Genome-wide approach identifies a novel gene-maternal pre-pregnancy BMI interaction on preterm birth

Preterm birth (PTB) contributes significantly to infant mortality and morbidity with lifelong impact. Few robust genetic factors of PTB have been identified. Such ‘missing heritability’ may be partly due to gene × environment interactions (G × E), which is largely unexplored. Here we conduct genome-wide G × E analyses of PTB in 1,733 African-American women (698 mothers of PTB; 1,035 of term birth) from the Boston Birth Cohort. We show that maternal COL24A1 variants have a significant genome-wide interaction with maternal pre-pregnancy overweight/obesity on PTB risk, with rs11161721 (PG × E=1.8 × 10−8; empirical PG × E=1.2 × 10−8) as the top hit. This interaction is replicated in African-American mothers (PG × E=0.01) from an independent cohort and in meta-analysis (PG × E=3.6 × 10−9), but is not replicated in Caucasians. In adipose tissue, rs11161721 is significantly associated with altered COL24A1 expression. Our findings may provide new insight into the aetiology of PTB and improve our ability to predict and prevent PTB.HSN268200782096CHHSN268201200008I20-FY02-56, #21-FY07-605R21ES011666R21HD0664712R01HD041702101-2314-B-400-009-MY2103-2314-B-400-004-MY32016YFC02065079164320121477087NICHD R24HD04285

Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children

Food allergy (FA) affects 2%-10% of US children and is a growing clinical and public health problem. Here we conduct the first genome-wide association study of well-defined FA, including specific subtypes (peanut, milk and egg) in 2,759 US participants (1,315 children and 1,444 parents) from the Chicago Food Allergy Study, and identify peanut allergy (PA)-specific loci in the HLA-DR and -DQ gene region at 6p21.32, tagged by rs7192 (P=5.5 × 10 -8) and rs9275596 (P=6.8 × 10 -10), in 2,197 participants of European ancestry. We replicate these associations in an independent sample of European ancestry. These associations are further supported by meta-analyses across the discovery and replication samples. Both single-nucleotide polymorphisms (SNPs) are associated with differential DNA methylation levels at multiple CpG sites (

Racial and ethnic differences in physical activity among mothers of young children: 2011–2018 NHANES

Abstract Background American women tend to reduce physical activity (PA) during the transition to motherhood. Their main barrier to participation in PA is lack of time due to new/increased parenting and housework responsibilities. Because there are known racial/ethnic variations in time spent on housework among American women, their PA changes during the transition to motherhood might also differ by racial/ ethnic background. This study aimed to compare PA between American mothers of young child(ren) under age 5 years (YC) and American women without children by their racial/ethnic background. Methods Secondary data analyses were conducted using 2011–2018 US National Health and Nutrition Survey data. The study sample included 4,892 women aged 20–45 years (Asian n = 760; Black n = 1,162; Hispanic n = 1,324; White n = 1,646). Participants completed a Physical Activity Questionnaire that asked about participation in transportation and leisure-time moderate- and vigorous-intensity PA (MVPA; minutes/week). Multivariable regression analyses were conducted to compare MVPA among women living without children and with YC (no older children) in each of the racial/ethnic groups. Results Overall, the prevalence of physical inactivity, defined as zero minutes of MVPA in a typical week, was 43% (95% CI = 38–49%) vs. 32% (95% CI = 29–35%) among women living with YC vs. without children. The adjusted odds of physical inactivity for women living with YC, compared to women living without children, was significantly higher among Asian (OR = 2.08 [95% CI = 1.37–3.17]) and White women (OR = 1.63 [95% CI = 1.11–2.38]), while it was statistically insignificant among Hispanic and Black women. Among women who reported participating in MVPA, Asian women living with YC had 35 fewer minutes/week of MVPA than their counterparts living without children (p = 0.06), while other racial and ethnic groups showed no significant differences. Conclusions American mothers of YC were less likely to engage in transportation or leisure-time MVPA, compared to those living without children. This association was particularly strong among Asian women. The study results suggest that a PA reduction in the transition to motherhood may be particularly large among Asian American women, calling for targeted efforts for PA promotion among Asian American mothers of YC; e.g., culturally-tailored community-based physical activity programs for Asian American mothers

