Holly R. Harris

Birthweight, Maternal Weight Trajectories and Global DNA Methylation of LINE-1 Repetitive Elements

Low birthweight, premature birth, intrauterine growth retardation, and maternal malnutrition have been related to an increased risk of cardiovascular disease, type 2 diabetes mellitus, obesity, and neuropsychiatric disorders later in life. Conversely, high birthweight has been linked to future risk of cancer. Global DNA methylation estimated by the methylation of repetitive sequences in the genome is an indicator of susceptibility to chronic diseases. We used data and biospecimens from an epigenetic birth cohort to explore the association between trajectories of fetal and maternal weight and LINE-1 methylation in 319 mother-child dyads. Newborns with low or high birthweight had significantly lower LINE-1 methylation levels in their cord blood compared to normal weight infants after adjusting for gestational age, sex of the child, maternal age at delivery, and maternal smoking during pregnancy (p = 0.007 and p = 0.036, respectively), but the magnitude of the difference was small. Infants born prematurely also had lower LINE-1 methylation levels in cord blood compared to term infants, and this difference, though small, was statistically significant (p = 0.004). We did not find important associations between maternal prepregnancy BMI or gestational weight gain and global methylation of the cord blood or fetal placental tissue. In conclusion, we found significant differences in cord blood LINE-1 methylation among newborns with low and high birthweight as well as among prematurely born infants. Future studies may elucidate whether chromosomal instabilities or other functional consequences of these changes contribute to the increased risk of chronic diseases among individuals with these characteristics.

Endometriosis: a high-risk population for major chronic diseases?

BACKGROUND Despite an estimated prevalence of 10% in women, the etiology of endometriosis remains poorly understood. Over recent decades, endometriosis has been associated with risk of several chronic diseases, such as cancer, autoimmune diseases, asthma/atopic diseases and cardiovascular diseases. A deeper understanding of these associations is needed as they may provide new leads into the causes or consequences of endometriosis. This review summarizes the available epidemiological findings on the associations between endometriosis and other chronic diseases and discusses hypotheses for underlying mechanisms, potential sources of bias and methodological complexities. METHODS We performed a comprehensive search of the PubMed/Medline and ISI Web of Knowledge databases for all studies reporting on the associations between endometriosis and other diseases published in English through to May 2014, using numerous search terms. We additionally examined the reference lists of all identified papers to capture any additional articles that were not identified through computer searches. RESULTS We identified 21 studies on the associations between endometriosis and ovarian cancer, 14 for breast cancer, 8 for endometrial cancer, 4 for cervical cancer, 12 for cutaneous melanoma and 3 for non-Hodgkins lymphoma, as well as 9 on the links between endometriosis and autoimmune diseases, 6 on the links with asthma and atopic diseases, and 4 on the links with cardiovascular diseases. Endometriosis patients were reported to be at higher risk of ovarian and breast cancers, cutaneous melanoma, asthma, and some autoimmune, cardiovascular and atopic diseases, and at decreased risk of cervical cancer. CONCLUSIONS Increasing evidence suggests that endometriosis patients are at higher risk of several chronic diseases. Although the underlying mechanisms are not yet understood, the available data to date suggest that endometriosis is not harmless with respects to womens long-term health. If these relationships are confirmed, these findings may have important implications in screening practices and in the management and care of endometriosis patients.

Methylation levels at imprinting control regions are not altered with ovulation induction or in vitro fertilization in a birth cohort

