Accelerated postnatal growth is a potentially modifiable risk factor for future obesity. To study how specific breast milk components contribute to early growth and obesity risk, we quantified one-carbon metabolism-related metabolites in human breast milk and found an inverse association between milk betaine content and infant growth. This association was replicated in an independent and geographically distinct cohort. To determine the potential role of milk betaine in modulating offspring obesity risk, we performed maternal betaine supplementation experiments in mice. Higher betaine intake during lactation increased milk betaine content in dams and led to lower adiposity and improved glucose homeostasis throughout adulthood in mouse offspring. These effects were accompanied by a transient increase in Akkermansia spp. abundance in the gut during early life and a long-lasting increase in intestinal goblet cell number. The link between breast milk betaine and Akkermansia abundance in the gut was also observed in humans, as infants exposed to higher milk betaine content during breastfeeding showed higher fecal Akkermansia muciniphila abundance. Furthermore, administration of A. muciniphila to mouse pups during the lactation period partially replicated the effects of maternal breast milk betaine, including increased intestinal goblet cell number, lower adiposity, and improved glucose homeostasis during adulthood. These data demonstrate a link between breast milk betaine content and long-term metabolic health of offspring.

Among all the body fluids, breast milk is one of the richest sources of microRNAs (miRNAs). MiRNAs packaged within the milk exosomes are bioavailable to breastfeeding infants. The role of miRNAs in determining infant growth and the impact of maternal overweight/obesity on human milk (HM) miRNAs is poorly understood. The objectives of this study were to examine the impact of maternal overweight/obesity on select miRNAs (miR-148a, miR-30b, miR-29a, miR-29b, miR-let-7a and miR-32) involved in adipogenesis and glucose metabolism and to examine the relationship of these miRNAs with measures of infant body composition in the first 6 months of life. Milk samples were collected from a cohort of 60 mothers (30 normal-weight [NW] and 30 overweight [OW]/obese [OB]) at 1-month and a subset of 48 of these at 3 months of lactation. Relative abundance of miRNA was determined using real-time PCR. The associations between the miRNAs of interest and infant weight and body composition at one, three, and six months were examined after adjusting for infant gestational age, birth weight, and sex. The abundance of miR-148a and miR-30b was lower by 30% and 42%, respectively, in the OW/OB group than in the NW group at 1 month. miR-148a was negatively associated with infant weight, fat mass, and fat free mass, while miR-30b was positively associated with infant weight, percent body fat, and fat mass at 1 month. Maternal obesity is negatively associated with the content of select miRNAs in human milk. An association of specific miRNAs with infant body composition was observed during the first month of life, suggesting a potential role in the infant’s adaptation to enteral nutrition.

BACKGROUND: Whether current dietary guidelines are appropriate for pregnancy and lactation has not been well studied. Many women of reproductive age are not meeting recommendations for dietary components such as fat, added sugar, and fiber. OBJECTIVE(S): To assess associations between maternal dietary components during pregnancy and lactation and infant growth and adiposity at 6 mo of age. METHOD(S): Mother-infant dyads (n = 349) from the prospective, observational Mothers and Infants Linked for Healthy Growth study were included (100% fully breastfed for 1 mo; 75% to 6 mo). Daily intake of fat, fiber, and added sugar was obtained using the National Cancer Institute Diet History Questionnaire II during the third trimester of pregnancy and at 1 and 3 mo postpartum. Furthermore, intakes were categorized as meeting/exceeding 2015-2020 Dietary Guidelines for Americans. Multiple linear regression models adjusted for numerous potential confounders tested relations between dietary components and infant adiposity (via DXA) and growth parameters. Regression coefficients (beta) for continuous variables were expressed per SD to allow for comparison of effect sizes. RESULT(S): Maternal intake of total fat and saturated fat was positively associated with infant percent body fat (%BF) (beta: 0.84 per SD, P = 0.04; beta: 0.96 per SD, P = 0.01, respectively). Added sugar intake was positively associated with infant weight-for-length z score (beta: 0.16 per SD, P = 0.02), and excessive added sugar intake was positively associated with %BF at 6 mo (beta: 0.75 per SD, P = 0.05). CONCLUSION(S): In a predominantly fully breastfeeding cohort of women, maternal intake of fat and added sugar during pregnancy and lactation were associated with small increases in infant adiposity and relative weight at 6 mo. Additional research is needed to determine if these relations persist later in infancy and if such elevations in adiposity are important for long-term obesity risk.Copyright © The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.

