Epigenome-wide association study of DNA methylation in maternal blood leukocytes with BMI in pregnancy and gestational weight gain.

OBJECTIVES: We aimed to discover CpG sites with differential DNA methylation in peripheral blood leukocytes associated with body mass index (BMI) in pregnancy and gestational weight gain (GWG) in women of European and South Asian ancestry. Furthermore, we aimed to investigate how the identified sites were associated with methylation quantitative trait loci, gene ontology, and cardiometabolic parameters. METHODS: In the Epigenetics in pregnancy (EPIPREG) sample we quantified maternal DNA methylation in peripheral blood leukocytes in gestational week 28 with Illumina's MethylationEPIC BeadChip. In women with European (n = 303) and South Asian (n = 164) ancestry, we performed an epigenome-wide association study of BMI in gestational week 28 and GWG between gestational weeks 15 and 28 using a meta-analysis approach. Replication was performed in the Norwegian Mother, Father, and Child Cohort Study, the Study of Assisted Reproductive Technologies (MoBa-START) (n = 877, mainly European/Norwegian). RESULTS: We identified one CpG site significantly associated with GWG (p 5.8 × 10-8) and five CpG sites associated with BMI at gestational week 28 (p from 4.0 × 10-8 to 2.1 × 10-10). Of these, we were able to replicate three in MoBa-START; cg02786370, cg19758958 and cg10472537. Two sites are located in genes previously associated with blood pressure and BMI. DNA methylation at the three replicated CpG sites were associated with levels of blood pressure, lipids and glucose in EPIPREG (p from 1.2 × 10-8 to 0.04). CONCLUSIONS: We identified five CpG sites associated with BMI at gestational week 28, and one with GWG. Three of the sites were replicated in an independent cohort. Several genetic variants were associated with DNA methylation at cg02786379 and cg16733643 suggesting a genetic component influencing differential methylation. The identified CpG sites were associated with cardiometabolic traits. GOV REGISTRATION NO: Not applicable.

Genetic risk score for gestational weight gain.

Gestational weight gain (GWG) involves health consequences for both mother and offspring. Genetic factors seem to play a role in the GWG trait. For small effect sizes of a single genetic polymorphism (SNP), a genetic risk score (GRS) summarizing risk-associated variation from multiple SNPs can serve as an effective approach to genetic association analysis. The aim of the study was to analyze the association between genetic risk score (GRS) and gestational weight gain (GWG). GWG was calculated for a total of 342 healthy Polish women of Caucasian origin, aged 19 to 45 years. The SNPs rs9939609 (FTO), rs6548238 (TMEM18), rs17782313 (MC4R), rs10938397 (GNPDA2), rs10913469 (SEC16B), rs1137101 (LEPR), rs7799039 (LEP), and rs5443 (GNB3) were genotyped using commercial TaqMan SNP assays. A simple genetic risk score was calculated into two ways: GRS1 based on the sum of risk alleles from each of the SNPs, while GRS2 based on the sum of risk alleles of FTO, LEPR, LEP, and GNB3. Positive association between GRS2 and GWG (ß = 0.12, p = 0.029) was observed. Genetic risk variants of TMEM18 (p = 0.006, OR = 2.6) and GNB3 (p < 0.001, OR = 3.3) are more frequent in women with increased GWG, but a risk variant of GNPDA2 (p < 0.001, OR = 2.7) is more frequent in women with adequate GWG, and a risk variant of LEPR (p = 0.011, OR = 3.1) in women with decreased GWG. GRS2 and genetic variants of TMEM18, GNB3, GNPDA2, and LEPR are associated with weight gain during pregnancy.

Placental epigenetic marks related to gestational weight gain reveal potential genes associated with offspring obesity parameters.

OBJECTIVE: Offspring exposed to gestational obesity have an increased risk for chronic diseases. Increasing evidence suggests that epigenetics may play a mechanistic role in metabolic programming. This study aimed to identify placental DNA methylation marks associated with gestational weight gain (GWG) and to study their association with offspring obesity parameters at school age. METHODS: A global methylation array was performed in 24 placentas from mothers with different degrees of GWG (screening sample). The methylation percentage of four cytosine-guanine (CpG) sites and the relative expression of the respective annotated genes were studied in 90 additional placentas (validation sample). Associations of these epigenetic marks with clinical parameters in the offspring at 6 years of age were examined. RESULTS: The screening analysis identified 104 CpG sites (97 genes) associated with GWG. The validation analysis of four selected CpG sites (annotating for FRAT1, SNX5, and KCNK3 genes) showed that the upregulation of SNX5 methylation, the downregulation of FRAT1 methylation, and KCNK3 underexpression associated with an adverse metabolic phenotype in children of women with increased GWG. CONCLUSIONS: These results suggest that placental regulation of FRAT1, SNX5, and KCNK3 relates to obesity parameters in offspring exposed to excessive GWG and thereby could condition the risk for future metabolic disorders.