STUDY QUESTION Do fertility treatments, including ovulation induction (OI), alter epigenetic mechanisms such as DNA methylation at imprinted loci? SUMMARY ANSWER We observed small but statistically significant differences in certain imprinting control regions (ICRs) based on the method of conception, however, these small changes in methylation did not correlate to the overall transcriptional levels of the genes adjacent to the ICRs (such as KCNQ1 and SNRPN). WHAT IS KNOWN AND WHAT THIS PAPER ADDS Assisted reproductive technology (ART) has been associated with an increase in the risk of rare childhood disorders caused by loss of imprinting (LOI). This study provides novel epigenetic analyses on infants conceived by OI and examines how methylation levels correlate with gene expression. DESIGN Data and biospecimens used in this study were from 147 participants of the Epigenetic Birth Cohort comprising 1941 mother-child dyads recruited between June 2007 and June 2009 at the Department of Obstetrics, Gynecology and Reproductive Biology at Brigham and Womens Hospital (BWH) in Boston, MA, USA. Wilcoxon rank-sum tests were used to examine the differences in median percent methylation at each differentially methylated region (DMR) between the spontaneous conception control group and the fertility treatment groups (OI and IVF). PARTICIPANTS AND SETTING For each woman who reported IVF we selected a woman who conceived spontaneously matched on age (± 2 years). To increase efficiency, we matched the same controls from the spontaneously conceived group to participants who reported OI. If an appropriate control was not identified that had been previously matched to an IVF participant, a new control was selected. The final analytic sample consisted of 61 spontaneous, 59 IVF and 27 OI conceptions. MAIN RESULTS AND THE ROLE OF CHANCE No functionally relevant differences in methylation levels were observed across five (out of six) imprinted DMRs in either the placenta or cord blood of infants conceived with OI or IVF compared with infants conceived spontaneously. While KCNQ1, SNRPN and H19 DMRs demonstrated small but statistically significant differences in methylation based on the method of conception, expression levels of the genes related to these control regions only correlated with the methylation levels of H19. BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION Limitations of our study include the limited sample size, lack of information on OI medication used and culture medium for the IVF procedures and underlying reasons for infertility among OI and IVF patients. We did not perform allele-specific expression analyses and therefore cannot make any inferences about LOI. GENERALIZABILITY TO OTHER POPULATIONS These results are likely to be generalizable to non-Hispanic white individuals in populations with similar ART and fertility treatments.

Vitamin C and survival among women with breast cancer: a meta-analysis.

BACKGROUND The association between dietary vitamin C intake and breast cancer survival is inconsistent and few studies have specifically examined vitamin C supplement use among women with breast cancer. The purpose of this study was to summarise results from prospective studies on the association between vitamin C supplement use and dietary vitamin C intake and breast cancer-specific mortality and total mortality. METHODS Studies were identified using the PubMed database through February 6, 2014 and by examining the references of retrieved articles. Prospective studies were included if they reported relative risks (RR) with 95% confidence intervals (95% CIs) for at least two categories or as a continuous exposure. Random-effects models were used to combine study-specific results. RESULTS The ten identified studies examined vitamin C supplement use (n=6) and dietary vitamin C intake (n=7) and included 17,696 breast cancer cases, 2791 total deaths, and 1558 breast cancer-specific deaths. The summary RR (95% CI) for post-diagnosis vitamin C supplement use was 0.81 (95% CI 0.72-0.91) for total mortality and 0.85 (95% CI 0.74-0.99) for breast cancer-specific mortality. The summary RR for a 100mg per day increase in dietary vitamin C intake was 0.73 (95% CI 0.59-0.89) for total mortality and 0.78 (95% CI 0.64-0.94) for breast cancer-specific mortality. CONCLUSION Results from this meta-analysis suggest that post-diagnosis vitamin C supplement use may be associated with a reduced risk of mortality. Dietary vitamin C intake was also statistically significantly associated with a reduced risk of total mortality and breast cancer-specific mortality.

Folate, vitamin B6, vitamin B12, methionine and alcohol intake in relation to ovarian cancer risk

Folate, methionine, vitamin B6 and vitamin B12 may influence carcinogenesis due to their roles in the one‐carbon metabolism pathway, which is critical for DNA synthesis, methylation and repair. Low intake of these nutrients has been associated with an increased risk of breast, colon and endometrial cancers. Previous studies that have examined the relation between these nutrients and ovarian cancer risk have been inconsistent and have had limited power to examine the relation by histologic subtype. We investigated the association between folate, methionine, vitamin B6, vitamin B12 and alcohol among 1910 women with ovarian cancer and 1989 controls from a case‐control study conducted in eastern Massachusetts and New Hampshire from 1992 to 2008. Diet was assessed via food frequency questionnaire. Participants were asked to recall diet one‐year before diagnosis or interview. Logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (95% CIs). We also examined whether the associations varied by ovarian cancer histologies using polytomous logistic regression. We observed an inverse association between dietary vitamin B6 (covariate‐adjusted OR = 0.76, 95% CI 0.64–0.92; ptrend = 0.002) and methionine intake (covariate‐adjusted OR = 0.72, 95% CI = 0.60–0.87; ptrend < 0.001) and ovarian cancer risk comparing the highest to lowest quartile. The association with dietary vitamin B6 was strongest for serous borderline (covariate‐adjusted OR = 0.49, 95% CI = 0.32–0.77; ptrend = 0.001) and serous invasive (covariate‐adjusted OR = 0.74, 95% CI = 0.58–0.94; ptrend = 0.012) subtypes. Overall, we observed no significant association between folate and ovarian cancer risk. One‐carbon metabolism related nutrients, especially vitamin B6 and methionine, may lower ovarian cancer risk.