Background: A premature infant's discharge from the neonatal intensive care unit (NICU) is dependent on factors such as respiratory stability, adequate growth, and the ability to consume oral feeds. Once infants have achieved respiratory stability, a tool that can better predict age at discharge is desirable. Thus, we conducted a secondary data analysis to assess the association between ultrasound measurements of abdominal muscle thickness and postmenstrual age (PMA) at full oral feedings. Methods: Forty-nine (n = 49) healthy, premature infants (mean gestational age = 32 weeks) were recruited from the NICU. Anthropometric measurements and ultrasound measurements of the rectus abdominis were conducted when infants were medically stable. Fat-free mass (FFM) was obtained using air displacement plethysmography. The relationship between ultrasound measurements of muscle thickness and PMA at full oral feedings was assessed using linear regression analysis. The relationship between FFM z-scores and PMA at full oral feedings was also assessed for comparison. Results: When adjusting for gestational age at birth, PMA at measurement, days of positive pressure respiratory support, weight, and length, ultrasound measurements of abdominal muscle thickness were independently, negatively associated with PMA at full oral feedings (β estimate: −0.71, P =.03). Conclusion: Preliminary results suggest infants with greater abdominal muscle thickness may reach full oral feedings at an earlier PMA (nearly 1 week per millimeter). Thus, ultrasound measurements of abdominal muscle thickness may be helpful in assessing readiness for discharge in healthy preterm infants. Further research is needed for development and validation of a prediction equation.

Background: Body mass index (BMI), a well-known risk factor for poor cardiovascular outcomes, is associated with differential DNA methylation (DNAm). Similarly, metabolic health has also been associated with changes in DNAm. It is unclear how overall metabolic health outside of BMI may modify the relationship between BMI and methylation profiles, and what consequences this may have on downstream cardiovascular disease. The purpose of this study was to identify cytosine-phosphate-guanine (CpG) sites at which the association between BMI and DNAm could be modified by overall metabolic health. Results: The discovery study population was derived from three Women’s Health Initiative (WHI) ancillary studies (n = 3977) and two Atherosclerosis Risk in Communities (ARIC) ancillary studies (n = 3520). Findings were validated in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort (n = 1200). Generalized linear models regressed methylation β values on the interaction between BMI and metabolic health Z score (BMI × MHZ) adjusted for BMI, MHZ, cell composition, chip number and location, study characteristics, top three ancestry principal components, smoking, age, ethnicity (WHI), and sex (ARIC). Among the 429,566 sites examined, differential associations between BMI × MHZ and DNAm were identified at 22 CpG sites (FDR q < 0.05), with one site replicated in MESA (cg18989722, in the TRAPPC9 gene). Three of the 22 sites were associated with incident coronary heart disease (CHD) in WHI. For each 0.01 unit increase in DNAm β value, the risk of incident CHD increased by 9% in one site and decreased by 6–10% in two sites over 25 years. Conclusions: Differential associations between DNAm and BMI by MHZ were identified at 22 sites, one of which was validated (cg18989722) and three of which were predictive of incident CHD. These sites are located in several genes related to NF-kappa-B signaling, suggesting a potential role for inflammation between DNA methylation and BMI-associated metabolic health.