FTO and ADRB2 Genetic Polymorphisms Are Risk Factors for Earlier Excessive Gestational Weight Gain in Pregnant Women with Pregestational Diabetes Mellitus: Results of a Randomized Nutrigenetic Trial.

Excessive gestational weight gain (GWG) is associated with increased risk of maternal and neonatal complications. We investigated obesity-related polymorphisms in the FTO gene (rs9939609, rs17817449) and ADRB2 (rs1042713, rs1042714) as candidate risk factors concerning excessive GWG in pregnant women with pregestational diabetes. This nutrigenetic trial, conducted in Brazil, randomly assigned 70 pregnant women to one of the groups: traditional diet (n = 41) or DASH diet (n = 29). Excessive GWG was the total weight gain above the upper limit of the recommendation, according to the Institute of Medicine guidelines. Genotyping was performed using real-time PCR. Time-to-event analysis was performed to investigate risk factors for progression to excessive GWG. Regardless the type of diet, AT carriers of rs9939609 (FTO) and AA carriers of rs1042713 (ADRB2) had higher risk of earlier exceeding GWG compared to TT (aHR 2.44; CI 95% 1.03-5.78; p = 0.04) and GG (aHR 3.91; CI 95% 1.12-13.70; p = 0.03) genotypes, respectively, as the AG carriers for FTO haplotype rs9939609:rs17817449 compared to TT carriers (aHR 1.79; CI 95% 1.04-3.06; p = 0.02).

Interaction between rs10830962 polymorphism in MTNR1B and lifestyle intervention on maternal and neonatal outcomes: secondary analyses of the DALI lifestyle randomized controlled trial.

BACKGROUND: Interactions between polymorphisms of the melatonin receptor 1B (MTNR1B) gene and lifestyle intervention for gestational diabetes have been described. Whether these are specific for physical activity or the healthy eating intervention is unknown. OBJECTIVES: The aim was to assess the interaction between MTNR1B rs10830962 and rs10830963 polymorphisms and lifestyle interventions during pregnancy. METHODS: Women with a BMI (in kg/m2) of ≥29 (n = 436) received counseling on healthy eating (HE), physical activity (PA), or both. The control group received usual care. This secondary analysis had a factorial design with comparison of HE compared with no HE and PA compared with no PA. Maternal outcomes at 24-28 wk were gestational weight gain (GWG), maternal fasting glucose, insulin, insulin resistance (HOMA-IR), disposition index, and development of GDM. Neonatal outcomes were cord blood leptin and C-peptide and estimated neonatal fat percentage. The interaction between receiving either the HE or PA intervention and genotypes of both rs10830962 and rs10830963 was assessed using multilevel regression analysis. RESULTS: GDM risk was increased in women homozygous for the G allele of rs10830962 (OR: 2.60; 95% CI: 1.34, 5.06) or rs10830963 (OR: 2.83; 95% CI: 1.24, 6.47). Significant interactions between rs10830962 and interventions were found: in women homozygous for the G allele but not in the other genotypes, the PA intervention reduced maternal fasting insulin (ß: -0.16; 95% CI: -0.33, 0.02; P = 0.08) and HOMA-IR (ß: -0.17; 95% CI: -0.35, 0.01; P = 0.06), and reduced cord blood leptin (ß: -0.84; 95% CI: -1.42, -0.25; P = 0.01) and C-peptide (ß: -0.62; 95% CI: -1.07, -0.17; P = 0.01). In heterozygous women, the HE intervention had no effect, whereas in women homozygous for the C allele, HE intervention reduced GWG (ß: -1.6 kg; 95% CI: -2.4, -0.8 kg). No interactions were found. CONCLUSIONS: In women homozygous for the risk allele of MTNR1B rs10830962, GDM risk was increased and PA intervention might be more beneficial than HE intervention for reducing maternal insulin resistance, cord blood C-peptide, and cord blood leptin.