Parental smoking during pregnancy and risk of overweight and obesity in the daughter

Objective:Emerging evidence suggests that prenatal exposures may affect long-term health outcomes. In utero exposure to smoking is associated with an increased risk of overweight and obesity in children and adolescents. However, few studies have examined how prenatal exposure to parental smoking influences the risk of obesity during adulthood and whether these associations are independent of childhood and adolescent adiposity. The aim of the current study was to investigate whether prenatal exposure to parental smoking influences body size during adulthood and whether any association may be mediated by childhood and adolescent body size.Methods:We investigated the association between parental smoking during pregnancy and the risk of being overweight and obese during adulthood and at age 18 and adiposity during childhood among 35 370 participants in the Nurses’ Health Study II. Data on smoking during pregnancy and socioeconomic variables were provided by the mothers, and anthropometric data and adult risk factors were reported by participants.Results:After adjustment for socioeconomic and behavioral variables, maternal smoking during pregnancy was associated with adiposity at ages 5–10, 18 and during adulthood. For age 18 overweight, the odd ratios, ORs (95% confidence intervals, CIs) for 1–14, 15–24 and 25+cigarettes per day were 1.13 (1.18–1.50), 1.40 (1.20–1.64) and 1.15 (0.79–1.69), and for obesity were 1.41 (1.14–1.75), 1.69 (1.31–2.18) and 2.36 (1.44–3.86). The corresponding ORs (95% CIs) for obesity during adulthood were 1.26 (1.16–1.37), 1.46 (1.30–1.63) and 1.43 (1.10–1.86). Risk of adiposity was not increased among daughters whose mothers stopped smoking during the first trimester (OR (95% CI) for overweight (1.03 (95% CI 0.90–1.17)) and for obesity (1.12 (95% CI 0.97–1.30)). Women whose fathers smoked during pregnancy were also at an increased risk of being overweight and obese during adulthood with covariate-adjusted ORs (95% CIs) for obesity of 1.19 (1.11–1.29) for 1–14 cigarettes per day, 1.27 (1.18–1.37) for 15–24 cigarettes per day and 1.40 (1.27–1.54) for 25+ cigarettes per day compared with fathers who did not smoke (Ptrend<0.0001). Paternal smoking during pregnancy was also associated with an increased risk of obesity at age 18 among those whose fathers smoked 15 or more cigarettes per day but was not associated with childhood body size.Conclusions:Maternal smoking during pregnancy was associated in a dose-response manner with overweight and obesity in the daughter across adolescence and adult life. Smoking cessation during the first trimester appears to mitigate this excess risk.Paternal smoking was also associated with the risk of being overweight and obese of the adult daughter and this association persisted after adjustment for maternal smoking.

Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci

Endometriosis is a chronic inflammatory condition in women that results in pelvic pain and subfertility, and has been associated with decreased body mass index (BMI). Genetic variants contributing to the heritable component have started to emerge from genome-wide association studies (GWAS), although the majority remain unknown. Unexpectedly, we observed an intergenic locus on 7p15.2 that was genome-wide significantly associated with both endometriosis and fat distribution (waist-to-hip ratio adjusted for BMI; WHRadjBMI) in an independent meta-GWAS of European ancestry individuals. This led us to investigate the potential overlap in genetic variants underlying the aetiology of endometriosis, WHRadjBMI and BMI using GWAS data. Our analyses demonstrated significant enrichment of common variants between fat distribution and endometriosis (P = 3.7 × 10−3), which was stronger when we restricted the investigation to more severe (Stage B) cases (P = 4.5 × 10−4). However, no genetic enrichment was observed between endometriosis and BMI (P = 0.79). In addition to 7p15.2, we identify four more variants with statistically significant evidence of involvement in both endometriosis and WHRadjBMI (in/near KIFAP3, CAB39L, WNT4, GRB14); two of these, KIFAP3 and CAB39L, are novel associations for both traits. KIFAP3, WNT4 and 7p15.2 are associated with the WNT signalling pathway; formal pathway analysis confirmed a statistically significant (P = 6.41 × 10−4) overrepresentation of shared associations in developmental processes/WNT signalling between the two traits. Our results demonstrate an example of potential biological pleiotropy that was hitherto unknown, and represent an opportunity for functional follow-up of loci and further cross-phenotype comparisons to assess how fat distribution and endometriosis pathogenesis research fields can inform each other.

Adherence to the World Cancer Research Fund/American Institute for Cancer Research recommendations and breast cancer risk.

The World Cancer Research Fund/American Association for Cancer Research (WCRF/AICR) has published eight nutrition‐related recommendations for the prevention of cancer. However, few prospective studies have examined these recommendations by breast cancer hormone receptor subtype and only one case–control study has included the dietary supplements recommendation in their evaluation. We investigated whether adherence to the WCRF/AICR cancer prevention recommendations was associated with breast cancer incidence, overall and by hormone receptor subtype, in the Swedish Mammography Cohort. Among 31,514 primarily postmenopausal women diet and lifestyle factors were assessed with a self‐administered food frequency questionnaire. A score was constructed based on adherence to the recommendations for body fatness, physical activity, energy density, plant foods, animal foods, alcoholic drinks and dietary supplements (score range 0–7). Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs). During 15 years of follow‐up 1,388 cases of breast cancer were identified. Women who met six to seven recommendations had a 51% decreased risk of breast cancer compared to women meeting only zero to two recommendations (95% CI = 0.35–0.70). The association between each additional recommendation met and breast cancer risk was strongest for the ER‐positive/PR‐positive subtype (HR = 0.86; 95% CI = 0.79–0.94), while for the ER‐negative/PR‐negative subtype the individual recommendations regarding plant and animal foods were most strongly associated with reduced risk. Our findings support that adherence to the WCRF/AICR recommendations reduces breast cancer risk in a population of primarily postmenopausal women. Promoting these recommendations to the public could help reduce breast cancer incidence.

Endometriosis and the risks of systemic lupus erythematosus and rheumatoid arthritis in the Nurses’ Health Study II

Objectives The aetiologies of endometriosis, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are all characterised by immune dysfunction. SLE and RA occur more often in women, and reproductive and hormonal factors have been shown to be related to increased risk. However, only one previous study has evaluated the temporal association between endometriosis and SLE or RA. We sought to investigate the association between laparoscopically confirmed endometriosis and subsequently diagnosed SLE and RA. Methods We analysed data from the Nurses’ Health Study II (n=114 453 women) over a 22-year follow-up period. Multivariable, time-varying Cox proportional hazards models were used to calculate HRs and 95% CIs for the association between laparoscopically confirmed endometriosis and confirmed incident SLE or RA. Results From 1989 to 2011, 103 incident cases of SLE and 390 cases of RA were confirmed. Laparoscopically confirmed endometriosis was significantly associated with subsequent SLE diagnosis (HR=2.03; CI 1.17 to 3.51) and RA diagnosis (HR=1.41; CI 1.05 to 1.89). These associations were robust to adjustment for SLE or RA risk factors and for potential confounders; however, adjustment for hysterectomy and oophorectomy attenuated both relations such that they were no longer significant. No significant differences by infertility status or age (<45 years) were observed. Conclusions Our findings suggest an association between endometriosis and risk of SLE and RA. It remains to be understood whether and how endometriosis itself, or hysterectomy or other factors associated with endometriosis, is related to risk of SLE or RA.

Vitamin C intake and breast cancer mortality in a cohort of Swedish women

Background:Vitamin C may influence cancer progression through its antioxidant properties. However, the evidence from observational epidemiologic studies on vitamin C intake and survival following breast cancer diagnosis is not consistent, and the safety of vitamin C supplements following breast cancer diagnosis has not been extensively studied.Methods:Using a food-frequency questionnaire we investigated whether vitamin C intake was associated with survival among 3405 women diagnosed with invasive breast cancer in the Swedish Mammography Cohort.Results:From 1987–2010, there were 1055 total deaths with 416 deaths from breast cancer. Women in the highest quartile of pre-diagnosis vitamin C intake had an adjusted HR (95% CI) of breast cancer death of 0.75 (0.57–0.99) compared with those in the lowest quartile (Ptrend=0.03). There was a borderline significant association between vitamin C intake and total mortality (HR=0.84; 95% CI=0.71–1.00; Ptrend=0.08). Among 717 breast cancer cases for whom post-diagnosis supplement use was available, there was no association between vitamin C supplement use (≈1000 mg) and breast cancer-specific mortality (HR=1.06; 95% CI=0.52–2.17).Conclusion:Our findings suggest that dietary vitamin C intake before breast cancer diagnosis may be associated with breast cancer survival. In addition, post-diagnosis vitamin C supplementation at the level observed in our population was not associated with survival.