BACKGROUND: Inflammatory effects of ambient particulate matter (PM) air pollution exposures may underlie PM-related increases in cardiovascular disease risk and mortality, although evidence of PM-associated leukocytosis is inconsistent and largely based on small, cross-sectional, and/or unrepresentative study populations. OBJECTIVES: Our objective was to estimate PM–leukocyte associations among U.S. women and men in the Women’s Health Initiative and Atherosclerosis Risk in Communities study (n = 165,675). METHODS: We based the PM–leukocyte estimations on up to four study visits per participant, at which peripheral blood leukocytes and geocoded address-specific concentrations of PM ≤ 10, ≤2:5, and 2:5–10 lm in diameter (PM10, PM2:5, and PM2:5–10, respectively) were available. We multiply imputed missing data using chained equations and estimated PM–leukocyte count associations over daily to yearly PM exposure averaging periods using center-specific, linear, mixed, longitudinal models weighted for attrition and adjusted for sociodemographic, behavioral, meteorological, and geographic covariates. In a subset of participants with available data (n = 8,457), we also estimated PM–leukocyte proportion associations in compositional data analyses. RESULTS: We found a 12 cells=lL (95% confidence interval: −9, 33) higher leukocyte count, a 1.2% (0.6%, 1.8%) higher granulocyte proportion, and a −1:1% (−1:9%, −0:3%) lower CD8+ T-cell proportion per 10-lg=m3 increase in 1-month mean PM2:5. However, shorter-duration PM10 exposures were inversely and only modestly associated with leukocyte count. DISCUSSION: The PM2:5 –leukocyte estimates, albeit imprecise, suggest that among racially, ethnically, and environmentally diverse U.S. populations, sustained, ambient exposure to fine PM may induce subclinical, but epidemiologically important, inflammatory effects. https://doi.org/10.1289/EHP5360.

Preterm infants have altered body composition compared to term infants, which impacts both neurodevelopment and metabolic health, but whether increased dietary intake during hospitalization, independent of illness, may improve body composition is unknown. This prospective, longitudinal study (n = 103) measured fat-free mass (FFM) and percent body fat (%BF) at discharge and four months corrected age for prematurity (CA) in very low birth weight (VLBW) preterm infants. Markers of illness and macronutrient intakes (protein and caloric) were recorded. Bayley Scales of Infant Development-III (BSID) were administered at 12 and 24 months of age in a subset of these infants (n = 66 and n = 50 respectively). Body composition z-scores were calculated using recently developed reference curves. Linear regression was used to test the associations between clinical factors and body composition z-scores, as well as z-scores and BSID scores. Increased calories and protein received in the first week after birth and protein intake throughout hospitalization were associated with increased FFM z-scores at discharge, but not with %BF z-scores. After adjustment for both early acute and chronic illness, associations of nutrient intake with FFM z-score remained unchanged. FFM z-scores at discharge were positively associated with scores on the BSID at 12 and 24 months CA. In conclusion, increased energy and protein intakes both early in hospitalization and across its entire duration are associated with higher FFM at discharge, a key marker for organ growth and neurodevelopment in the VLBW neonate. Optimizing caloric intake, irrespective of illness is critical for enhancing body composition, and by extension, neurodevelopmental outcomes for preterm infants.

Monitoring whole body composition (fat mass and fat-free mass) in preterm infants may assist in optimizing nutrition and promoting growth and neurodevelopment in the neonatal intensive care unit. Currently, body composition assessment is not part of routine clinical evaluation of premature infants. Instead, weight and length are used to assess growth but are known to be poor predictors of adiposity shortly after birth. Although body composition methods, such as magnetic resonance imaging, stable-isotope dilution, and dual-energy x-ray absorptiometry, have been examined in infants, they involve exposure to radiation and are invasive, expensive, and/or unsuitable for repeated measurements in a medically fragile population. Several body composition methods with potential for clinical use have been explored in premature infants, including air displacement plethysmography, bioimpedance, skinfold measurements, and ultrasound. In this review, we examine each method and evaluate its feasibility for incorporation into clinical care. Although these methods show promise for use in premature infants, further research is needed before they can be recommended for routine body composition assessment in the clinical setting.