Interpregnancy weight gain and childhood obesity: analysis of a UK population-based cohort.

BACKGROUND: Maternal obesity increases the risk of adverse long-term health outcomes in mother and child including childhood obesity. We aimed to investigate the association between interpregnancy weight gain between first and second pregnancies and risk of overweight and obesity in the second child. METHODS: We analysed the healthcare records of 4789 women in Hampshire, UK with their first two singleton live births within a population-based anonymised linked cohort of routine antenatal records (August 2004 and August 2014) with birth/early life data for their children. Measured maternal weight and reported height were recorded at the first antenatal appointment of each pregnancy. Measured child height and weight at 4-5 years were converted to age- and sex-adjusted body mass index (BMI z-score). Log-binomial regression was used to examine the association between maternal interpregnancy weight gain and risk of childhood overweight and obesity in the second child. This was analysed first in the whole sample and then stratified by baseline maternal BMI category. RESULTS: The prevalence of overweight/obesity in the second child was 19.1% in women who remained weight stable, compared with 28.3% in women with ≥3 kg/m2 weight gain. Interpregnancy gain of ≥3 kg/m2 was associated with increased risk of childhood overweight/obesity (adjusted relative risk (95% CI) 1.17 (1.02-1.34)), with attenuation on adjusting for birthweight of the second child (1.08 (0.94-1.24)). In women within the normal weight range at first pregnancy, the risks of childhood obesity (≥95th centile) were increased with gains of 1-3 kg/m2 (1.74 (1.07-2.83)) and ≥3 kg/m2 (1.87 (1.18-3.01)). CONCLUSION: Children of mothers within the normal weight range in their first pregnancy who started their second pregnancy with a considerably higher weight were more likely to have obesity at 4-5 years. Supporting return to pre-pregnancy weight and limiting weight gain between pregnancies may achieve better long-term maternal and offspring outcomes.

Association Between Periconceptional Weight of Maternal Grandmothers and Attention-Deficit/Hyperactivity Disorder in Grandchildren.

Importance: Neurodevelopmental disorders have been proposed to involve alterations to epigenetic regulation, and epigenetic effects may extend to germline cells to affect later generations. Weight status may affect DNA methylation, and maternal weight before and during pregnancy has been associated with offspring DNA methylation as well as attention-deficit/hyperactivity disorder (ADHD). Objective: To assess whether a woman's weight before and during pregnancy is associated with ADHD in her grandchild. Design, Setting, and Participants: This cohort study analyzed data from 19 835 grandmother-mother dyads and 44 720 grandchildren in the Nurses' Health Study II (NHS-II) cohort (2001-2013), a population-based prospective cohort study. Cluster-weighted generalized estimating equations were modeled to estimate the association of grandmother's prepregnancy body mass index (BMI) and gestational weight gain with grandchild risk of ADHD. Data analyses were conducted from May 2018 to April 2021. Grandmothers reported their height and weight before, and weight gain during, their pregnancy with the NHS-II participants. Mothers self-reported height and weight prior to pregnancy. From those data, grandmother BMI and mother BMI were calculated as weight in kilograms divided by height in meters squared and categorized as underweight (<18.5), healthy/normal (18.5-24.9), overweight (25.0-29.9), or obese (≥30). Main Outcomes and Measures: Cases of ADHD identified by maternal report of having a child with a diagnosis of ADHD. Results: In total, 19 835 grandmothers (97.6% White race/ethnicity; 2113 [10.7%] prepregnancy underweight and 1391 [7.0%] prepregnancy overweight or obese) were included in this cohort study. Of 44 720 grandchildren, 3593 (8%) received a diagnosis of ADHD. Higher odds of ADHD among grandchildren were found for those whose grandmother was underweight compared with healthy weight prior to pregnancy with the NHS-II participant (adjusted odds ratio, 1.25; 95% CI, 1.10-1.42). By contrast, grandmother gestational weight gain was not significantly associated with risk of grandchild ADHD (adjusted odds ratio for <20 lbs [9.1 kg], 1.06; 95% CI, 0.96-1.16; adjusted odds ratio for >29 lbs [13.2 kg], 1.01; 95% CI, 0.91-1.13). Mother prepregnancy BMI showed an association with ADHD among offspring, with a stronger association detected for obese status (adjusted odds ratio, 1.27; 95% CI, 1.07-1.49) than for overweight status (adjusted odds ratio, 1.13; 95% CI, 1.02-1.26) compared with normal weight as a reference group. The positive association between grandmother prepregnancy underweight and ADHD risk among the grandchildren remained unchanged after further adjustment for potential mediators, including maternal prepregnancy BMI. Conclusions and Relevance: The results of this cohort study indicate that grandmother underweight prior to pregnancy is associated with an increased risk of ADHD among grandchildren, independent of grandmother gestational weight gain and independent of maternal prepregnancy weight status.

