Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions.

Children conceived with assisted reproductive technology (ART) have an increased risk of adverse outcomes, including congenital malformations and imprinted gene disorders. In a retrospective North Carolina-based-birth-cohort, we examined the effect of ovulation drugs and ART on CpG methylation in differentially methylated CpGs in known imprint control regions (ICRs). Nine ICRs containing 48 CpGs were assessed for methylation status by pyrosequencing in mixed leukocytes from cord blood. After restricting to non-smoking, college-educated participants who agreed to follow-up, ART-exposed (n = 27), clomifene-only-exposed (n = 22), and non-exposed (n = 516) groups were defined. Associations of clomifene and ART with ICR CpG methylation were assessed with linear regression and stratifying by offspring sex. In males, ART was associated with hypomethylation of the PEG3 ICR [ß(95% CI) = -1.46 (-2.81, -0.12)] and hypermethylation of the MEG3 ICR [3.71 (0.01, 7.40)]; clomifene-only was associated with hypomethylation of the NNAT ICR [-5.25 (-10.12, -0.38)]. In female offspring, ART was associated with hypomethylation of the IGF2 ICR [-3.67 (-6.79, -0.55)]. Aberrant methylation of these ICRs has been associated with cardiovascular disease and metabolic and behavioral outcomes in children. The results suggest that the increased risk of adverse outcomes in offspring conceived through ART may be due in part to altered methylation of ICRs. Larger studies utilizing epigenome-wide interrogation are warranted.

Stressful life events, social support, and epigenetic aging in the Women's Health Initiative.

BACKGROUND: Elevated psychosocial stress has been linked with accelerated biological aging, including composite DNA methylation (DNAm) markers that predict aging-related outcomes ("epigenetic age"). However, no study has examined whether stressful life events (SLEs) are associated with epigenetic age acceleration in postmenopausal women, an aging population characterized by increased stress burden and disease risk. METHODS: We leveraged the Women's Health Initiative, a large muti-ancestry cohort of postmenopausal women with available psychosocial stress measures over the past year and epigenomic data. SLEs and social support were ascertained via self-report questionnaires. Whole blood DNAm array (450 K) data were used to calculate five DNAm-based predictors of chronological age, health span and life span, and telomere length (HorvathAge, HannumAge, PhenoAge, GrimAge, DNAmTL). RESULTS: After controlling for potential confounders, higher SLE burden was significantly associated with accelerated epigenetic aging, as measured by GrimAge (ß: 0.34, 95% CI: 0.08, 0.59) and DNAmTL (ß: -0.016, 95% CI: -0.028, -0.004). Exploratory analyses showed that SLEs-GrimAge associations were stronger in Black women as compared to other races/ethnicities and in those with lower social support levels. In women with lower social support, SLEs-DNAmTL associations showed opposite association in Hispanic women as compared to other race/ethnicity groups. CONCLUSIONS: Our findings suggest that elevated stress burden is associated with accelerated epigenetic aging in postmenopausal women. Lower social support and/or self-reported race/ethnicity may modify the association of stress with epigenetic age acceleration. These findings advance understanding of how stress may contribute to aging-related outcomes and have important implications for disease prevention and treatment in aging women.

Associations between maternal obesity, gestational cytokine levels and child obesity in the NEST cohort.

BACKGROUND: Although maternal systemic inflammation is hypothesized to link maternal pre-pregnancy obesity to offspring metabolic dysfunction, patient empirical data are limited. OBJECTIVES: In this study, we hypothesized that pre-pregnancy obesity alters systemic chemo/cytokines concentrations in pregnancy, and this alteration contributes to obesity in children. METHODS: In a multi-ethnic cohort of 361 mother-child pairs, we measured prenatal concentrations of plasma TNF-α, IL-6, IL-8, IL-1ß, IL-4, IFN-γ, IL-12 p70 subunit, and IL-17A using a multiplex ELISA and examined associations of pre-pregnancy obesity on maternal chemo/cytokine levels, and associations of these cytokine levels with offspring body mass index z score (BMI-z) at age 2-6 years using linear regression. RESULTS: After adjusting for maternal smoking, ethnicity, age, and education, pre-pregnancy obesity was associated with increased concentrations of TNF-α (P = .026) and IFN-γ (P = .06). While we found no evidence for associations between TNF-α concentrations and offspring BMI-z, increased IFN-γ concentrations were associated with decreased BMI-z (P = .0002), primarily in Whites (P = .0011). In addition, increased maternal IL-17A concentrations were associated with increased BMI-z in offspring (P = .0005) with stronger associations in African Americans (P = .0042) than Whites (P = .24). CONCLUSIONS: Data from this study are consistent with maternal obesity-related inflammation during pregnancy, increasing the risk of childhood obesity in an ethnic-specific manner.

Using community-based participatory research principles to develop more understandable recruitment and informed consent documents in genomic research.

BACKGROUND: Heart Healthy Lenoir is a transdisciplinary project aimed at creating long-term, sustainable approaches to reduce cardiovascular disease risk disparities in Lenoir County, North Carolina using a design spanning genomic analysis and clinical intervention. We hypothesized that residents of Lenoir County would be unfamiliar and mistrustful of genomic research, and therefore reluctant to participate; additionally, these feelings would be higher in African-Americans. METHODOLOGY: To test our hypothesis, we conducted qualitative research using community-based participatory research principles to ensure our genomic research strategies addressed the needs, priorities, and concerns of the community. African-American (n = 19) and White (n = 16) adults in Lenoir County participated in four focus groups exploring perceptions about genomics and cardiovascular disease. Demographic surveys were administered and a semi-structured interview guide was used to facilitate discussions. The discussions were digitally recorded, transcribed verbatim, and analyzed in ATLAS.ti. RESULTS AND SIGNIFICANCE: From our analysis, key themes emerged: transparent communication, privacy, participation incentives and barriers, knowledge, and the impact of knowing. African-Americans were more concerned about privacy and community impact compared to Whites, however, African-Americans were still eager to participate in our genomic research project. The results from our formative study were used to improve the informed consent and recruitment processes by: 1) reducing misconceptions of genomic studies; and 2) helping to foster participant understanding and trust with the researchers. Our study demonstrates how community-based participatory research principles can be used to gain deeper insight into the community and increase participation in genomic research studies. Due in part to these efforts 80.3% of eligible African-American participants and 86.9% of eligible White participants enrolled in the Heart Healthy Lenoir Genomics study making our overall enrollment 57.8% African-American. Future research will investigate return of genomic results in the Lenoir community.