Purpose of reviewThis narrative review presents the current state of available evidence regarding the role of breast milk carbohydrates on infant outcomes, with a primary focus on growth and body composition.Recent findingsTo date, there is a paucity of available data that exists in this realm. The current literature focuses on the role of two carbohydrate fractions in breast milk, and their relationships with infant outcomes in the first six months of life: oligosaccharides and fructose. A small but growing body of research indicates robust associations of both oligosaccharides and fructose in breast milk with infant weight and length, as well as bone, fat, and lean mass. There is also emerging evidence to support the role of these same carbohydrate fractions in breast milk in infant cognitive development.SummaryThe present state of the science suggests that oligosaccharides and fructose in breast milk play a role in infant growth and body composition and introduces intriguing associations of these two carbohydrate fractions with infant cognitive development as well.

Background: DNA methylation patterns associated with habitual diet have not been well studied. Methods: Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides) in 5 population-based cohorts including 6662 European ancestry, 2702 African ancestry, and 360 Hispanic ancestry participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease risk factors and examined their longitudinal associations with all-cause mortality. Results: We identified 30 CpGs associated with either Mediterranean-style diet score or Alternative Healthy Eating Index, or both, in European ancestry participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni corrected P<1.6×10-3). Hypermethylation of cg18181703 (SOCS3) was associated with higher scores of both Mediterranean-style diet score and Alternative Healthy Eating Index and lower risk for all-cause mortality (P=5.7×10-15). Ten additional diet-associated CpGs were nominally associated with all-cause mortality (P<0.05). MR analysis revealed 8 putatively causal associations for 6 CpGs with 4 cardiovascular disease risk factors (body mass index, triglycerides, high-density lipoprotein cholesterol concentrations, and type 2 diabetes mellitus; Bonferroni corrected MR P<4.5×10-4). For example, hypermethylation of cg11250194 (FADS2) was associated with lower triglyceride concentrations (MR, P=1.5×10-14).and hypermethylation of cg02079413 (SNORA54; NAP1L4) was associated with body mass index (corrected MR, P=1×10-6). Conclusions: Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in European ancestry individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.

Aim: We conducted a methylome-wide association study to examine associations between DNA methylation in whole blood and central adiposity and body fat distribution, measured as waist circumference, waist-to-hip ratio and waist-to-height ratio adjusted for body mass index, in 2684 African-American adults in the Atherosclerosis Risk in Communities study. Materials & methods: We validated significantly associated cytosine-phosphate-guanine methylation sites (CpGs) among adults using the Women's Health Initiative and Framingham Heart Study participants (combined n = 5743) and generalized associations in adolescents from The Raine Study (n = 820). Results & conclusion: We identified 11 CpGs that were robustly associated with one or more central adiposity trait in adults and two in adolescents, including CpG site associations near TXNIP, ADCY7, SREBF1 and RAP1GAP2 that had not previously been associated with obesity-related traits.

Within Stress, Early Experiences, and Development (SEED) science, there is a growing body of research demonstrating complex associations not only between stress, development, and psychopathology, but also with chronic disease risk factors. We argue that it is important for SEED researchers to consider including child anthropometric and physical health measures to more comprehensively capture processes of risk and resilience. Broader adoption of harmonized anthropometry and health measures in SEED research will facilitate collaborations, yielding larger datasets for research in high-risk populations, and greater opportunity to replicate existing findings. In this review, we identify optimal anthropometric and cardiometabolic health measurement methods used from infancy through adolescence, including those that are low-burden and inexpensive. Methods covered include: waist, hip, and head circumference, height, length, weight, pubertal development, body composition, blood pressure, arterial stiffness, carotid intima media thickness, and serum measures of cardiometabolic risk and inflammation. We provide resources for SEED researchers to integrate these methods into projects or to better understand these methods when reading the literature as well as where to find collaborators for more in-depth studies incorporating these measures. With broader integration of psychological and physical health measures in SEED research, we can better inform theory and interventions to promote health and resilience in individuals who have experienced early stress.

Background: Neonatal exposure to antibiotics, in the absence of infection, results in abnormal learning and memory in animals and is linked to changes in gut microbes. The relevance of early-life antibiotic exposure to brain function in humans is not known. Methods: Recognition memory was assessed at 1 month of age in 15 term-born infants exposed to antibiotics (with negative cultures) and 57 unexposed infants using event-related potentials (ERPs). Linear regression analysis, adjusting for covariates, was employed to compare groups with respect to ERP features representing early stimulus processing (P2 amplitude) and discrimination between mother and stranger voices. Results: Infants exposed to antibiotics exhibited smaller P2 amplitudes for both voice conditions (p = 0.001), with greatest reductions observed for mother’s voice in frontal and central scalp regions (p < 0.04). Infants exposed to antibiotics showed larger P2 amplitudes to stranger’s as compared to mother’s voice, a reversal of the typical response exhibited by unexposed infants. Abnormal ERP responses did not consistently correlate with increased inflammatory cytokines within the antibiotic-exposed group. Conclusions: Otherwise healthy infants exposed to antibiotics soon after birth demonstrated altered auditory processing and recognition memory responses, supporting the possibility of a microbiota–gut–brain axis in humans during early life. Impact: Infants exposed to antibiotics after birth demonstrate altered auditory processing and recognition memory responses at 1 month of age.Preclinical models support a role for gut microbiomes in modulating brain function and behavior, particularly in developing brains. This study is one of the first to explore the relevance of these findings for human infants.The findings of this study have implications for the management and follow-up of at-risk infants with exposure to gut-microbiome disrupting factors and lay foundation for future studies to further characterize the short- and long-term effects of gut microbiome perturbation on brain development.[Figure not available: see fulltext.][Figure not available: see fulltext.][Figure not available: see fulltext.][Figure not available: see fulltext.]

Aims: It is unclear if the presence of type-2 diabetes in one spouse is associated with the development of diabetes in the other spouse. We studied the concordance of diabetes among black and white participants in the Atherosclerosis Risk in Communities (ARIC) study and summarized existing studies in a meta-analysis. Methods: We conducted a prospective cohort analysis of ARIC data from 8077 married men and women (mean age 54 years) without diabetes at baseline (1987–1989). Complementary log–log models that accounted for interval censoring was used to model the hazard ratio (HR) for the association of spousal diabetes status with the incidence of diabetes. For the meta-analysis, we searched MEDLINE and EMBASE for observational studies published through December 2018 that evaluated spousal concordance for diabetes. Results: During a median follow-up of 22 years, 2512 incident cases of diabetes were recorded. In models with adjustment for general adiposity, spousal cardiometabolic factors and other diabetes risk factors, adults who had a spouse with diabetes had elevated risk for incident diabetes compared to those without a spouse diagnosed with diabetes (HR 1.20, 95% confidence interval 1.02–1.41). This association did not differ by sex or race. Summarized estimates from the 17 studies (489,798 participants from 9 countries) included in the meta-analysis showed a positive association between spousal diabetes status and the development of diabetes (Pooled odds ratio 1.88, 95% CI 1.52–2.33). Conclusions: Results from this large prospective biracial cohort and meta-analysis provides evidence that spouses of persons with diabetes are a high-risk group for diabetes.

Background: Maternal obesity is a risk factor for childhood obesity; this is a major public health concern given that 40% of pregnant women are either overweight or obese. Whether differences in milk composition in lean compared with obese women contribute to childhood obesity is unclear. Objectives: We aimed to analyze relationships between maternal obesity and human milk metabolites, infant body composition, and postnatal weight gain. Methods: This was a prospective study in which mothers intending to breastfeed exclusively, and their newborn infants, were enrolled at delivery (n = 35 mother-infant pairs). We excluded mothers with diabetes, other medical conditions, or pregnancy complications. Participants were grouped by maternal prepregnancy BMI <25 (lean) or ≥25 kg/m2 (overweight/obese). We analyzed infant body composition by dual-energy X-ray absorptiometry and used untargeted liquid chromatography-gas chromatography-mass spectrometry to measure the milk content of 275 metabolites at 1 and 6 mo postpartum. Results: At 1 mo postpartum, 10 metabolites differed between overweight/obese and lean groups with nominal P < 0.05, but none was altered with a false discovery rate <0.25. Many differentially abundant metabolites belonged to the same chemical class; e.g., 4/10 metabolites were nucleotide derivatives, and 3/10 were human milk oligosaccharides. Milk adenine correlated positively with both continuously distributed maternal BMI and with infant adiposity and fat accrual. Analysis of milk composition at 6 mo postpartum revealed 20 differentially abundant metabolites (P < 0.05) in overweight/obese compared with lean women, including 6 metabolites with a false discovery rate of < 0.25. At both 1 and 6 mo, human milk abundance of 1,5-anhydroglucitol, which has not previously been described in milk, was positively associated with maternal BMI. Conclusions: Maternal obesity is associated with changes in the human milk metabolome. While only a subset of metabolites correlated with both maternal and infant weight, these point to potentialmilk-dependent mechanisms for mother-child transmission of obesity. This trial was registered at www.clinicaltrials.gov as NCT02535637.

Observational studies demonstrate that women with severe periodontitis have a higher risk of adverse pregnancy outcomes like preterm birth and low birthweight. Standard treatment for periodontitis in the form of scaling and root planing during the second trimester failed to reduce the risk of preterm or low birthweight. It is premature to dismiss the association between periodontitis and adverse pregnancy outcomes because one explanation for the failure of scaling and root planing to reduce the risk of adverse pregnancy outcomes is that periodontal pathogens spread to the placental tissue prior to periodontal treatment. In the placenta, orally derived organisms could cause direct tissue damage or mediate a maternal immune response that impairs the growth of the developing fetus. Sequencing studies demonstrate the presence of organisms derived from the oral microbiome in the placenta, but DNA-based sequencing studies should not be the only technique to evaluate the placental microbiome because they may not detect important shifts in the metabolic capability of the microbiome. In humans, polymerase chain reaction and histology have detected periodontal pathogens in placental tissue in association with multiple adverse pregnancy outcomes. We conclude that both placental and oral microbiomes may play a role in periodontitis-associated adverse pregnancy outcomes. However, the measure to determine the association between periodontal pathogens in the placenta and adverse pregnancy outcomes should be the amount and prevalence, not the mere presence of such microorganisms. Placental colonization with periodontal pathogens thus potentially represents the missing link between periodontitis and adverse pregnancy outcomes.

Background: Air-displacement plethysmography (ADP) is a good candidate for monitoring body composition in newborns and young infants, but reference centile curves are lacking that allow for assessment at birth and across the first 6 mo of life. Objectives: Using pooled data from 4 studies, we aimed to produce new charts for assessment according to gestational age at birth (30 + 1 to 41 + 6 wk) and postnatal age at measurement (1-27 wk). Methods: The sample comprised 222 preterm infants born in the United States who were measured at birth; 1029 term infants born in Ireland who were measured at birth; and 149 term infants born in the United States and 57 term infants born in Italy who were measured at birth, 1 and 2 wk, and 1, 2, 3, 4, 5, and 6 mo of age. Infants whose birth weights were <3rd or >97th centile of the INTERGROWTH-21st standard were excluded, thereby ensuring that the charts depict body composition of infants whose birth weights did not indicate suboptimal fetal growth. Sex-specific centiles for fat mass (kg), fat-free mass (kg), and percentage body fat were estimated using the lambda-mu-sigma (LMS) method. Results: For each sex and measure (e.g., fat mass), the new charts comprised 2 panels. The first showed centiles according to gestational age, allowing term infants to be assessed at birth and preterm infants to be monitored until they reached term. The second showed centiles according to postnatal age, allowing all infants to be monitored to age 27 wk. The LMS values underlying the charts were presented, enabling researchers and clinicians to convert measurements to centiles and z scores. Conclusions: The new charts provide a single tool for the assessment of body composition, according to ADP, in infants across the first 6 mo of life and will help enhance early-life nutritional management.