The transcriptome-wide association search for genes and genetic variants which associate with BMI and gestational weight gain in women with type 1 diabetes.

BACKGROUND: Clinical data suggest that BMI and gestational weight gain (GWG) are strongly interconnected phenotypes; however, the genetic basis of the latter is rather unclear. Here we aim to find genes and genetic variants which influence BMI and/or GWG. METHODS: We have genotyped 316 type 1 diabetics using Illumina Infinium Omni Express Exome-8 v1.4 arrays. The GIANT, ARIC and T2D-GENES summary statistics were used for TWAS (performed with PrediXcan) in adipose tissue. Next, the analysis of association of imputed expression with BMI in the general and diabetic cohorts (Analysis 1 and 2) or GWG (Analysis 3 and 4) was performed, followed by variant association analysis (1 Mb around identified loci) with the mentioned phenotypes. RESULTS: In Analysis 1 we have found 175 BMI associated genes and 19 variants (p < 10-4) which influenced GWG, with the strongest association for rs11465293 in CCL24 (p = 3.18E-06). Analysis 2, with diabetes included in the model, led to discovery of 1812 BMI associated loci and 207 variants (p < 10-4) influencing GWG, with the strongest association for rs9690213 in PODXL (p = 9.86E-07). In Analysis 3, among 648 GWG associated loci, 2091 variants were associated with BMI (FDR < 0.05). In Analysis 4, 7 variants in GWG associated loci influenced BMI in the ARIC cohort. CONCLUSIONS: Here, we have shown that loci influencing BMI might have an impact on GWG and GWG associated loci might influence BMI, both in the general and T1DM cohorts. The results suggest that both phenotypes are related to insulin signaling, glucose homeostasis, mitochondrial metabolism, ubiquitinoylation and inflammatory responses.

In Utero Exposure to Maternal Overweight or Obesity is Associated with Altered Offspring Brain Function in Middle Childhood.

OBJECTIVE: The impact of in utero exposure to maternal overweight and obesity on offspring metabolic health is well documented. Neurodevelopmental outcomes among these children are, however, less well studied. To address this gap, the current study investigated brain function among 4- to 6-year-old children exposed to maternal overweight or obesity during gestation compared with that of children born to mothers with healthy BMI in pregnancy. METHODS: Resting-state functional magnetic resonance imaging was used to study neuronal activity and connectivity during a passive viewing task (movie) among 101 typically developing children enrolled in the Healthy Start study, a longitudinal prebirth cohort in Colorado. RESULTS: Forty-nine children (48%) were exposed to maternal overweight or obesity in utero (mean age = 5 years, SD = 0.9). Children born to mothers with overweight or obesity demonstrated hyperactivity in the left posterior cingulate cortex and hypoactivity in the dorsal anterior cingulate and the supplementary motor area (P < 0.05 for all). Children born to mothers with overweight or obesity also showed ubiquitously weaker brain connectivity (P < 0.05 for all). CONCLUSIONS: These novel results suggest altered brain function among children exposed to maternal overweight and obesity in utero.

Maternal Gestational Diabetes Mellitus Modifies the Relationship Between Genetically Determined Body Mass Index During Pregnancy and Childhood Obesity.

