Behavioural early-life exposures and body composition at age 15 years.

BACKGROUND/OBJECTIVES: Previous studies have demonstrated associations between some early-life exposures and later obesity, but most have used body mass index in childhood or adulthood as the outcome. The objective of this study was to investigate whether early-life exposures were associated with directly measured fat and lean mass in adolescence. SUBJECTS/METHODS: This study used data on 4750 mother-offspring pairs, collected as a part of the Avon Longitudinal Study of Parents and Children, Bristol, UK between 1991 and 1992; associations between behavioural exposures occurring from conception up to 5 years of age (maternal and paternal smoking during pregnancy, breastfeeding, age at introduction to solids, dietary patterns and physical inactivity during early childhood) and offspring body composition measured by dual-energy X-ray absorptiometry at ~15 years were assessed. RESULTS: After full adjustment for potential confounders, maternal smoking during pregnancy, having a junk food diet and spending more time watching television in early childhood were all associated with higher fat mass at age 15, whereas maternal smoking, having a healthy diet and playing computer games more frequently in early childhood were all associated with a higher lean mass at age 15. Associations with paternal smoking were generally weaker for both fat and lean mass, but as there was no strong statistical evidence for maternal vs paternal differences, confounding by social factors rather than a direct effect of maternal smoking cannot be ruled out. Early feeding was not associated with fat or lean mass at age 15. CONCLUSIONS: This study does not provide compelling evidence for associations between most early-life factors and body composition in adolescence. However, possible associations with dietary patterns and physical inactivity in early childhood require further investigation in other cohorts that have direct measurements of adolescent body composition.

Maternal iron levels early in pregnancy are not associated with offspring IQ score at age 8, findings from a Mendelian randomization study.

BACKGROUND/OBJECTIVES: Iron is fundamental to many basic biological functions, and animal studies suggest that iron deficiency early in life can have a lasting impact on the developing brain. SUBJECTS/METHODS: We used a population-based cohort of mothers and their children to assess the effect of iron status among pregnant women on the cognitive ability of their offspring. But to avoid the inherent confounding that occurs within observational epidemiology studies we examined the association of maternal genotype at single-nucleotide polymorphisms in the genes HFE (rs1799945) and (rs1800562), TF (rs3811647) and TMPRSS6 (rs1800562), which are related to iron, haemoglobin or transferrin levels, on their child's cognitive test scores at age 8. RESULTS: We found strong associations between HFE and TMPRSS6 genotypes and mother's haemoglobin levels early in pregnancy (P-values are all ≤ 4.1 × 10(-5)) and a genetic score comprised of alleles at these loci was even more strongly associated with haemoglobin levels (P=3.0 × 10(-18)), suggesting that this was a good instrument to use to look at the effect of prenatal iron levels on offspring cognition. However, mother's genotype at the above loci was not associated with offspring IQ at age 8. CONCLUSIONS: We therefore concluded that there is no evidence of an effect of exposure to low levels of iron (within the normal range) in pregnancy on offspring cognition at age 8. However, pregnant women in the UK with low haemoglobin levels are prescribed iron supplements and so we were unable to look at the effect of iron deficiency in our study.

Childhood intelligence is heritable, highly polygenic and associated with FNBP1L.

Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6-18 years) from 17,989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22-46% of phenotypic variation in childhood intelligence in the three largest cohorts (P=3.9 × 10(-15), 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P=0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P=6 × 10(-5)), 3.5% (P=10(-3)) and 0.5% (P=6 × 10(-5)) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance.

Genetic variants in genes related to lipid metabolism and atherosclerosis, dyslipidemia and atorvastatin response.

OBJECTIVE: Using candidate gene approach, we have investigated the effect of single nucleotide polymorphism (SNP) in genes related to lipid metabolism and atherosclerosis on dyslipidemia and atorvastatin response. METHODS: The study included 157 patients treated with atorvastatin and 145 controls. Genomic DNA was isolated and genotyped using SNPlex technology. RESULTS: Allele and genotype disease association test revealed that APOB rs693 (OR: 2.2 [1.5-3.2], p=0.0001) and CD36 rs1984112 (OR: 3.7 [1.9-7.0], p=0.0002) SNPs were independent risk factors for hypercholesterolemia. Only APOB rs693 T variant allele was associated with increased LDL cholesterol levels (>160mg/dL). After atorvastatin treatment (10mg/day/4weeks), LIPC -514T allele was positively associated with LDL cholesterol reduction. CONCLUSION: The current study reinforces the current knowledge that carrying APOB rs693 is an independent risk factor for dyslipidemia and higher LDL levels. Furthermore, we found that a variant of CD36 was associated with dyslipidemia as a risk (rs1984112) factor. Finally, atorvastatin response could be predicted by LIPC -514C>T SNP and physical activity. In conclusion, our data evidences the contribution of genetic markers and their interaction with environmental factor in the variability of statin response.