Purpose: Previous studies have reported that taller people have an increased risk of colorectal cancer (CRC). We examined the association of two height components—leg length and sitting height—with CRC risk in 14,532 individuals aged 45–64 years in the Atherosclerosis Risk in Communities study. Methods: Anthropometrics were measured at baseline (1987–1989). Incident CRC cases (n = 382) were ascertained from 1987 to 2012. Cox proportional hazards regression was used to estimate multivariable-adjusted hazard ratios for CRC and colon cancer across quintiles of sex-specific leg length and sitting height. Results: The highest (versus the lowest) quintile of leg length was associated with a 36% greater CRC risk (p-trend = 0.04), and 51% greater colon cancer risk (p-trend = 0.01). For the top four quintiles combined, risk was increased by 34% for CRC and by 45% for colon cancer versus the lowest quintile. Total height and sitting height were not significantly associated with CRC or colon cancer risk. A small number of cases (n = 57) limited our ability to conduct subgroup analyses for rectal cancer. Conclusions: A positive association of leg length with CRC and colon cancer risk suggests that biological mechanisms leading to greater leg length during puberty may explain the association between taller height and CRC.

Background: DNA methylation (DNAm) may contribute to processes that underlie associations between air pollution and poor health. Therefore, our objective was to evaluate associations between DNAm and ambient concentrations of particulate matter (PM) ≤2.5, ≤10, and 2.5–10 μm in diameter (PM2.5; PM10; PM2.5–10). Methods: We conducted a methylome-wide association study among twelve cohort- and race/ethnicity-stratified subpopulations from the Women's Health Initiative and the Atherosclerosis Risk in Communities study (n = 8397; mean age: 61.5 years; 83% female; 45% African American; 9% Hispanic/Latino American). We averaged geocoded address-specific estimates of daily and monthly mean PM concentrations over 2, 7, 28, and 365 days and 1 and 12 months before exams at which we measured leukocyte DNAm in whole blood. We estimated subpopulation-specific, DNAm-PM associations at approximately 485,000 Cytosine-phosphate-Guanine (CpG) sites in multi-level, linear, mixed-effects models. We combined subpopulation- and site-specific estimates in fixed-effects, inverse variance-weighted meta-analyses, then for associations that exceeded methylome-wide significance and were not heterogeneous across subpopulations (P < 1.0 × 10−7; PCochran's Q > 0.10), we characterized associations using publicly accessible genomic databases and attempted replication in the Cooperative Health Research in the Region of Augsburg (KORA) study. Results: Analyses identified significant DNAm-PM associations at three CpG sites. Twenty-eight-day mean PM10 was positively associated with DNAm at cg19004594 (chromosome 20; MATN4; P = 3.33 × 10−8). One-month mean PM10 and PM2.5–10 were positively associated with DNAm at cg24102420 (chromosome 10; ARPP21; P = 5.84 × 10−8) and inversely associated with DNAm at cg12124767 (chromosome 7; CFTR; P = 9.86 × 10−8). The PM-sensitive CpG sites mapped to neurological, pulmonary, endocrine, and cardiovascular disease-related genes, but DNAm at those sites was not associated with gene expression in blood cells and did not replicate in KORA. Conclusions: Ambient PM concentrations were associated with DNAm at genomic regions potentially related to poor health among racially, ethnically and environmentally diverse populations of U.S. women and men. Further investigation is warranted to uncover mechanisms through which PM-induced epigenomic changes may cause disease.