OBJECTIVE: To analyze the interactions between maternal gestational diabetes mellitus (GDM) and genetically determined maternal body mass index (BMI) during pregnancy on offspring childhood obesity. RESEARCH DESIGN AND METHODS: A total of 1114 Chinese mother-child pairs (560 GDM and 554 non-GDM) were included between August 2009 and July 2011. Maternal genetic risk score (GRS) of BMI during pregnancy was derived on the basis of 12 single nucleotide polymorphisms identified from a genome-wide association study. Offspring's BMI, BMI-for-age z score, weight, weight-for-age z score, waist circumference, sum of skinfolds, and body fat percentage during childhood were measured or calculated. RESULTS: Maternal GRS of BMI during pregnancy significantly interacted with maternal GDM status on childhood risks of overweight and obesity (all P for interaction <.05). After multivariable adjustment, per unit of GRS was associated with a 24% (P<.001) and a 28% (P<.001) increased risk of overweight and obesity among children of GDM mothers, whereas no significant associations were observed among children of mothers without GDM. In addition, per unit GRS of BMI during pregnancy was significantly associated with 0.16 kg/m2 higher BMI (P=.002), 0.09 higher BMI-for-age z score (P=.002), 0.24 kg higher weight (P=.04), 0.06 higher weight-for-age z score (P=.02), 0.28 cm higher waist circumference (P=.03), 0.94 mm higher sum of skinfolds (P=.004), and 0.37% higher body fat percentage (P=.03) among children of GDM mothers. There were no significant associations between maternal GRS of BMI during pregnancy and offspring's obesity-related outcomes among children of mothers without GDM. CONCLUSION: Our findings for the first time indicate that maternal GDM status may modify the relation between genetically determined maternal BMI during pregnancy and offspring's obesity risk during childhood.

Contraction-associated proteins expression by human uterine smooth muscle cells depends on maternal serum and progranulin associated with gestational weight gain.

Pregnant women with obesity are at increased risk of parturition dysfunction; however, the biological mechanism has remained unknown. We hypothesized that molecules circulating in the serum of pregnant women with obesity may induce the aberrant expression of contraction-associated proteins (CAPs), leading to insufficient uterine contractions. This study aimed to investigate the effects of maternal serum on CAPs expression by human uterine smooth muscle cells (UtSMCs) and elucidate the influence of maternal obesity. Blood samples were collected from singleton pregnant women at 36-41 weeks of gestation before the onset of labor. UtSMCs were incubated in the serum, and the mRNA expressions of PTGFR, OXTR, GJA1, and PTGS2 were examined by RT-PCR. Progranulin (PGRN) is a circulating glycoprotein associated with insulin resistance characterized by the accumulation of visceral fat. The serum PGRN levels of the samples were measured by ELISA. After incubated with PGRN (100-1,000 ng/mL), mRNA expression of PTGFR, OXTR, and GJA1 and protein expression of CX43 were examined by RT-PCR and western blotting, respectively. The mRNA expressions of PTGFR, OXTR, and GJA1 showed significantly negative correlations with gestational weight gain (GWG). Serum PGRN levels showed a significantly positive correlation with GWG. High levels of PGRN suppressed the mRNA expression of GJA1 and the protein expression of CX43. The change in maternal serum induced by GWG suppressed the CAPs expression by UtSMCs. PGRN is one of the factors in the serum responsible for inhibiting the expression of CX43.

Exploration of the Vaginal and Gut Microbiome in African American Women by Body Mass Index, Class of Obesity, and Gestational Weight Gain: A Pilot Study.

OBJECTIVE: This study determines the differences in the distal gut and vaginal microbiome in African American (AA) women by prepregnancy body mass index and gestational weight gain (GWG) comparing women with and without obesity and by obesity class. STUDY DESIGN: We prospectively sampled the vaginal and distal gut microbiome in pregnant AA women at two time points during pregnancy. Samples were analyzed using high-throughput sequencing of the V4 region of the 16S ribosomal ribonucleic acid gene. RESULTS: Distinct differences in vaginal and distal gut α-diversity were observed at time point 1 between women with and without obesity by total GWG. Significant differences in distal gut ß-diversity were also found at time point 1 in obese women by GWG. Within the Bacteroides genus, a significant association was observed by total GWG among obese women which was absent in nonobese women. Women with class III obesity who experienced low GWG had the lowest abundance of distal gut Bacteroides and appreciably higher relative abundance of a consortia of vaginal taxa including Atopobium, Gardnerella, Prevotella, and Sneathia. CONCLUSION: These results contribute new evidence showing that GWG in combination with obesity and obesity class is associated with an altered distal gut and vaginal composition early in pregnancy among AA women.

Second Trimester Maternal Leptin Levels Are Associated with Body Mass Index and Gestational Weight Gain but not Birth Weight of the Infant.

INTRODUCTION: Obesity is increasing among the pregnant population. Leptin has an important role in the regulation of energy balance and hunger. The aim of this study was to investigate the association between maternal leptin levels with maternal obesity, gestational weight gain (GWG), single nucleotide polymorphisms (SNPs) within the leptin gene, and the age-adjusted birth weight of the child. MATERIAL AND METHODS: Maternal leptin levels (n = 740) and SNPs (n = 504) were analyzed in blood samples taken within the Uppsala Biobank of Pregnant women at pregnancy weeks 16-19. RESULTS: Maternal leptin levels differed significantly between body mass index (BMI) groups. Normal weight women had the lowest median leptin levels and levels increased with each BMI group. Leptin SNP genotype was not associated with leptin levels or BMI. There was also no association between maternal leptin levels and age-adjusted birth weight of the child except for a negative association between leptin levels and birth weight in the morbid obese group. DISCUSSION/CONCLUSION: Maternal BMI was identified as the best positive explanatory factor for maternal leptin levels. Leptin was a strong positive explanatory factor for GWG. Birth weight of children of uncomplicated pregnancies was, however, dependent on maternal height, BMI, GWG, and parity but not leptin levels, except for in morbid obese women where a negative association between maternal leptin levels and birth weight was found. We speculate that this indicates altered placental function, not manifested in pregnancy complication. We conclude that maternal leptin levels do not affect the birth weight of the child more than BMI, GWG, and parity.

The relationship among GNB3 rs5443, PNPLA3 rs738409, GCKR rs780094 gene polymorphisms, type of maternal gestational weight gain and neonatal outcomes (STROBE-compliant article).

The gestational weight gain is determined by food habits, environmental and genetic factors.The aims of this paper were to establish relationships between maternal gene polymorphisms (patatin-like phospholipase domain-containing protein 3 rs738409 [PNPLA3 rs738409], glucokinase regulatory protein rs780094 [GCKR rs780094], and guanine nucleotide-binding protein rs5443 [GNB3 rs5443]) and mothers' gestational weight gain, but also neonatal outcomes (birth weight, length, and ponderal index [PI]).We performed a cross-sectional study in a sample of 158 mothers and their product of conception' in an Obstetrics-Gynecology Clinic from Romania. We divided the pregnant women according to the Institute of Medicine recommendations into 3 subgroups: (1) insufficient gestational weight gain; (2) normal gestational weight gain; and (3) excessive gestational weight gain.The gestational weight gain among pregnant women included in this study was classified as insufficient (10.1%), normal (31%), and excessive (58.9%). We found a tendency towards statistical significance for mothers that were overweight or obese before pregnancy to present an excessive gestational weight gain as compared to the normal weight ones. Similarly, we identified a tendency for statistical significance regarding the association between the variant genotype of GNB3 rs5443 and excessive gestational weight gain. We noticed differences that tended to be statistical significant concerning aspartate aminotransferase values between the 3 subgroups, mothers with excessive gestational weight gain having higher values than mothers with normal gestational weight gain (median, IQR: 22.89[17.53; 31.59] for mothers with excessive gestational weight gain versus 22.71[18.58; 27.37] for mothers with normal gestational weight gain). In mothers with excessive gestational weight gain, we found a significant association between the variant genotype of PNPLA3 rs738409 polymorphism and neonatal PI noticing a decrease of this index in case of newborns from mothers carrying the variant genotype.Excessive gestational weight gain was noticed in pregnant women that were obese and overweight before pregnancy. We found a positive association between the variant genotype of GNB3 rs5443 polymorphism and excessive gestational weight gain. Similarly, the presence of variant genotype of PNPLA3 rs738409 in mothers was associated with a lower PI in their newborns. Our study pointed out the most important factors that influence gestational weight gain and related birth outcomes.

MC4R and ENPP1 gene polymorphisms and their implication in maternal and neonatal risk for obesity.

