Genetic variants associated with adult blood pressure and kidney function do not affect fetal kidney volume. The Generation R Study

Background

Smaller kidneys with reduced number of nephrons in early life lead to impaired kidney function and risk for hypertension and chronic kidney disease. These associations might be partly explained by common genetic variation.

Aims

To assess the associations between common genetic variants, which have recently shown to be associated with blood pressure or kidney function, with fetal kidney volume.

Study design

A prospective population based cohort study in Rotterdam, The Netherlands.

Subjects

855 children, followed from early fetal life onwards (born 2003–2005).

Predictor

Common genetic variants previously associated with blood pressure or kidney function.

Outcome measures

Combined third trimester fetal kidney volume.

Results

After taking into account multiple testing, only rs12940887 (near ZNF652) was significantly associated with fetal kidney volume (β: 0.88 (95% CI: 0.40; 1.37) cm³ per minor allele, P-value < 0.001), but the effect showed the opposite direction as expected. The remaining common genetic variants were not associated with fetal kidney volume. We also did not find associations of genetic variants previously shown to affect newborn kidney volume, with third trimester fetal kidney volume.

Conclusions

Our results suggest that common genetic variants, associated with kidney function or disease and blood pressure, do not affect the third trimester fetal kidney volume. Further studies are needed to elucidate the mechanisms underlying the associations between small kidney size and increased risks of hypertension and impaired kidney function in adulthood.     

Maternal smoking during pregnancy and child emotional problems: the relevance of maternal and child 5-HTTLPR genotype

Serotonin is involved in the development of neural circuits modulating emotional behavior. The short allele (s) of a polymorphism (5-HTTLPR) of the serotonin transporter gene is a risk factor for psychopathology in the presence of environmental stressors. Maternal smoking is associated with growth restriction of the human fetal brain and adverse effects of nicotine on the developing serotonin system have been documented. We hypothesized that maternal smoking interacts with both child and mother 5-HTTLPR genotype as a risk factor for later child emotional problems. In a sample of n?=?1,529 mother-child dyads, smoking habits were assessed by questionnaires during pregnancy. Child emotional problems were measured by the Child Behavior Checklist at the child's age of 3 years. Maternal smoking during pregnancy significantly increased the risk for emotional problems in children carrying the s-allele; β?=?0.24, P?=?0.03 (mother-report), and β?=?0.46, P?=?0.001 (father-report). In children heterozygous at 5-HTTLPR and exposed to maternal prenatal smoking (n?=?79) risk of emotional problems increased with each additional s-allele the mother carried. The associations between 5-HTTLPR and child emotional problems were not moderated by paternal prenatal smoking. These findings imply that the vulnerability for emotional problems in s-allele carriers may already originate in fetal life.     

Fetal size in mid- and late pregnancy is related to infant alertness: the generation R study

The vulnerability for behavioral problems is partly shaped in fetal life. Numerous studies have related indicators of intrauterine growth, for example, birth weight and body size, to behavioral development. We investigated whether fetal size in mid- and late pregnancy is related to infant irritability and alertness. In a population-based birth cohort of 4,255 singleton full-term infants ultrasound measurements of fetal head and abdominal circumference in mid- and late pregnancy were performed. Infant irritability and alertness scores were obtained by the Mother and Baby Scales at 3 months and z-standardized. Multiple linear regression analyses revealed curvilinear associations (inverted J-shape) of measures of fetal size in both mid- and late pregnancy with infant alertness. Fetal size characteristics were not associated with infant irritability. These results suggest that alterations of intrauterine growth affecting infant alertness are already detectable from mid-pregnancy onwards.     

Recognition of scared faces and the serotonin transporter gene in young children: the Generation R Study

Background: Previous research highlights the significance of a functional polymorphism located in the promoter region (5‐HTTLPR) of the serotonin transporter gene in emotional behaviour. This study examined the effect of the 5‐HTTLPR polymorphism on emotion processing in a large number of healthy preschoolers. Methods: The 5‐HTTLPR genotype was classified in 605 children as homozygous for the short allele (SS), homozygous for the long allele (LL), or heterozygous (LS). Emotion‐processing was assessed using age‐appropriate computer tasks where children matched happy, sad, angry, and fearful facial expressions preceded by a shape‐matching task to assess basic matching ability. Results: We found that young children could differentiate between emotion categories (F = 12.1, p < .001). The effect of 5‐HTTLPR genotype depended on the emotion category presented (F = 2.3, p = .031). This effect was explained by the finding that SS children were less accurate at recognising fearful faces than LL or LS children (F = 5.3, p = .005). We did not find any significant differences as a result of 5‐HTTLPR genotype for happy, sad or angry expressions (p > .05). Conclusions: Results indicate that 5‐HTTLPR allele status selectively impacts the processing of fearful but not other facial expressions. This pattern is already apparent in very young typically developing children. Results may signal an early vulnerability for affective problems before disorders emerge.     

