the presence of many genetic loci with small effects on blood pressure regulation both in adults and children, indicating also a (partly) common polygenic regulation of blood pressure throughout different periods of life.     

Growth hormone regimens in Australia: analysis of the first 3 years of treatment for idiopathic growth hormone deficiency and idiopathic short stature

Objective To investigate response to growth hormone (GH) in the first, second and third years of treatment for all idiopathic GH‐deficient (GHD) and idiopathic short stature (ISS) patients in Australia. Context Eligibility for subsidized GH treatment in Australia is determined on auxological criteria for the indication of Short Stature and Slow Growth (SSSG), which includes ISS (SSSG‐ISS). The biochemical GHD (BGHD, peak GH < 10 mU/l) and SSSG indications are treated similarly: starting dose of 4·5 mg/m²/week with provision for incremental dosing. Some ISS patients were specifically diagnosed with familial short stature (SSSG‐FSS). Design Responses for each year of treatment for BGHD, SSSG‐ISS and SSSG‐FSS cohorts were compared in relation to influencing variables and with international benchmarks. The effect of incremental dosing was assessed. Patients Australian BGHD, SSSG‐ISS and SSSG‐FSS patients who had completed 1, 2, or 3 years of treatment and were currently receiving GH. Measurements Growth hormone dose, change in height‐standard deviation score (ΔSDS) and growth velocity (GV). Results First‐year response was 2–3 times greater than that in subsequent years: ΔSDS_{1st year} = 0·92, 0·50 and 0·46 for BGHD, SSSG‐ISS and SSSG‐FSS, respectively. Responses were similar to international reports and inversely related to age at commencement of GH. First‐year GV‐for‐age for BGHD patients was similar to international standards for idiopathic GHD. However, girls had an inferior response to boys when treatment commenced at <6 years of age. First‐year GV‐for‐age for SSSG‐ISS/FSS patients was less than ISS standards. Dose increments attenuated the first‐ to second‐year decline in response to BGHD but marginally improved the responses for SSSG‐ISS/FSS. Conclusions The Australian auxology‐based GH programme produces comparable responses to international programmes. A lower starting dose is offset by the initiation of treatment at younger ages. Incremental dosing does not appear optimal. A first‐year dose of 6·4–6·9 mg/m²/week for GHD and 8·9 mg/m²/week for ISS with early commencement of GH treatment may be most efficacious.     

Functional connectivity between parietal and frontal brain regions and intelligence in young children: The Generation R study

It has been shown in adults that individual differences in intelligence are related to the integrity of the interaction between parietal and frontal brain regions. Since connectivity between distant brain regions strengthens during childhood, it is unclear when in the course of development this relationship emerges. Thus, the goal of this study was to determine whether parietal‐frontal functional connectivity is associated with intelligence in young children. We performed independent component analyses on resting‐state fMRI data of 115 children (6–8 years old) to select seed and target regions for a seed/target region correlation analysis. We found that higher nonverbal intelligence was associated with increased functional connectivity between right parietal and right frontal regions, and between right parietal and dorsal anterior cingulate regions. The association between intelligence and functional connectivity between certain brain regions was stronger in girls than boys. In conclusion, we found that connectivity between the parietal and frontal lobes is critically involved in intelligence in young children. Hum Brain Mapp 34:3299–3307, 2013. © 2012 Wiley Periodicals, Inc.     

The association between insulin-like growth factor-I and cardiac repolarization

ObjectivePrevious studies reported associations between insulin-like growth factor I (IGF-I) serum concentration and cardiac morbidity and mortality, but the association between IGF-I serum concentration and cardiac repolarization has not been investigated in a population-based study so far. Therefore, we analyzed the impact of IGF-I concentrations on QTc, QT and RR intervals in two population based studies, The Study of Health in Pomerania (SHIP) and the Rotterdam Study.Design457 individuals from SHIP and 155 individuals from the Rotterdam Study older than 55 years and without cardiovascular diseases and a left ventricular hypertrophy were investigated. IGF-I was determined by automated two-site chemiluminescence immunoassays and electrocardiograms were recorded by an ACTA electrocardiograph at a sampling frequency of 500 Hz. The association of IGF-I with QTc, QT and RR intervals was investigated by multivariable linear regression analyses adjusted for age, gender, diabetes mellitus, myocardial infarction, hypertension, body mass index, serum potassium and calcium in both studies separately and in pooled analysis.ResultsThere were no significant associations between log-transformed IGF-I and QTc interval in the single populations, whereas a significant inverse association was detectable in the pooled population (β, ? 15.6; 95%-confidence interval, ? 25.7, ? 5.5). The QTc interval was significantly higher in the first tertile of IGF-I compared to the third tertile (β, 5.4; 95%-confidence interval, 9.5–1.3) in the pooled analysis.ConclusionThe inverse association between IGF-I serum concentrations and QTc interval in our study is suggestive of a higher risk for cardiac arrhythmias and thus might provide additional evidence for increased cardiovascular mortality in subjects with low IGF-I secretion.     