The aims of this study were to establish the role of MC4Rrs17782313 and ENPP1rs1044498 gene polymorphisms on pre-pregnancy BMI and the newborn's status. We performed a cross-sectional study on 185 mothers and their offspring. The groups were divided into: control group- underweight or normal mothers with BMIinitial < 25 kg/m2 (n1 = 134) and study group-overweight/obese mothers with BMIinitial ≥ 25 kg/m2 (n2 = 51). All subjects underwent demographic, anthropometric, paraclinical, bioimpedance and genetic parameters. We found association between initial BMI and gestational weight gain (GWG), and a higher frequency of excessive GWG in overweight/obese women (p = 0.037). Higher values of anthropometric and bioimpedance parameters were observed in overweight/obese versus underweight/normal women. The MC4R rs17782313 and ENPP1 rs1044498 variant genotypes had an increased risk of pre-pregnancy overweight (OR = 1.41; 95% CI:[0.72; 2.78]; OR = 1.34; 95% CI:[0.65; 2.75]). The newborns from mothers with excessive GWG had a higher birth weight (BW) (p = 0.001). Higher MUAC values were noticed in newborns with MC4R rs17782313 wild-type genotype. Also, BW was correlated with GWG status smoking in pregnancy, gestational age and neonatal ENPP1rs1044498 variant genotype (p = 0.026). Our study pointed out the role of MC4R rs17782313 and ENPP1 rs1044498 genotypes in obesity determinisms in mothers and their newborns in correlation with BMI, MUAC, TST and bioimpedance parameters.

Metabolic and Immunological Shifts during Mid-to-Late Gestation Influence Maternal Blood Methylation of CPT1A and SREBF1.

Mid-to-late gestation is a unique period in which women experience dynamic changes in lipid metabolism. Although the recent intensive epigenome-wide association studies (EWAS) using peripheral leukocytes have revealed that lipid-related traits alter DNA methylation, the influence of pregnancy-induced metabolic changes on the methylation levels of these differentially methylated sites is not well known. In this study, we performed a prospective cohort study of pregnant women (n = 52) using the MassARRAY EpiTYPER assay and analyzed the methylation levels of variably methylated sites, including CPT1A intron 1 and SREBF1 intron 1 CpGs, which were previously verified to be robustly associated with adiposity traits. Although methylation of SREBF1 was associated with body mass index (BMI) and low-density lipoprotein cholesterol at mid-gestation, this association was attenuated at late gestation, which was consistent with the metabolic switch from an anabolic to a catabolic state. However, the BMI association with CPT1A intron 1 methylation appeared to strengthen at late gestation; this association was mediated by pre-pregnancy BMI-dependent change in the leukocyte proportion during mid-to-late gestation. Thus, the methylation of adiposity-related differentially methylated regions was sensitive to metabolic and immunological changes during mid-to-late gestation.

The relationship between MMP9 and ADRA2A gene polymorphisms and mothers-newborns' nutritional status: an exploratory path model (STROBE compliant article).

BACKGROUND: The aim of this study was to evaluate the direct effects of matrix metalloproteinase (MMP9 rs17577, MMP9 rs17576) and alfa 2 adrenergic receptor (ADRA2A rs553668) gene polymorphisms investigated in mothers and their newborns on maternal weight gain (MWG) during pregnancy and the newborn's birth weight (BW), taking into account the presence of other related factors. METHODS: We performed a cross-sectional study in 197 mother-newborn pairs in an Obstetrics Gynecology Clinic, in order to evaluate the demographic and anthropometric parameters, and gene polymorphism. RESULTS: BW was positively correlated with maternal age (p = 0.021) and the educational level (p = 0.002), and negatively correlated with smoking status in pregnant women (p < 0.001). The MMP9 rs17577 variant genotypes in mothers led to a lower BW (p = 0.049). The mothers with a variant genotype of ADRA2A rs553668 gene polymorphism had newborns with a higher BW (p = 0.030). MWG and gestational age (GesAge) influenced BW (p < 0.05). We noticed that newborns' variant genotype of MMP9 rs17577 was related to a significant increase in BW (p = 0.010), while the newborns who carried the variant genotype of MMP9 rs17576 expressed a negative correlation, decreasing the BW (p = 0.032). CONCLUSION: Our study emphasizes the role of MMP9 rs17577, MMP9 rs17576, and ADRA2A rs553668 SNPs in BW determinism.

Similarities in Maternal Weight and Birth Weight Across Pregnancies and Across Sisters.