Growth, development and health from early fetal life until young adulthood: the Generation R Study

In this paper the Generation R Study is presented. This study examines growth, development and health in urban children from fetal life until young adulthood. With an integrated approach of epidemiological, clinical and basic research, it focuses on four primary areas of research: (1) growth and physical development; (2) behavioural and cognitive development; (3) diseases in childhood; and (4) health and health care for pregnant women and children. The general aims of the study are: 1. to describe normal and abnormal growth, development and health from fetal life until young adulthood in a multiethnic population-based cohort; 2. to identify biological, social and environmental determinants of normal and abnormal growth, development and health from fetal life until adulthood; 3. to examine the utilisation and effectiveness of current strategies for prevention and early identification of groups at risk. Eventually, this study will contribute to the development of strategies for optimising health and health care for pregnant women and children. The Generation R Study is a prospective population-based cohort study in Rotterdam, the Netherlands. In this urban setting, 10 000 children will be examined from early fetal life until young adulthood. Data are collected by physical examinations, questionnaires, interviews, ultrasound and biological samples. The study entered its pilot phase to test the logistics in December 2001. Full participant recruitment and complete data collection started in 2002.     

Bone Mass and Strength in School‐Age Children Exhibit Sexual Dimorphism Related to Differences in Lean Mass: The Generation R Study

Bone strength, a key determinant of fracture risk, has been shown to display clear sexual dimorphism after puberty. We sought to determine whether sex differences in bone mass and hip bone geometry as an index of strength exist in school‐age prepubertal children and the degree to which the differences are independent of body size and lean mass. We studied 3514 children whose whole‐body and hip scans were measured using the same densitometer (GE‐Lunar iDXA) at a mean age of 6.2 years. Hip dual‐energy X‐ray absorptiometry (DXA) scans underwent hip structural analyses (HSA) with derivation of bone strength indices. Sex differences in these parameters were assessed by regression models adjusted for age, height, ethnicity, weight, and lean mass fraction (LMF). Whole‐body bone mineral density (BMD) and bone mineral content (BMC) levels were 1.3% and 4.3% higher in girls after adjustment by LMF. Independent of LMF, boys had 1.5% shorter femurs, 1.9% and 2.2% narrower shaft and femoral neck with 1.6% to 3.4% thicker cortices than girls. Consequent with this geometry configuration, girls observed 6.6% higher stresses in the medial femoral neck than boys. When considering LMF, the sexual differences on the derived bone strength indices were attenuated, suggesting that differences in muscle loads may reflect an innate disadvantage in bone strength in girls, as consequence of their lower muscular acquisition. In summary, we show that bone sexual dimorphism is already present at 6 years of age, with boys having stronger bones than girls, the relation of which is influenced by body composition and likely attributable to differential adaptation to mechanical loading. Our results support the view that early life interventions (ie, increased physical activity) targeted during the pre‐ and peripubertal stages may be of high importance, particularly in girls, because before puberty onset, muscle mass is strongly associated with bone density and geometry in children. © 2015 American Society for Bone and Mineral Research.     

Streptococcus pneumoniae exposure is associated with human metapneumovirus seroconversion and increased susceptibility to in vitro HMPV infection

It remains largely unknown which factors determine the clinical outcome of human metapneumovirus (HMPV) infections. The aim of the present study was to analyse whether exposure to bacterial pathogens can influence HMPV infections. From 57 children, serum samples and colonization data for Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus and Streptococcus pneumoniae were collected at 1.5, 6, 14 and 24 months of age. Seroconversion rates to HMPV were determined and related to bacterial carriage. Frequent nasopharyngeal carriage (≥2 times in the first 2 years of life) of S. pneumoniae, but not of the other three pathogens, was associated with increased seroconversion rates of infants to HMPV at the age of 2 years (frequently vs. less exposed, 93% vs. 59%; p <0.05). Subsequently, the susceptibility of well-differentiated normal human bronchial epithelial cells (wd-NHBE) pre-incubated with bacterial pathogens to in vitro HMPV infection was evaluated. Pre-incubation of wd-NHBE with S. pneumoniae resulted in increased susceptibility to infection with HMPV-enhanced green fluorescent protein (EGFP), as determined by enumeration of EGFP-positive cells. This was not the case for cells pre-incubated with H. influenzae, M. catarrhalis on S. aureus. We conclude that exposure to S. pneumoniae can modulate HMPV infection.