Additional file 1 of Racial and ethnic differences in physical activity among mothers of young children: 2011–2018 NHANES

Supplementary Table 1. Adjusted odds ratios of physical inactivity outside of work among woman participants aged 20-45 years in the 2011-18 US NHANE

Impact of intrauterine exposure to maternal diabetes on preterm birth: fetal DNA methylation alteration is an important mediator

Abstract Background In utero exposure to diabetes has been shown to contribute to preterm birth, though the underlying biological mechanisms are yet to be fully elucidated. Fetal epigenetic variations established in utero may be a possible pathway. This study aimed to investigate whether in utero exposure to diabetes was associated with a change in newborn DNA methylation, and whether the identified CpG sites mediate the association between diabetes and preterm birth in a racially diverse birth cohort population. Methods This study included 954 mother–newborn pairs. Methylation levels in the cord blood were determined using the Illumina Infinium MethylationEPIC BeadChip 850 K array platform. In utero exposure to diabetes was defined by the presence of maternal pregestational or gestational diabetes. Preterm birth was defined as gestational age at birth less than 37 weeks. Linear regression analysis was employed to identify differentially methylated CpG sites. Differentially methylated regions were identified using the DMRcate Package. Results 126 (13%) newborns were born to mothers with diabetes in pregnancy and 173 (18%) newborns were born preterm, while 41 newborns were born both preterm and to mothers with diabetes in pregnancy. Genomic-wide CpG analysis found that eighteen CpG sites in cord blood were differentially methylated by maternal diabetes status at an FDR threshold of 5%. These significant CpG sites were mapped to 12 known genes, one of which was annotated to gene Major Histocompatibility Complex, Class II, DM Beta (HLA-DMB). Consistently, one of the two identified significant methylated regions overlapped with HLA-DMB. The identified differentially methylated CpG sites mediated the association between diabetes in pregnancy and preterm birth by 61%. Conclusions In this US birth cohort, we found that maternal diabetes was associated with altered fetal DNA methylation patterns, which substantially explained the link between diabetes and preterm birth

Gestational Diabetes Mellitus, Postpartum Lipidomic Signatures, and Subsequent Risk of Type 2 Diabetes: A Lipidome-Wide Association Study

OBJECTIVE To identify a postpartum lipidomic signature associated with gestational diabetes (GDM) and investigate the role of the identified lipids in the progression to type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS This was a prospective cohort study of 1409 women who were enrolled at 24-72 hours after delivery of a singleton baby and followed prospectively at the Boston Medical Center, Boston, MA. Lipidome was profiled by liquid chromatography–tandem mass spectrometry platform. Diagnoses of GDM and incident T2D were extracted from medical records and verified using plasma glucose levels.  RESULTS Mean (SD) age of study women at baseline was 28.5±6.6 years. 219 (16.4%) women developed incident diabetes over a median (interquartile range) follow-up of 11.8 (8.2-14.8) years. We identified 33 postpartum lipid species associated with GDM, including 16 inverse associations (primarily cholesterol esters and phosphatidylcholine plasmalogens), and 17 positive associations (primarily diacyglycerols and triacyglycerols). Of these, 4 were associated with risk of incident T2D and mediated about 12% of the progression from GDM to T2D. The identified lipid species modestly improved the predictive performance for incident T2D above classical risk factors when the entire follow-up period was considered.  CONCLUSIONS GDM was associated with a wide range of lipid metabolic alterations at early postpartum, among which some lipid species were also associated with incident T2D and mediated the progression from GDM to T2D. The improvements attained by including lipid species in the prediction of T2D provides new insights regarding the early detection and prevention of progression to T2D.</p