Objectives The current study examined how prepregnancy body mass index (BMI), gestational weight gain, and birth weight cluster between births within women and between women who are sisters. Methods Using data from the National Longitudinal Survey of Youth 1979 cohort, we utilized nested, multivariable hierarchical linear models to examine the correlation of these three outcomes between births (n = 6006) to women (n = 3605) and sisters (n = 3170) so that we can quantify the clustering by sibship and by woman for these three pregnancy-related outcomes. Results After controlling for confounding covariates, prepregnancy BMI (intraclass correlation (ICC) 0.24, 95% CI 0.16, 0.32), gestational weight gain (ICC 0.23, 95% CI 0.16, 0.31), and infant's birthweight (ICC 0.07, 95% CI 0.003, 0.13) were correlated between sisters. Additionally, all three outcomes were significantly correlated between births for each sister, suggesting that prepregnancy BMI (ICC 0.82, 95% CI 0.81, 0.83), gestational weight gain (ICC 0.45, 95% CI 0.42, 0.49), and birth weight (ICC 0.31, 95% CI 0.28, 0.35) track between pregnancies in the same woman. Conclusions for Practice The observed clustering both within women and between sisters suggests that shared genetic and environmental factors among sisters play a role in pregnancy outcomes above and beyond that of women's own genetic and environmental factors. Findings suggest that asking a woman about her sisters' pregnancy outcomes could provide insight into the possible outcomes for her current pregnancy. Future research should test if collecting such a family history and providing tailored clinical recommendations accordingly would be useful.

Effects of the interaction between glycated haemoglobin genetic risk score and postpartum weight reduction on glycaemic changes: A gene-weight interaction analysis.

AIM: To investigate the effects of the interaction between glycated haemoglobin (HbA1c) genetic risk score and weight changes during and after pregnancy (postpartum weight reduction and gestational weight gain) on long-term glycaemic changes in the largest cohort of women with a history of gestational diabetes mellitus (GDM). METHODS: This was a retrospective cohort using the baseline data from the Tianjin Gestational Diabetes Mellitus Prevention Programme. A genetic risk score was established by combining 10 HbA1c-related single-nucleotide polymorphisms, which were identified by genome-wide association studies. General linear regression models were applied to evaluate the effect of interaction between HbA1c genetic risk score and weight changes during and after pregnancy (postpartum weight reduction and gestational weight gain) on glycaemic changes. RESULTS: 'A total of 1156 women with a history of GDM were included in this respective cohort study. Statistical differences in pre-pregnancy weight, pre-delivery weight and postpartum weight were evidenced across different groups of postpartum weight reduction. After adjusting for covariates, statistical significance for changes in HbA1c level was only observed in the postpartum weight reduction <5 kg/y group (P = 0.002), and a significant effect of interaction between HbA1c genetic risk score and postpartum weight reduction on long-term changes in HbA1c was evidenced (P interaction = 0.01). In women with postpartum weight reduction ≥8 kg/y, those with a lower HbA1c genetic risk score had a greater decrease in HbA1c level. CONCLUSIONS: HbA1c genetic risk score interacts with postpartum weight reduction to affect long-term changes in HbA1c levels among women with a history of GDM.

The Circadian Rhythm-Related MTNR1B Genotype, Gestational Weight Gain, and Postpartum Glycemic Changes.

Context: Disturbed circadian rhythms and sleep quality during pregnancy have been related to gestational weight gain and gestational diabetes mellitus (GDM), which affect postpartum glucose metabolism and future risk of type 2 diabetes. Objective: We assessed whether the circadian rhythm-related melatonin receptor 1B (MTNR1B) genotype was associated with 1 to 5 years of postpartum glycemic changes among women with a history of GDM and whether gestational weight gain modified such associations. Design, Settings, and Participants: The established circadian rhythm-associated MTNR1B genetic variant (rs10830963) was genotyped in 1025 Chinese women with a history of GDM. Body weight and glycemic traits, during and after pregnancy, were longitudinally collected. Main Outcome Measures: The main outcome measure was postpartum glycemic changes. Results: We found that women carrying different MTNR1B genotypes showed distinct postpartum changes in 2-hour oral glucose tolerance test: 0.36, 0.20, and -0.19 mM per additional copy of the shorter sleep duration-related G allele in women with inadequate, adequate, and excessive gestational weight gain, respectively (for interaction, P = 0.028). The corresponding changes in fasting glucose were 0.14, 0.13, and 0.01 mM, although the modification effect of gestational weight gain on the genetic association was marginally significant (for interaction, P = 0.067). Conclusions: Our findings suggest that gestational weight gain may modify the circadian rhythm-related MTNR1B genetic variant on long-term glycemic changes, highlighting the significance of gestational weight management in diabetes prevention among women with GDM.