Parental depressive and anxiety symptoms during pregnancy and attention problems in children: a cross-cohort consistency study.

BACKGROUND: Maternal depression and anxiety during pregnancy have been associated with offspring-attention deficit problems. AIM: We explored possible intrauterine effects by comparing maternal and paternal symptoms during pregnancy, by investigating cross-cohort consistency, and by investigating whether parental symptoms in early childhood may explain any observed intrauterine effect. METHODS: This study was conducted in two cohorts (Generation R, n = 2,280 and ALSPAC, n = 3,442). Pregnant women and their partners completed questionnaires to assess symptoms of depression and anxiety. Child attention problems were measured in Generation R at age 3 with the Child Behavior Checklist, and in ALSPAC at age 4 with the Strengths and Difficulties Questionnaire. RESULTS: In both cohorts, antenatal maternal symptoms of depression (Generation R: OR 1.23, 95% CI 1.05-1.43; ALSPAC: OR 1.33, 95% CI 1.19-1.48) and anxiety (Generation R: OR 1.24, 95% CI 1.06-1.46; ALSPAC: OR 1.32, 95% CI 1.19-1.47) were associated with a higher risk of child attention problems. In ALSPAC, paternal depression was also associated with a higher risk of child attention problems (OR 1.11, 95% CI 1.00-1.24). After adjusting for maternal symptoms after giving birth, antenatal maternal depression and anxiety were no longer associated with child attention problems in Generation R. Moreover, there was little statistical evidence that antenatal maternal and paternal depression and anxiety had a substantially different effect on attention problems of the child. CONCLUSIONS: The apparent intrauterine effect of maternal depression and anxiety on offspring-behavioural problems may be partly explained by residual confounding. There was little evidence of a difference between the strength of associations of maternal and paternal symptoms during pregnancy with offspring-attention problems. That maternal symptoms after childbirth were also associated with offspring-behavioural problems may indicate a contribution of genetic influences to the association.

Novel splice donor site mutation in MERTK gene associated with retinitis pigmentosa.

BACKGROUND/AIM: Mutations in MERTK, a member of the MER/AXL/TYRO3 receptor kinase family, have been associated with disruption of the Retinal Pigment Epithelium (RPE) phagocytosis pathway and settling of autosomal recessive RP (arRP) in humans. This study reports a novel MERTK mutation (IVS16+1G>T) in a Spanish consanguineous family presenting arRP. METHODS: 21 genes were screened by high-throughput SNP multiplexing assay. Subsequent direct sequencing was performed in exons and intronic boundaries of the cosegregating gene. The effect of the mutation in mRNA splicing was confirmed by cDNA analysis. RESULTS: Haplotypic data revealed MERTK cosegregation with RP in affected individuals. MERTK sequencing showed a G-to-T substitution at the first nucleotide of intron 16. Finally, cDNA analysis confirmed the lack of exon 16 in the mRNA splicing process. CONCLUSIONS: IVS16+1G>T disrupts the splice donor site causing exon 16 skipping. Absence of exon 16 causes a frameshift and, subsequently, the introduction of a premature termination codon into exon 17 creating an altered mRNA transcript with a seriously affected tyrosine kinase domain.

Sodium intake in infancy and blood pressure at 7 years: findings from the Avon Longitudinal Study of Parents and Children.

BACKGROUND: Infancy may be a sensitive period regarding effects of sodium intake on future blood pressure (BP). This has only been demonstrated in one randomized trial of low sodium formulae with follow-up in adolescence in one-third of participants. OBJECTIVE: To prospectively assess associations between sodium intake in infancy and BP at 7 years in the Avon Longitudinal Study of Parents and Children (ALSPAC). SUBJECTS: A total of 533 children with sodium data at 4 months and 710 children with sodium at 8 months. RESULTS: 0.4% of participants at 4 months and 73.0% at 8 months exceeded recommended levels for infant sodium intake. After minimal adjustment (child age, sex, energy), sodium intake at 4 months was positively associated with systolic blood pressure (SBP) at 7 years (beta=0.54 mm Hg/mmol; 95% CI: 0.09, 0.98 mm Hg; P=0.02). This changed little following adjustment for confounders but attenuated after adjusting for breastfeeding. This association was not mediated by sodium intake at 7 years. Due to high sodium-potassium correlations, effects of sodium independent of potassium could not be estimated with reasonable precision. Sodium intake neither at 8 months nor at 7 years was associated with SBP at 7 years. CONCLUSION: The association between sodium intake at 4 months and future SBP requires replication in studies that can control for effects of potassium before we can conclude that early infancy is a sensitive period with respect to effects of sodium on future BP. The majority of infants exceeded recommended levels of sodium intake at 8 months, and interventions to reduce sodium in infants' diets should be considered.