Distribution and Determinants of Plasma Homocysteine Levels in Rural Chinese Twins across the Lifespan

Plasma homocysteine (Hcy) is a modifiable, independent risk factor for cardiovascular disease (CVD) and is affected by both environmental and genetic factors. This study aimed to describe the gender- and age-specific distribution of Hcy concentration for 1117 subjects aged 10–66 years, a subset of a community-based rural Chinese twin cohort. In addition, we examined environmental and genetic contributions to variances in Hcy concentration by gender and age groups. We found that the distribution pattern for Hcy varied by both age and gender. Males had higher Hcy than females across all ages. Elevated Hcy was found in 43% of male adults and 13% of female adults. Moreover, nearly one fifth of children had elevated Hcy. Genetic factors could explain 52%, 36% and 69% of the variation in Hcy concentration among children, male adults and female adults, respectively. The MTHFR C677T variant was significantly associated with Hcy concentrations. Smokers with the TT genotype had the highest Hcy levels. Overall, our results indicate that elevated Hcy is prevalent in the children and adults in this rural Chinese population. The early identification of elevated Hcy will offer a window of opportunity for the primary prevention of CVD and metabolic syndrome

Maternal Biomarkers of Acetaminophen Use and Offspring Attention Deficit Hyperactivity Disorder

Previous studies have suggested a positive association between self-reported maternal acetaminophen use during pregnancy and risk of attention deficit hyperactivity disorder (ADHD) in offspring. We sought to examine the prospective association between maternal plasma biomarkers of acetaminophen intake and ADHD diagnosis in the offspring. This report analyzed 1180 children enrolled at birth and followed prospectively as part of the Boston Birth Cohort, including 188 with ADHD diagnosis based on electronic medical record review. Maternal biomarkers of acetaminophen intake were measured in plasma samples obtained within 1&ndash;3 days postpartum. Odds ratios for having ADHD diagnosis or other developmental disorders were estimated using multinomial logistic regression models, adjusting for pertinent covariables. Compared to neurotypical children, we observed significant positive dose-responsive associations with ADHD diagnosis for each maternal acetaminophen biomarker. These dose&ndash;responsive associations persisted after adjusting for indication of acetaminophen use and other pertinent covariates; and were specific to ADHD, rather than other neurodevelopmental disorders. In the stratified analyses, differential point estimates of the associations were observed across some strata of covariates. However, these differences were not statistically significant. Maternal acetaminophen biomarkers were specifically associated with increased risk of ADHD diagnosis in offspring. Additional clinical and mechanistic investigations are warranted

A Prospective Birth Cohort Study on Maternal Cholesterol Levels and Offspring Attention Deficit Hyperactivity Disorder: New Insight on Sex Differences

Growing evidence suggests that maternal cholesterol levels are important in the offspring’s brain growth and development. Previous studies on cholesterols and brain functions were mostly in adults. We sought to examine the prospective association between maternal cholesterol levels and the risk of attention deficit hyperactivity disorder (ADHD) in the offspring. We analyzed data from the Boston Birth Cohort, enrolled at birth and followed from birth up to age 15 years. The final analyses included 1479 mother-infant pairs: 303 children with ADHD, and 1176 neurotypical children without clinician-diagnosed neurodevelopmental disorders. The median age of the first diagnosis of ADHD was seven years. The multiple logistic regression results showed that a low maternal high-density lipoprotein level (≤60 mg/dL) was associated with an increased risk of ADHD, compared to a higher maternal high-density lipoprotein level, after adjusting for pertinent covariables. A “J” shaped relationship was observed between triglycerides and ADHD risk. The associations with ADHD for maternal high-density lipoprotein and triglycerides were more pronounced among boys. The findings based on this predominantly urban low-income minority birth cohort raise a new mechanistic perspective for understanding the origins of ADHD and the gender differences and future targets in the prevention of ADHD