Silent brain infarcts: A cause of depression in the elderly?

The present study included 1047 elderly participants. At baseline, brain magnetic resonance imaging (MRI) was performed to detect infarcts and white matter lesions; further, depressive disorders were assessed. Participants were followed up during 3.6 years to determine incident and recurrent depression. We found an increased risk of recurrent depression associated with silent brain infarcts.     

Physical activity types and health-related quality of life among middle-aged and elderly adults: The Rotterdam Study

Objectives

Physical activity (PA) is associated with health-related quality of life (HRQL). The specific PA types that provide beneficial effects in an older population remain unclear. We assessed the association of total PA, walking, cycling, domestic work, sports and gardening with HRQL in middle-aged and elderly adults.

Design

Cross-sectional study.

Setting

Rotterdam, the Netherlands.

Participants

5,554 participants, with a mean age of 69 years.

Measurements

Total PA was categorized in five groups to evaluate the dose-response effect of PA and specific PA types were categorized in tertiles. HRQL was measured with the EuroQoL 5-dimension. The outcome of every HRQL domain (i.e. mobility, self-care, daily activities, pain and mood) was expressed as having any problems versus not having problems. Logistic and linear regression analyses were used, adjusting for confounders, to examine associations of total PA and PA types with HRQL domains.

Results

In both middle-aged (<65 years) and elderly adults (>65 years), we found a dose-response association between total PA and better HRQL (i.e. lower odds of having problems in HRQL domains). In the middle-aged, sports was the only PA type associated with lower odds of having problems with all HRQL domains. In the elderly, all PA types were associated with less problems with HRQL domains, but cycling contributed most to the beneficial effect.

Conclusions

Total PA was associated with better HRQL. Sports and cycling were the activity types that contributed most to this association in the middle-aged and elderly, respectively. Since PA levels tend to decline with aging, cycling and sports should be promoted with the aim to improve HRQL.

     

Fetal and Infant Growth Patterns and Kidney Function at School Age

Low birth weight is associated with ESRD. To identify specific growth patterns in early life that may be related to kidney function in later life, we examined the associations of longitudinally measured fetal and infant growth with kidney function in school-aged children. This study was embedded in a population-based prospective cohort study among 6482 children followed from fetal life onward. Fetal and childhood growth was measured during second and third trimesters of pregnancy, at birth, and at 6, 12, 24, 36, and 48 months postnatally. At the age of 6 years, we measured kidney volume by ultrasound. GFR was estimated using blood creatinine levels. Higher gestational age-adjusted birth weight was associated with higher combined kidney volume and higher eGFR (per 1 SD score increase in birth weight; 1.27 cm³ [95% confidence interval, 0.61 to 1.93] and 0.78 ml/min per 1.73 m² [95% CI, 0.16 to 1.39], respectively). Fetal weight, birth weight, and weight at 6 months were positively associated with childhood kidney volume, whereas higher second trimester fetal weight was positively associated with higher GFR (all P values<0.05). Fetal and childhood lengths were not consistently associated with kidney function. In this cohort, lower fetal and early infant weight growth is associated with smaller kidney volume in childhood, whereas only lower fetal weight growth is associated with lower kidney function in childhood, independent of childhood growth. Whether these associations lead to an increased risk of kidney disease needs to be studied further.Low birth weight is associated with higher risks of ESRD and hypertension in later life.^1–3 Clearly, low birth weight is not the causal factor per se leading to kidney diseases in later life. Birth weight is the result of various exposures and growth patterns in fetal life and the starting point of childhood growth. It has been hypothesized that especially third trimester fetal growth restriction leads to persistently smaller kidneys with a reduced number of nephrons, which may predispose the individual to kidney disease in adulthood.^4–6 This hypothesis is supported by both animal and human studies, showing that kidney volume and nephron number are reduced in fetal growth-restricted subjects and hypertensive subjects.^7–9 Although nephrogenesis is known to continue until 36 weeks of gestation and cease thereafter, not much is known about the specific critical periods and early growth patterns related to kidney function in later life.¹⁰ Also, whether and to what extent the associations of low birth weight with CKD are explained by preterm birth are not known.¹ Longitudinal studies suggested that the associations of low birth weight with hypertension were stronger in subjects with rapid weight gain in childhood, but results are inconclusive.^11,12 A similar growth pattern has not been identified as a risk factor for kidney diseases yet.Prospective studies linking fetal and early childhood growth patterns to kidney outcomes in later life might help to identify early critical periods for developing impaired kidney function in later life.Therefore, we examined, in a population-based prospective cohort study among 6482 children followed from early fetal life onward (Figure 1), the associations of birth weight, gestational age, birth weight for gestational age, and longitudinally measured fetal and early childhood growth patterns with kidney size and function at school age. We used subclinical variations of kidney function in childhood as outcomes, because they relate to kidney disease in later life.¹³Open in a separate windowFigure 1.Flow chart: exclusion criteria and numbers of participants are given. Total numbers of available outcome measurements are given.