[show abstract][hide abstract] ABSTRACT: Investigation of the biological mechanism by which folate acts to affect fetal development can inform appraisal of expected benefits and risk management. This research is ethically imperative given the ubiquity of folic acid fortified products in the US. Considering that folate is an essential component in the one-carbon metabolism pathway that provides methyl groups for DNA methylation, epigenetic modifications provide a putative molecular mechanism mediating the effect of folic acid supplementation on neonatal and pediatric outcomes.
In this study we use a Mendelian Randomization (Mendelian Randomization) approach to assess the effect of red blood cell (RBC) folate on genome-wide DNA methylation in cord blood. Site-specific CpG methylation within the proximal promoter regions of approximately 14,500 genes was analyzed using the Illumina Infinium Human Methylation27 Bead Chip for 50 infants from the Epigenetic Birth Cohort at Brigham and Women's Hospital in Boston. Using methylenetetrahydrofolate reductase genotype as the instrument, the Mendelian Randomization approach identified 7 CpG loci with a significant (mostly positive) association between RBC folate and methylation level. Among the genes in closest proximity to this significant subset of CpG loci, several enriched biologic processes were involved in nucleic acid transport and metabolic processing. Compared to the standard ordinary least squares regression method, our estimates were demonstrated to be more robust to unmeasured confounding.
To the authors' knowledge, this is the largest genome-wide analysis of the effects of folate on methylation pattern, and the first to employ Mendelian Randomization to assess the effects of an exposure on epigenetic modifications. These results can help guide future analyses of the causal effects of periconceptional folate levels on candidate pathways.
[show abstract][hide abstract] ABSTRACT: Epigenome-wide association studies (EWAS) hold promise for the detection of new regulatory mechanisms that may be susceptible to modification by environmental and lifestyle factors affecting susceptibility to disease. Epigenome-wide screening methods cover an increasing number of CpG sites, but the complexity of the data poses a challenge to separating robust signals from noise. Appropriate study design, a detailed a priori analysis plan and validation of results are essential to minimize the danger of false positive results and contribute to a unified approach. Epigenome-wide mapping studies in homogenous cell populations will inform our understanding of normal variation in the methylome that is not associated with disease or aging. Here we review concepts for conducting a stringent and powerful EWAS, including the choice of analyzed tissue, sources of variability and systematic biases, outline analytical solutions to EWAS-specific problems and highlight caveats in interpretation of data generated from samples with cellular heterogeneity.
[show abstract][hide abstract] ABSTRACT: Later menopause is a risk factor for breast and endometrial cancer, yet few studies have investigated dietary predictors of this potentially modifiable event. In particular, dairy contains hormones and growth factors that could potentially impact menopausal timing. We therefore assessed the association between regular consumption of dairy foods and related nutrients and age at natural menopause. We conducted a prospective analysis with up to 20 y of follow-up in 46,059 participants in the Nurses' Health Study who were premenopausal in 1980. We observed 30,816 events of natural menopause over 401,754 person-years. In the total population, the estimated mean age at natural menopause was 51.5 y for women who consumed no low-fat dairy and 51.5, 51.6, 51.7, and 51.8 y for women who consumed 0.1-1.0, 1.1-2.0, 2.1-3.0, and >3 servings of low-fat dairy daily, respectively. Premenopausal women <51 y of age consuming >3 servings of low-fat dairy per day were 14% less likely (HR: 0.86; 95% CI: 0.77, 0.96; P-trend < 0.0001) to report natural menopause in the next month relative to those consuming 0.1-1 servings/d. Similar results were obtained for skim milk (for >6 servings/wk vs. 0-1 servings/mo: HR: 0.93; 95% CI: 0.89, 0.97; P-trend < 0.0001) but not for total high-fat dairy or whole milk. Dairy foods were not associated with age at menopause among women ≥51 y of age. These findings support the growing body of literature on the hormonally active nature of milk and dairy foods.
Journal of Nutrition 08/2013; · 4.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Prior studies suggest that women who use antidepressants during pregnancy have an increased risk for preeclampsia, yet the comparative safety of specific antidepressants remains unclear. US nationwide Medicaid Analytic eXtract (MAX) data have not been used to study medication safety during pregnancy.
We identified 100,942 pregnant women with depression from 2000 to 2007 MAX data. We used pharmacy dispensing records to ascertain exposure to selective serotonin reuptake inhibitor (SSRI), serotonin-norepenephrine reuptake inhibitor (SNRI), tricyclic, bupropion, other antidepressant monotherapy or polytherapy, and specific antidepressants, during the second trimester and first half of the third trimester. Relative risks (RRs) and 95% confidence intervals (CIs) were adjusted for delivery year, preeclampsia risk factors, depression severity proxies, other antidepressant indications, other medications, and healthcare utilization.
The risk of preeclampsia was 5.4% among women with depression and no antidepressant exposure. Compared with these women, the risk for preeclampsia was higher among those receiving SNRI (RR: 1.52, 95% CI = 1.26-1.83) and tricyclic monotherapy (RR: 1.62, 95% CI = 1.23-2.12), but not SSRI monotherapy (RR: 1.00, 95% CI = 0.93-1.07) or other antidepressants. Compared with women receiving SSRI monotherapy, preeclampsia risk was higher among women with SNRI (RR: 1.54, 95% CI = 1.28-1.86) and tricyclic (RR: 1.64, 95% CI = 1.25-2.16) monotherapy. None of the specific SSRIs was associated with preeclampsia. The RR with venlafaxine was 1.57 (95% CI = 1.29-1.91) and with amitriptyline 1.72 (95% CI = 1.24-2.40).
In this population, SNRIs and tricyclics were associated with a higher risk of preeclampsia than SSRIs.
[show abstract][hide abstract] ABSTRACT: 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 risk of obesity in 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 in 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 risk of overweight and obesity in 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, age 18, and during adulthood. For age 18 overweight the ORs (95% CIs) for 1-14, 15-24, and 25+cigarettes/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 in 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 obesity (1.12 [95% CI 0.97-1.30]). Women whose fathers smoked during pregnancy were also at increased risk of overweight and obesity in adulthood with covariate-adjusted ORs (95% CIs) for obesity of 1.19 (1.11-1.29) for 1-14 cigarettes/day, 1.27 (1.18-1.37) for 15-24 cigarettes/day, and 1.40 (1.27-1.54) for 25+ cigarettes/day compared to 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/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 through adolescence and adult life. Smoking cessation during the first trimester appears to mitigate this excess risk. Paternal smoking was also associated with risk of overweight and obesity of the adult daughter and this association persisted after adjustment for maternal smoking.International Journal of Obesity accepted article preview online, 29 May 2013; doi:10.1038/ijo.2013.101.
International journal of obesity (2005) 05/2013; · 5.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: Imprinted genes are monoallelically expressed according to the parent of origin and are critical for proper placental and embryonic development. Disruption of methylation patterns at imprinted loci resulting in loss of imprinting (LOI) may lead to serious imprinting disorders (e.g., Beckwith-Wiedemann syndrome) and is described in some cancers (e.g., Wilms' tumor). As most research has focused on children with cancer or other abnormal phenotypes, the imprinting status in healthy infants at birth has not been characterized. We examined the prevalence of H19 and IGF2 LOI at birth by allele-specific expression assays analysis on 114 human individuals. Overall expression and methylation analyses were performed on a subset of samples. We found that LOI of H19 was observed for 4% of individuals in cord blood and 3.3% in placenta, and for IGF2 of 22% of individuals in the cord blood and 0% in placenta. Interestingly, LOI status did not correspond to aberrant methylation levels of the imprinted DMRs or with changes in overall gene expression for the majority of individuals. Our observations suggest that LOI is present in phenotypically healthy infants. Determining a "normal" human epigenotype range is important for discovering factors required to maintain a healthy pregnancy and embryonic development.-Rancourt, R. C., Harris, H. R., Barault, L., Michels, K. B. The prevalence of loss of imprinting of H19 and IGF2 at birth.
[show abstract][hide abstract] ABSTRACT: OBJECTIVE: Human papillomavirus (HPV) infections and abnormal Pap test results are common, and most do not progress to cervical cancer. Because it is difficult to predict which mild Pap abnormalities will develop into precancerous lesions, many women undergo painful and costly evaluations and even unnecessary treatment. The objective of this study was to develop a risk prediction model based on clinical and demographic information to identify women most likely to develop significant precancerous lesions (cervical intraepithelial neoplasia grades 2/3 [CIN 2/3] or adenocarcinoma in situ [AIS]) among women with mild Pap abnormalities (atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion). MATERIALS AND METHODS: The Abnormal Pap Smear Registry includes women who received treatment at the Brigham and Women's Hospital/Dana Farber Cancer Institute Pap Smear Evaluation Center beginning in 2006. It includes 1,072 women with mild cervical dysplasia (atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion) on their referral Pap test. We derived a clinical prediction model to predict the probability of developing CIN 2/3 or AIS using multivariate logistic regression with a split-sample approach. RESULTS: By the end of the follow-up, 93 of the 1,072 women developed CIN 2/3 or AIS (8.7%). There were several differences between women who developed CIN 2/3 or AIS and women who did not. However, once we put these into the regression model, the only variable that was significantly associated with CIN 2/3 or AIS was having a history of an abnormal Pap or biopsy result (odds ratio = 2.44; 95% CI =1.03-5.76). The resulting prediction model had poor discriminative ability and was poorly calibrated. CONCLUSIONS: Despite accounting for known risk factors, we were unable to predict individual patients' probability for progression on the basis of available data.
[show abstract][hide abstract] ABSTRACT: PURPOSE: Physical and sexual abuse are prevalent social hazards. We sought to examine the association between childhood physical and sexual abuse and age at menarche. METHODS: Among 68,505 participants enrolled in the Nurses' Health Study II, we investigated the association between childhood physical abuse and sexual abuse and menarche before age 11 years (early) or after age 15 years (late) using multivariate logistic regression analysis, mutually adjusting for both types of abuse. RESULTS: Fifty-seven percent of respondents reported some form of physical or sexual abuse in childhood. We found a positive dose-response association between severity of sexual abuse in childhood and risk for early menarche. Compared with women who reported no childhood sexual abuse, the adjusted odds ratio (AOR) for early menarche in women who reported childhood sexual abuse was 1.20 (95% confidence interval [CI]: 1.10, 1.37) for sexual touching and 1.49 (95% CI: 1.34, 1.66) for forced sexual activity. Severe physical abuse predicted early menarche (AOR = 1.22, 95% CI: 1.10, 1.37). Childhood physical abuse had a dose-response association with late age at menarche: AOR 1.17 (95% CI: 1.04, 1.32) for mild, 1.20 (95% CI: 1.08, 1.33) for moderate, and 1.50 (95% CI: 1.27, 1.77) for severe physical abuse. Sexual abuse was not associated with late menarche. CONCLUSIONS: Childhood abuse was prevalent in this large cohort of U.S. women. Severity of childhood sexual abuse was associated with risk for early onset of menarche, and physical abuse was associated with both early and late onset of menarche.
Journal of Adolescent Health 02/2013; 52(2):241-247. · 2.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: To determine whether use of serotonin or non-serotonin reuptake inhibitors near to delivery is associated with postpartum hemorrhage.
2000-07 nationwide Medicaid data (Medicaid Analytic eXtract).
106 000 pregnant women aged 12-55 with a diagnosis of mood or anxiety disorder. Women were categorized into four mutually exclusive exposure groups according to pharmacy dispensing data: current (delivery date), recent (1-30 days before delivery date), past (1-5 months before delivery date), and no exposure (reference group).
Risk of postpartum hemorrhage by timing of exposure and by serotonin or non-serotonin reuptake inhibitors, classes of antidepressant, and antidepressant types. Relative risks and 95% confidence intervals adjusted for delivery year, risk factors for postpartum hemorrhage, indicators of severity of mood/anxiety disorder, other indications for antidepressants, and other drugs. High dimensional propensity score (hdPS) methods were used to empirically identify and adjust for additional factors.
12 710 (12%) women had current exposure to serotonin reuptake inhibitor monotherapy, and 1495 (1.4%) women had current exposure to non-serotonin reuptake inhibitor monotherapy. The risk of postpartum hemorrhage was 2.8% among women with mood/anxiety disorders but no exposure to antidepressants, 4.0% in the current users of serotonin reuptake inhibitors, 3.8% in the current users of non-serotonin reuptake inhibitors, 3.2% in the recent users of serotonin reuptake inhibitors, 3.1% in the recent users of non-serotonin reuptake inhibitors, 2.5% in the past users of serotonin reuptake inhibitors, and 3.4% in the past users of non-serotonin reuptake inhibitors. Compared with no exposure, women with current exposure to serotonin reuptake inhibitors had a 1.47-fold increased risk of postpartum hemorrhage (95% confidence interval 1.33 to 1.62) and women with current non-serotonin reuptake inhibitor exposure had a 1.39-fold increased risk (1.07 to 1.81). Results were similar with hdPS adjustment. Women with current exposure to serotonin reuptake inhibitors had an adjusted excess risk of 1.26% (0.90% to 1.62%), with a number needed to harm of 80, and for women with current exposure to non-serotonin reuptake inhibitors the excess risk was 1.03% (0.07% to 1.99%), with a number needed to harm of 97. For exposure to serotonin reuptake inhibitors the relative risk was 1.19 (1.03 to 1.38) for recent exposure and 0.93 (0.82 to 1.06) for past exposure; for non-serotonin reuptake inhibitors the figures were 1.17 (0.80 to 1.70) and 1.26 (1.00 to 1.59), respectively. Current exposure to selective serotonin reuptake inhibitor monotherapy was also associated with postpartum hemorrhage (1.42, 1.27 to 1.57), as was current serotonin norepinephrine (noradrenaline) reuptake inhibitor (1.90, 1.37 to 2.63) and tricyclic monotherapy (1.77, 0.90 to 3.47). All types of selective serotonin reuptake inhibitors available for analysis and venlafaxine, a serotonin norepinephrine reuptake inhibitor, were significantly associated with postpartum hemorrhage.
Exposure to serotonin and non-serotonin reuptake inhibitors, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclics, close to the time of delivery was associated with a 1.4 to 1.9-fold increased risk for postpartum hemorrhage. While potential confounding by unmeasured factors cannot be ruled out, these findings suggest that patients treated with antidepressants during late pregnancy are more likely to experience postpartum hemorrhage.
[show abstract][hide abstract] ABSTRACT: There is growing interest in identifying surrogate tissues to identify epimutations in cancer patients since primary target tissues are often difficult to obtain. Methylation patterns at imprinted loci are established during gametogenesis and post fertilization and their alterations have been associated with elevated risk of cancer. Methylation at several imprinted differentially methylated regions (GRB10 ICR, H19 ICR, KvDMR, SNRPN/SNURF ICR, IGF2 DMR0, and IGF2 DMR2) were analyzed in DNA from leukocytes and mammary tissue (normal, benign diseases, or malignant tumors) from 87 women with and without breast cancer (average age of cancer patients: 53; range: 31-77). Correlations between genomic variants and DNA methylation at the studied loci could not be assessed, making it impossible to exclude such effects. Methylation levels observed in leukocyte and mammary tissue DNA were close to the 50% expected for monoallellic methylation. While no correlation was observed between leukocyte and mammary tissue DNA methylation for most of the analyzed imprinted genes, Spearman's correlations were statistically significant for IGF2 DMR0 and IGF2 DMR2, although absolute methylation levels differed. Leukocyte DNA methylation levels of selected imprinted genes may therefore serve as surrogate markers of DNA methylation in cancer tissue.
PLoS ONE 01/2013; 8(2):e55896. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: In the absence of clinical trial data, large post-marketing observational studies are essential to evaluate the safety and effectiveness of medications during pregnancy. We identified a cohort of pregnancies ending in live birth within the 2000-2007 Medicaid Analytic eXtract (MAX). Herein, we provide a blueprint to guide investigators who wish to create similar cohorts from healthcare utilization data and we describe the limitations in detail.
Among females ages 12-55, we identified pregnancies using delivery-related codes from healthcare utilization claims. We linked women with pregnancies to their offspring by state, Medicaid Case Number (family identifier) and delivery/birth dates. Then we removed inaccurate linkages and duplicate records and implemented cohort eligibility criteria (i.e., continuous and appropriate enrollment type, no private insurance, no restricted benefits) for claim information completeness.
From 13,460,273 deliveries and 22,408,810 child observations, 6,107,572 pregnancies ending in live birth were available after linkage, cleaning, and removal of duplicate records. The percentage of linked deliveries varied greatly by state, from 0 to 96%. The cohort size was reduced to 1,248,875 pregnancies after requiring maternal eligibility criteria throughout pregnancy and to 1,173,280 pregnancies after further applying infant eligibility criteria. Ninety-one percent of women were dispensed at least one medication during pregnancy.
Mother-infant linkage is feasible and yields a large pregnancy cohort, although the size decreases with increasing eligibility requirements. MAX is a useful resource for studying medications in pregnancy and a spectrum of maternal and infant outcomes within the indigent population of women and their infants enrolled in Medicaid. It may also be used to study maternal characteristics, the impact of Medicaid policy, and healthcare utilization during pregnancy. However, careful attention to the limitations of these data is necessary to reduce biases.
PLoS ONE 01/2013; 8(6):e67405. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: The worldwide prevalence of neural tube defects (NTDs) has fallen noticeably during the past 30 years, but the specific etiology and causative mechanism of NTDs remain unknown. Since introduction of mandatory fortification of grains with folic acid, a further decrease in NTD prevalence has been reported in North America and other countries with large variations among ethnic subgroups. However, a significant portion of NTDs still persists. Population data suggest that women of childbearing age may not yet be adequately targeted, while the general population may be overfortified with folic acid. While an excessive folate intake may be associated with adverse effects, there remains uncertainty about the minimum effective folate intake and status required for NTD prevention, and the safe upper folate level. Besides folate, several other lifestyle and environmental factors as well as genetic variations may influence NTD development, possibly by affecting one-carbon metabolism and thus epigenetic events. In conclusion, mandatory folic acid fortification plays a significant part in the reduction of NTD prevalence, but possibly at a cost and with a portion of NTDs remaining. More effective preventive strategies require better understanding of the etiology of this group of birth defects.
Critical reviews in food science and nutrition 01/2013; 53(11):1180-90. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Fetal exposure to parental smoking may lead to developmental adaptations and promote various diseases in later life. This study evaluated the associations of parental smoking during pregnancy with the risk of hypertension in the daughter in adulthood, and assessed whether these associations are explained by birth weight or body weight throughout life. We used data on 33 086 participants of the Nurses' Health Study II and the Nurses' Mothers' Cohort. Cox proportional hazards models were used to examine the associations of maternal and paternal smoking during pregnancy with the nurse daughter, with self-reported physician-diagnosed hypertension from 1989 until 2007. Overall, 8575 (25.9%) mothers and 18 874 (57.0%) fathers smoked during pregnancy. During follow-up, 7825 incident cases of adult-onset hypertension were reported. Both maternal and paternal smoking of ≥15 cigarettes/d during pregnancy were associated with increased risks of hypertension (rate ratio, 1.19; 95% CI, 1.09-1.29; and rate ratio, 1.18; 95% CI, 1.12-1.25, respectively) in the age-adjusted models. Further adjustment for birth weight did not affect the effect estimates appreciably, whereas additional adjustment for body shape and weight until age 18, or current body mass index, attenuated the associations with both maternal and paternal smoking (rate ratio, 1.07; 95% CI, 0.98-1.16; and rate ratio, 1.06; 95% CI, 1.01-1.12, respectively). The associations of parental smoking during pregnancy with the risk of hypertension in the offspring were largely explained by body weight throughout life, suggesting that these associations may not reflect direct intrauterine mechanisms.
[show abstract][hide abstract] ABSTRACT: The pregnancy-lactation cycle (PLC) is a period in which the breast is transformed from a less-developed, nonfunctional organ into a mature, milk-producing gland that has evolved to meet the nutritional, developmental, and immune protection needs of the newborn. Cessation of lactation initiates a process whereby the breast reverts to a resting state until the next pregnancy. Changes during this period permanently alter the morphology and molecular characteristics of the breast (molecular histology) and produce important, yet poorly understood, effects on breast cancer risk. To provide a state-of-the-science summary of this topic, the National Cancer Institute invited a multidisciplinary group of experts to participate in a workshop in Rockville, Maryland, on March 2, 2012. Topics discussed included: 1) the epidemiology of the PLC in relation to breast cancer risk, 2) breast milk as a biospecimen for molecular epidemiological and translational research, and 3) use of animal models to gain mechanistic insights into the effects of the PLC on breast carcinogenesis. This report summarizes conclusions of the workshop, proposes avenues for future research on the PLC and its relationship with breast cancer risk, and identifies opportunities to translate this knowledge to improve breast cancer outcomes.
[show abstract][hide abstract] ABSTRACT: 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 Women's 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.
Human Reproduction 05/2012; 27(7):2208-16. · 4.67 Impact Factor
[show abstract][hide abstract] ABSTRACT: Genomic imprinting is the epigenetic regulation of genes to enable monoallelic expression according to parental origin. Imprinting is established in the germline and is particularly important in the regulation of fetal development; loss of imprinting (LOI) has been implicated in the development of a variety of childhood disorders and several cancer types. We investigated loss of imprinting in PEG3, MEST and ARHI/DIRAS3 in breast cancer. Blood and tissue samples from women with benign breast disease or no abnormalities (n = 52) and patients with invasive breast cancer (n = 37) were provided by the Clinical Breast Care Project at the Walter Reed Army Medical Center (Washington, USA). DNA extracted from the samples was bisulfite converted and the methylation status of the three genes determined by pyrosequencing. Loss of PEG3 imprinting was observed in 2% of benign tissues and 34% of invasive cancers. LOI in MEST was similarly observed in 4% of benign tissues and 39% of invasive cancers, while in ARHI/DIRAS3 it was observed in 11% of benign samples and 54% of invasive ones. LOI was not observed in blood samples for any of the three genes, suggesting that these epigenetic alterations are highly tissue-specific. There was no correlation between the methylation profiles of the three genes (Spearman's rank correlation coefficient; p = >0.25). Loss of imprinting in PEG3, MEST and ARHI/DIRAS3 appears to be a frequent event in breast cancer, and it is more common in invasive forms than benign proliferative breast disease. The impact of the observed methylation changes upon allele-specific expression is currently investigated.
AACR 103rd Annual Meeting 2012, Chicago, IL, USA; 03/2012