Maternal inflammation during pregnancy and childhood adiposity

Objective: Maternal pre-pregnancy obesity is associated with offspring obesity. Underlying mechanisms may involve a maternal obesity-mediated proinflammatory state during pregnancy. Maternal C-reactive protein (CRP) level during pregnancy is a biomarker of low-grade systemic inflammation. Methods: Among 1,116 mother-child pairs, this study examined associations of maternal second-trimester CRP plasma level, measured by high-sensitivity CRP arrays, with mid-childhood DXA fat mass index (FMI), trunk fat mass index (trunkFMI), fat-free mass index (FFMI), and early and mid-childhood BMI-z and waist circumference (WC). Main analyses were adjusted for maternal sociodemographic and lifestyle-related characteristics, gestational age at blood draw, and child's age and sex. Results: Higher maternal CRP level was associated with higher mid-childhood FMI and trunkFMI (adjusted difference: 0.15 kg/m2 [95% CI: 0.01, 0.29] [P = 0.04] and 0.06 kg/m2 [95% CI: 0.00, 0.12] [P = 0.06], per SD increment in maternal CRP, respectively), but not FFMI. Higher maternal CRP level was associated with higher early and mid-childhood BMI-z and WC in the basic models [P < 0.05], but these associations attenuated after adjustment for maternal characteristics (adjusted difference in early and mid-childhood BMI-z and WC: 0.05 [95% CI: −0.03, 0.13] [P = 0.20], 0.10 cm [95% CI: −0.17, 0.37] [P = 0.46], 0.07 [95% CI: −0.01, 0.14] [P = 0.09], 0.34 cm [95% CI: −0.25, 0.94] [P = 0.26], per SD increment in maternal CRP, respectively). Conclusions: Higher second-trimester maternal CRP level was associated with higher mid-childhood overall and central adiposity

DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathw

Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index

The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values <5 × 10-5, Bonferroni-corrected P<0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; Poverall: 2.47 × 10-06/Pfemales: 3.45 × 10-07/Pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation