At birth, elevated IGF-I levels have been linked to birth weight extremes; high birth weight and low birth weight are risk factors for adult-onset chronic diseases including obesity, cardiovascular disease, and type 2 diabetes. We examined associations between plasma IGF-I levels and birth weight among infants born to African American and White obese and nonobese women. Prepregnancy weight and height were assessed among 251 pregnant women and anthropometric measurements of full term infants (≥37 weeks of gestation) were taken at birth. Circulating IGF-I was measured by ELISA in umbilical cord blood plasma. Linear regression models were utilized to examine associations between birth weight and high IGF-I, using the bottom two tertiles as referents. Compared with infants with lower IGF-I levels (≤3rd tertile), those with higher IGF-I levels (>3rd tertile) were 130 g heavier at birth, (β-coefficient = 230, se = 58.0, P = 0.0001), after adjusting for gender, race/ethnicity, gestational age, delivery route, maternal BMI and smoking. Stratified analyses suggested that these associations are more pronounced in infants born to African American women and women with BMI ≥30 kg/m2; the cross product term for IGF-I and maternal BMI was statistically significant (P ≤ 0.0004). Our findings suggest that the association between IGF-I levels and birth weight depends more on maternal obesity than African American race/ethnicity.
Evidence from human and animal research indicates that choline metabolic pathways may be activated during a variety of diseases, including cancer. We report results of a case-control study of 2821 lung cancer cases and 2923 controls that assessed associations of choline and betaine dietary intakes with lung cancer. Using multivariable logistic regression analyses, we report a significant association between higher betaine intake and lower lung cancer risk that varied by smoking status. Specifically, no significant association was observed between betaine intake and lung cancer among never-smokers. However, higher betaine intake was significantly associated with reduced lung cancer risk among smokers, and the protective effect was more evident among current than former smokers: for former and current smokers, the ORs (95% CI) of lung cancer for individuals with highest as compared to lowest quartiles of intake were 0.70(0.55–0.88) and 0.51(0.39–0.66) respectively. Significant linear trend of higher betaine intake and lower lung cancer risk was observed among both former (ptrend = 0.002) and current (ptrend<0.0001) smokers. A similar protective effect was also observed with choline intake both in overall analysis as well as among current smokers, with p-values for chi-square tests being 0.001 and 0.004 respectively, but the effect was less evident, as no linear trend was observed. Our results suggest that choline and betaine intake, especially higher betaine intake, may be protective against lung cancer through mitigating the adverse effect of smoking.
We analyzed the association between meat intake, heterocyclic amines (HCAs) and bladder cancer (BC) risk in a large case-control study comprised of 884 BC cases and 878 healthy controls, recruited from 1999 to 2009. Epidemiologic and dietary data were collected via an in-person interview. Compared to the lowest quartile of red meat intake, the odds ratios (ORs) for the second, third and fourth quartiles were 1.17 (95% CI: 0.87–1.58), 1.47 (95% CI: 1.09–1.99) and 1.95 (95% CI: 1.41–2.68), respectively, (p-for trend <0.001). In a subset of participants with intakes of HCAs available, compared with those with the lowest quartile of intake, the ORs for the second, third and fourth quartiles were 1.47 (95% CI: 0.60–3.64), 2.58 (95% CI: 1.09–6.11) and 3.32 (95% CI: 1.37–8.01), respectively, (p for trend <0.001). In cumulative analysis of SNPs in the pathway, compared with subjects carrying 0–4 unfavorable genotypes, subjects carrying 5 and 6 or more unfavorable genotypes were at 1.60-fold (95% CI: 1.20–2.12) and 2.37-fold (95% CI: 1.82–3.10) increased risk, respectively. Moreover, subjects carrying six or more unfavorable genotypes and whose red meat intake was in the highest quartile were at 5.09-fold increased risk (95% CI: 2.89–8.96; p < 0.001). These results strongly support that high red meat intake, high intake of HCAs and carrying high number of unfavorable genotypes in the HCA metabolic pathways are associated with increased risk of BC in the study population.
bladder cancer risk; red meat intake; heterocyclic amines
Sexual development begins in utero and enters a dormant phase during infancy. The influence of maternal gestational weight gain (GWG) on daughter's age at menarche has not been explored.
We investigated the association between maternal GWG and age at menarche (<11 years, 11–15 years, >15 years of age) in a large cohort study of U.S. nurses, The Nurses' Health Study II (NHS II), and the Nurses' Mothers' Cohort Study.
Among 32,218 respondents, 7% reported age at menarche age 15. Compared with women whose mothers gained 20–29 lbs during pregnancy, those whose mothers reported <10 lbs or >40 lbs of GWG were 30% more likely to report early onset menarche (<11 years of age) in logistic regression models adjusted for sociodemographic and maternal characteristics, and childhood body size and physical activity: adjusted odds ratio (OR) 1.31, 95% confidence interval (CI) 1.05-1.62, and 1.27, 95% CI 1.06-1.56. Maternal GWG was not associated with late menarche in the fully adjusted model (ptrend=0.07).
These results suggest that either extreme of maternal GWG may influence risk for early age at menarche in daughters. Maternal GWG may be a modifiable risk factor for early menarche.
Vitamin D may have a protective role in the etiology of multiple sclerosis (MS), but the effect of gestational vitamin D on adult onset MS has not been studied.
In 2001, 35,794 mothers of participants of the Nurses’ Health Study II completed a questionnaire inquiring about their experiences and diet during pregnancy with their nurse-daughter. We studied the association of maternal milk intake, maternal dietary vitamin D intake, and predicted maternal serum 25-hydroxyvitamin D (25(OH)D) during pregnancy and their daughters’ risk of developing MS.
MS was diagnosed in 199 women. The relative risk (RR) of MS was lower among women born to mothers with high milk or vitamin D intake during pregnancy. The multivariate adjusted RR of MS was 0.62 (95% CI: 0.40– 0.95; p trend=0.001) for nurses whose mothers consumed 2–3 glasses of milk per day compared with those whose mothers consumed fewer than 3 glasses per month, and 0.57 (95% CI: 0.35–0.91; p trend=0.002) for nurses with mothers in the highest quintile of dietary vitamin D intake compared with those in the lowest. The predicted 25(OH) vitamin D level in the pregnant mothers was also inversely associated with the risk of MS in their daughters. Comparing extreme quintiles the adjusted RR was 0.59; (95% CI: 0.37–0.92; p trend =0.002).
Higher maternal milk and vitamin D intake during pregnancy may be associated with a lower risk of developing MS in the offspring.
Multiple sclerosis; Epidemiology; prenatal; vitamin D
Depressed mood in pregnancy has been linked to low birth weight (LBW, < 2,500 g), a risk factor for adult-onset chronic diseases in offspring. We examined maternal depressed mood in relation to birth weight and evaluated the role of DNA methylation at regulatory sequences of imprinted genes in this association. We measured depressed mood among 922 pregnant women using the CES-D scale and obtained birth weight data from hospital records. Using bisulfite pyrosequencing of cord blood DNA from 508 infants, we measured methylation at differentially methylated regions (DMRs) regulating imprinted genes IGF2/H19, DLK1/MEG3, MEST, PEG3, PEG10/SGCE, NNAT and PLAGL1. Multiple regression models were used to examine the relationship between depressed mood, birth weight and DMR methylation levels. Depressed mood was associated with a more that 3-fold higher risk of LBW, after adjusting for delivery mode, parity, education, cigarette smoking, folic acid use and preterm birth. The association may be more pronounced in offspring of black women and female infants. Compared with infants of women without depressed mood, infants born to women with severe depressed mood had a 2.4% higher methylation at the MEG3 DMR. Whereas LBW infants had 1.6% lower methylation at the IGF2 DMR, high birth weight (> 4,500 g) infants had 5.9% higher methylation at the PLAGL1 DMR compared with normal birth weight infants. Our findings confirm that severe maternal depressed mood in pregnancy is associated with LBW, and that MEG3 and IGF2 plasticity may play important roles.
depression; DNA Methylation; epigenetics; fetal growth retardation; health status disparities; low birth weight
Studies of vitamin E and cancer have focused on the α-tocopherol form of the vitamin. However, other forms of vitamin E, in particular γ-tocopherol may have unique mechanistic characteristics relevant to lung cancer prevention. In an ongoing study of 1,088 incident lung cancer cases and 1,414 healthy matched controls, we studied the associations between 4 tocopherols (α-, β-, γ-, and δ-tocopherol) in the diet and lung cancer risk. Using multiple logistic regression analysis, the adjusted odds ratios (OR) and 95% confidence intervals (CI) of lung cancer for increasing quartiles of dietary α-tocopherol intake were 1.0, 0.63 (0.50–0.79), 0.58 (0.44–0.76) and 0.39 (0.28–0.53), respectively (p-trend < 0.0001). For dietary intake of β-tocopherol, the OR and 95% CI for all subjects were: 1.0, 0.79 (0.63–0.98), 0.59 (0.45–0.78) and 0.56 (0.42–0.74), respectively (p-trend < 0.0001). Similar results for dietary γ-tocopherol intake were observed: 1.0, 0.84 (0.67–1.06), 0.76 (0.59–0.97) and 0.56 (0.42–0.75), respectively (p- trend = 0.0002). No significant association between δ-tocopherol intake and lung cancer risk was detected. When the 4 tocopherols were summed as total tocopherol intake, a monotonic risk reduction was also observed. When we entered the other tocopherols in our model, only the association with dietary α-tocopherol intake remained significant; i.e., increasing intake of dietary α-tocopherol accounted for 34–53% reductions in lung cancer risk. To the best of our knowledge, this is the first report of the independent associations of the 4 forms of dietary tocopherol (α-, β-, γ- and δ-tocohperol) on lung cancer risk. Given the limitations with case-control studies, these findings need to be confirmed in further investigations.
dietary tocopherols; lung cancer risk; diet and lung cancer; vitamin E and lung cancer
Mexican-American girls have one of the fastest rates of decline in age at menarche. To date, no study has addressed the role of psychosocial factors on age at menarche in this population. Using data from a longitudinal cohort of Mexican-American girls from the Houston, Texas, metropolitan area recruited in 2005, the authors investigated associations between family life and socioeconomic environment and age at menarche in 523 girls. After adjusting for maternal age at menarche, daughter's age, and body mass index at baseline, perception of family life environment as conflict-prone was significantly associated with an earlier age at menarche (< 11 years). Additionally, there was a 2-fold higher risk (odds ratio = 2.22, 95% confidence interval: 1.12, 4.40) of early menarche among daughters of mothers who were single parents compared with those who were not. Furthermore, girls who matured early had a 2.5-fold increased risk (odds ratio = 2.69, 95% confidence interval: 1.04, 6.96) of experimenting with cigarettes compared with those who had an average-to-late age at menarche (≥ 11 years). This study provides important information regarding the role of family life environment and single parenting on age at menarche in Mexican Americans. Awareness of the impact of the family life environment and fathers’ absence during the early years should be emphasized when addressing early age at menarche across cultures.
family cohesion; family conflict; menarche; Mexican Americans; single parenting; smoking; social support
Altered methylation at Insulin-like Growth Factor 2 (IGF2) regulatory regions has previously been associated with obesity, and several malignancies including colon, esophageal, and prostate adenocarcinomas, presumably via changes in expression and/or loss of imprinting, but the functional significance of these DNA methylation marks have not been demonstrated in humans. We examined associations among DNA methylation at IGF2 differentially methylated regions (DMRs), circulating IGF2 protein concentrations in umbilical cord blood (UCB) and birth weight in newborns.
Questionnaire data were obtained from 300 pregnant women recruited between 2005 and 2009. UCB DNA methylation was measured by bisulfite pyrosequencing. UCB plasma concentrations of soluble IGF2 were measured by ELISA assays. Generalized linear regression models were used to examine the relationship between DMR methylation and IGF2 levels.
Lower IGF2 DMR methylation was associated with elevated plasma IGF2 protein concentrations (β = −9.87, p < 0.01); an association that was stronger in infants born to obese women (pre-pregnancy BMI > 30 kg/m2, β = −20.21, p < 0.0001). Elevated IGF2 concentrations were associated with higher birth weight (p < 0.0001) after adjusting for maternal race/ethnicity, pre-pregnancy BMI, cigarette smoking, gestational diabetes, and infant sex. These patterns of association were not apparent at the H19 DMR.
Our data suggest that variation in IGF2 DMR methylation is an important mechanism by which circulating IGF2 concentrations, a putative risk factor for obesity and cancers of the colon, esophagus, and prostate, are modulated; associations that may depend on pre-pregnancy obesity.
IGF2; H19; ELISA; DNA methylation; Epigenetics; Epidemiology
Results from studies examining the association between hormone therapy (HT) and lung cancer risk disagree.
We examined the associations between HT use and lung cancer risk among 60,592 postmenopausal women enrolled in the prospective California Teachers Study cohort. Between 1995 and 2007, 727 women were diagnosed with lung cancer. Multivariable Cox proportional hazards regression models were fit using age as the time metric.
No measure of HT use was associated with lung cancer risk (all p-values for trend≥0.4). In addition, no variations in risk by smoking status (never, ever, former, current), type of HT (E-alone, E+P use), type of menopause, or lung cancer histology were observed.
Our findings do not support an association between HT and lung cancer.
This large-scale, prospective study, which capitalizes on the detailed hormone use, smoking history, and type of menopause information available within this unique cohort, was unable to find any association between intake of HT and lung cancer risk.
The role of tumor estrogen receptors (ERs) and serum estrogen in lung cancer is inconclusive. We investigated the hypothesis that ERs and functional single-nucleotide polymorphisms in the estrogen biosynthesis pathway are associated with poorer lung cancer survival. Lung cancer patients (n = 305) from a National Cancer Institute-Maryland (NCI-MD) case–case cohort in the Baltimore metropolitan area were used as a test cohort. To validate, 227 cases from the NCI-MD case–control cohort and 293 cases from a Norwegian lung cancer cohort were studied. Information on demographics, tobacco and reproductive histories was collected in an interviewer-administered questionnaire. Serum estrogen, progesterone, tumor messenger RNA expression of hormone receptors and germ line DNA polymorphisms were analyzed for associations with lung cancer survival. Patients in the highest tertile of serum estrogen had worse survival in all three cohorts (P combined < 0.001). Furthermore, the variant allele of estrogen receptor alpha (ER-α) polymorphism (rs2228480) was significantly associated with increased tumor ER-α levels and worse survival in all three cohorts [hazard ratio (HR) = 2.59, 95% confidence interval (CI): 1.20– 4.01; HR = 1.76, 95% CI: 1.08–2.87 and HR = 2.85, 95% CI: 1.31–4.36). Other polymorphisms associated with lower serum estrogen correlated with improved survival. Results were independent of gender and hormone replacement therapy. We report a significant association of increased serum estrogen with poorer survival among lung cancer male and female patients. Understanding the genetic control of estrogen biosynthesis and response in lung cancer could lead to improved prognosis and therapy.
Mexican American (MA) girls are entering puberty earlier than in the past, yet few studies have explored the perceptions surrounding puberty among this group. We conducted separate focus groups for fathers, mothers, and daughters aged 6 to 12 years to explore perceptions of body image, pubertal development, communications, and sources of puberty-related information in MA participants. Our results revealed parental concerns about daughters’ weight and pubertal development, as well as differences in their communication with their daughters. Although both parents willingly discussed pubertal issues concerning their daughters, mothers had a more active role in conveying pubertal information to daughters. Among the girls, there was a gap in knowledge about the pubertal process between the younger and older girls. Our findings present opportunities and challenges for addressing obesity as a pubertal risk factor in MA girls; however, more studies are needed to understand family beliefs and sociocultural dynamics surrounding puberty in MAs.
adolescents; female; body image; families; fathers; focus groups; Mexican Americans; relationships; mother–child; women’s health; young women
Using data from a case-control study, we previously reported that low dietary intakes of magnesium (Mg), iron (Fe), zinc (Zn), copper (Cu), but not selenium (Se) and calcium (Ca) were associated with increased lung cancer risk. Due to dietary recall bias in case-control studies our objective was to assess whether these findings hold in a prospective cohort study.
We analyzed data from the NIH-AARP Diet and Health study of 482,875 subjects (288,257 men and 194,618 women) who were cancer-free and completed a food frequency questionnaire (FFQ) at enrollment between 1995 and 2003. Cox proportional hazards models were computed to estimate the relative risk (RR) adjusted for potential confounders.
During a mean follow-up of 7 years, 7,052 lung cancer cases were identified. For all subjects, we observed no significant associations between total (diet + supplement) Ca, Mg, Fe, Cu, Se, and Zn intakes and lung cancer risk. Total Ca intake was protective (P-trend<0.05) for current smokers and subjects with adenocarcinomas. Total Mg intake increased risk (P-trend<0.05) in men and current smokers. Total Fe intake was inversely associated with risk in women (P-trend<0.01). For dietary minerals, Mg increased risk (P-trend<0.05) in all subjects, among men and current smokers. Increased dietary Ca intake reduced risk in women (P-trend=0.05). Dietary Fe decreased risk in all subjects and among women (P-trend<0.05). Mineral intake from supplements did not affect lung cancer risk.
Dietary mineral consumption may influence lung cancer risk, but the associations differ by type of mineral and population subgroups.
Diet; minerals; lung cancer; smoking
To compare cord blood concentrations of total adiponectin in the offspring of pregnancies with and without preeclampsia.
Using a Luminex analyzer, cord blood adiponectin was measured in 182 singleton pregnancies with preeclampsia and compared to adiponectin measured in 511 singleton pregnancies without preeclampsia.
Adiponectin levels in cord blood increased with increasing gestational age, but overall, crude levels were similar in pregnancies with and without preeclampsia. However, in pregnancies with early delivery (weeks 32–36), and in pregnancies with delivery after spontaneous contractions, adiponectin levels were higher in the preeclampsia group.
In preterm pregnancies and in pregnancies with spontaneous contractions, adiponectin levels in cord blood were higher in the preeclampsia group than in pregnancies without preeclampsia, maybe reflecting the need to optimize energy in preeclampsia.
Preeclampsia; Cord blood; Adiponectin; Infant development
Folic acid (FA) supplementation before and during pregnancy has been associated with decreased risk of neural tube defects although recent reports suggest it may also increase the risk of other chronic diseases. We evaluated exposure to maternal FA supplementation before and during pregnancy in relation to aberrant DNA methylation at two differentially methylated regions (DMRs) regulating insulin-like growth factor 2 (IGF2) expression in infants. Aberrant methylation at these regions has been associated with IGF2 deregulation and increased susceptibility to several chronic diseases. Using a self-administered questionnaire, we assessed FA intake before and during pregnancy in 438 pregnant women. Pyrosequencing was used to measure methylation at two IGF2 DMRs in umbilical cord blood leukocytes. Mixed models were used to determine relationships between maternal FA supplementation before or during pregnancy and DNA methylation levels at birth. Average methylation at the H19 DMR was 61.2%. Compared to infants born to women reporting no FA intake before or during pregnancy, methylation levels at the H19 DMR decreased with increasing FA intake (2.8%, p = 0.03 and 4.9%, p = 0.04, for intake before and during pregnancy, respectively). This methylation decrease was most pronounced in male infants (p = 0.01). Methylation alterations at the H19 DMR are likely an important mechanism by which FA risks and/or benefits are conferred in utero. Because stable methylation marks at DMRs regulating imprinted genes are acquired before gastrulation, they may serve as archives of early exposures with the potential to improve our understanding of developmental origins of adult disease.
folic acid; epigenetics; IGF2; periconception; prenatal; exposure
Diethylstilbestrol (DES) is an estrogenic endocrine disruptor with long-term health effects, possibly including depression, following exposure in utero. Understanding the relation between in utero DES exposure and depression will provide insight to the potential adverse effects of bisphenol A, a functionally similar and ubiquitous endocrine disruptor. The association between in utero DES exposure and depression was assessed among participants in the Nurses’ Health Study II who first reported their history of antidepressant use in 1993 and lifetime history of depressive symptoms in 2001. DES exposure was reported by 1,612 (2.2%) women. A history of depression at baseline was higher among women exposed to DES in utero compared with those not exposed (age-adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI): 1.26, 1.72) (P < 0.001). Incident depression (first use of antidepressants among women who also reported depressive symptoms) during follow-up (1995–2005) was reported by 19.7% of women exposed to DES and 15.9% unexposed (age-adjusted OR = 1.41, 95% CI: 1.22, 1.63) (P < 0.001). Adjustment for risk factors of depression and correlates of DES exposure moderately attenuated the association (multivariable-adjusted OR = 1.30, 95% CI: 1.13, 1.51) (P = 0.0004). These results suggest that the neurophysiologic effects of in utero exposure to DES could lead to an increased risk of depression in adult life. Further research should assess whether in utero exposure to bisphenol A has similar adverse effects.
antidepressive agents; bisphenol A-glycidyl methacrylate; cohort studies; depression; diethylstilbestrol; endocrine disruptors
We evaluated the association between energy balance and risk of bladder cancer and assessed joint effects of genetic variants in the mTOR pathway genes with energy balance. The study included 803 Caucasian bladder cancer patients and 803 healthy Caucasian controls matched to cases by age (± 5 years) and gender. High energy intake (OR=1.60; 95% CI=1.23-2.09) and low physical activity (OR=2.82; 95% CI=2.10-3.79) were each associated with significantly increased risk of bladder cancer with dose-response trends (P for trend<0.001). However, obesity (BMI ≥30) was not associated with the risk. Among 222 SNPs, 28 SNPs located in 6 genes of mTOR pathway were significantly associated with the risk. Further, the risk associated with high energy intake and low physical activity was only observed among subjects carrying a high number of unfavorable genotypes in the pathway. Moreover, when physical activity, energy intake and genetic variants were analyzed jointly, the study population was clearly stratified into a range of low to high risk subgroups as defined energy balance status. Compared to subjects within the most favorable energy balance category (low energy intake, intensive physical activity, low number of unfavorable genotypes), subjects in the worst energy balance category (high energy intake, low physical activity, and carrying seven or more unfavorable genotypes) had 21.93-fold increased risk (95% CI=6.7 to 71.77). Our results provide the first strong support that physical activity, energy intake and genetic variants in the mTOR pathway jointly influence bladder cancer susceptibility and these results have implications in bladder cancer prevention.
bladder cancer; energy intake; physical activity; obesity; PI3K-AKT-mTOR Pathway
In the current era of diet-gene analyses, large sample sizes are required to uncover the etiology of complex diseases. As such, consortia form and often combine available data. Food frequency questionnaires, which commonly use 2 different types of responses about the frequency of intake (predefined responses and open-ended responses), may be pooled to achieve the desired sample size. The common practice is to categorize open-ended responses into the predefined response categories. A problem arises when the predefined categories are noncontiguous: possible open-ended responses may fall in gaps between the predefined categories. Using simulated data modeled from frequency of intake among 1,664 controls in a lung cancer case-control study at The University of Texas M. D. Anderson Cancer Center (Houston, Texas, 2000–2005), the authors describe the effect of different categories of open-ended responses that fall in between noncontiguous, predefined response sets on estimates of the mean difference in intake and the odds ratios. A significant inflation of false positives appears when comparing mean differences of intake, while the bias in estimating odds ratios may be acceptably small. Therefore, if pooling data cannot be restricted to the same type of response, inferences should focus on odds ratio estimation to minimize bias.
computer simulation; data interpretation, statistical; diet surveys
High birth weight (HBW) is an established risk factor for childhood acute lymoblastic leukemia (ALL). The purpose of this study was to evaluate if birth weight (BW) corrected-for-gestational age is a better predictor than BW alone for occurrence of ALL and other malignancies in children.
Materials and Methods
Birth certificate data of 2254 children with cancer who were younger than 5 years old at diagnosis and registered at Texas Cancer Registry during 1995–2003 were compared to 11734 age-matched controls. Multivariable logistic regression was used to compare models with BW corrected-for-gestational age and BW alone.
Compared to children who were appropriate for gestational age (AGA), children who were large for gestational age (LGA) at birth had a 1.66 times (95%CI 1.32–2.10) higher odds of ALL. Similarly, children with a BW≥ 4,000 grams had a 1.5 times (95%CI 1.18–1.89) higher odds for ALL, compared to children who weighed >2,500 grams and <4,000 grams at birth. Using model diagnostics, the model containing BW corrected-for-gestational age was a better predictor than the model with BW alone [Akaike’s Information Criterion (AIC) 4646 vs. 4658, respectively]. Odds ratios were similar for LGA children who were <4,000 grams and LGA children who were ≥4,000 grams (OR=1.5, 95%CI 0.97–2.5 and OR=1.67, 95%CI 1.29–2.16, respectively). BW was not an independent risk factor for acute myeloid leukemia or brain tumors.
BW corrected-for-gestational age is a better predictor than BW alone of risk for ALL. Future studies using BW variable should incorporate gestational age in their analyses.
birth weight; childhood acute lymphoblastic leukemia; gestational age
Folic acid (FA) added to foods during fortification is 70-85% bioavailable compared to 50% of folate occurring naturally in foods. Thus, if FA supplements also are taken during pregnancy, both mother and fetus can be exposed to FA exceeding the Institute of Medicine's recommended tolerable upper limit (TUL) of 1,000 micrograms per day (μg/d) for adult pregnant women. The primary objective is to estimate the proportion of women taking folic acid (FA) doses exceeding the TUL before and during pregnancy, and to identify correlates of high FA use.
During 2005-2008, pre-pregnancy and pregnancy-related data on dietary supplementation were obtained by interviewing 539 pregnant women enrolled at two obstetrics-care facilities in Durham County, North Carolina.
Before pregnancy, 51% of women reported FA supplementation and 66% reported this supplementation during pregnancy. Before pregnancy, 11.9% (95% CI = 9.2%-14.6%) of women reported supplementation with FA doses above the TUL of 1,000 μg/day, and a similar proportion reported this intake prenatally. Before pregnancy, Caucasian women were more likely to take FA doses above the TUL (OR = 2.99; 95% = 1.28-7.00), compared to African American women, while women with chronic conditions were less likely to take FA doses above the TUL (OR = 0.48; 95%CI = 0.21-0.97). Compared to African American women, Caucasian women were also more likely to report FA intake in doses exceeding the TUL during pregnancy (OR = 5.09; 95%CI = 2.07-12.49).
Fifty-one percent of women reported some FA intake before and 66% during pregnancy, respectively, and more than one in ten women took FA supplements in doses that exceeded the TUL. Caucasian women were more likely to report high FA intake. A study is ongoing to identify possible genetic and non-genotoxic effects of these high doses.
Emerging evidence suggests that exposures during fetal life affect adult metabolism. We assessed the relation between recalled maternal pre-pregnancy body mass, gestational weight gain (GWG), and adiposity in the daughter.
Retrospective cohort study among mother-nurse daughter dyads in the Nurses’ Health Study II and the Nurses’ Mothers’ Cohort. Mothers of participants completed questionnaires regarding their nurse-daughter in 2001.
26,506 mother-nurse daughter dyads born between 1946 and 1964.
Main outcome measures
Body mass index of the nurse-daughter at age 18 and in 2001.
At age 18, 561 (2.1%) daughters were obese (BMI greater than 30), and in 2001, 5,442 (22.0%) were obese. Adjusting for covariates, women whose mothers had a recalled pre-pregnancy BMI of 29 had a 6.1-fold increased risk of obesity at age 18 and a 3.4-fold risk of obesity in 2001, compared with women whose mothers had a pre-pregnancy BMI of 21. We found a U-shaped association between recalled GWG and offspring obesity. Compared with a maternal weight gain of 15–19 lb, GWG <10 lbs was associated with a significant increase in obesity risk at age 18 (odds ratio[OR] 1.54, 95% confidence interval[CI] 1.02–2.34) and in 2001 (OR 1.27, 95%CI 1.05–1.53). High weight gain (40+ lbs) was also associated with obesity risk at age 18 (OR 1.81, 95%CI 1.22–2.69) and in 2001 (OR 1.74, 95%CI 1.48–2.04). These associations were stronger among mothers who were overweight prior to pregnancy (p for interaction = 0.03), and they persisted with adjustment for birth weight.
A high recalled pre-pregnancy BMI and extremes of recalled GWG are associated with an increased risk of adolescent and adult obesity in offspring, particularly when the mother is overweight. Pre-pregnancy weight and GWG may be modifiable fetal origins of overweight and obesity in women.
pregnancy; obesity; gestational weight gain; prenatal programming; birth weight
In utero exposures have been proposed as possible determinants of later disease risk. Given that a later age at menarche is a breast cancer risk factor, and that higher childhood physical activity has been associated with a later menarcheal age, it is possible that a pregnant mothers’ activity may also influence this outcome. The purpose of this study was to determine if mothers’ physical activity during pregnancy is related to their daughters’ menarcheal age. Participants of the Nurse’s Health Study II reported their age at menarche to the nearest year, while their mothers (n=33,016) completed surveys regarding their health and lifestyle habits during their pregnancy with their daughters. Mothers reported their home, occupational, and leisure-time physical activity, as well as the activity of their daughters at ages 5–10 years. Using multiple linear regression analysis with adjustment for specific covariates including daughters’ childhood body size, neither home nor occupational activity alone were associated with age at menarche of the daughter, but there was a direct association with leisure-time physical activity (ptrend<0.001). Compared to women inactive in their leisure-time, women who were highly active had daughters with menarche 1.1 (95% CI, 0.3 –1.9) months later. Using a composite variable of both home and leisure-time activity, daughters of women who were highly active at home and in their leisure-time had daughters with menarche 3.1 (95%CI, 0.4 – 5.9) months later than those who were highly inactive in both. Physical activity during pregnancy may be associated with a modest delay in menarcheal age in offspring.
exercise; menarche; pregnancy; puberty
Magnesium (Mg) is required for maintenance of genomic stability; however, data on the relationship between dietary Mg intake and lung cancer are lacking. In an ongoing lung cancer case–control study, we identified 1139 cases and 1210 matched healthy controls with data on both diet and DNA repair capacity (DRC). Dietary intake was assessed using a modified Block-NCI food frequency questionnaire and DRC was measured using the host-cell reactivation assay to assess repair in lymphocyte cultures. After adjustment for potential confounding factors including DRC, the odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer with increasing quartiles of dietary Mg intake were 1.0, 0.83 (0.66–1.05), 0.64 (0.50–0.83) and 0.47 (0.36–0.61), respectively, for all subjects (P-trend < 0.0001). Similar results were observed by histology and clinical stage of lung cancer. Low dietary Mg intake was associated with poorer DRC and increased risk of lung cancer. In joint effects analyses, compared with those with high dietary Mg intake and proficient DRC, the OR (95% CI) for lung cancer in the presence of both low dietary Mg and suboptimal DRC was 2.36 (1.83–3.04). Similar results were observed for men and women. The effects were more pronounced among older subjects (>60 years), current or heavier smokers, drinkers, those with a family history of cancer in first-degree relatives, small cell lung cancer and late-stage disease. These intriguing results need to be confirmed in prospective studies.
To determine if aberrant DNA methylation at differentially methylated regions (DMRs) regulating Insulin-like Growth Factor 2 (IGF2) expression in umbilical cord blood (UCB) is associated with overweight or obesity in a multiethnic cohort.
UCB leukocytes of 204 infants born between 2005 and 2009 in Durham, NC were analyzed for DNA methylation at two IGF2 DMRs using Pyrosequencing. Anthropometric and feeding data were collected at age one year. Methylation differences were compared between children >85th percentile of CDC weight-for-age (WFA) and those ≤85th percentile of WFA at one year using generalized linear models, adjusting for post-natal caloric intake, maternal cigarette smoking and race/ethnicity.
The methylation percentages at the H19 imprint center DMR was higher in infants with WFA>85th percentile (62.7%, 95%CI=59.9–65.5%) compared with infants with WFA≤85th percentile (59.3%, 95%CI=58.2–60.3), (p=0.02). At the intragenic IGF2 DMR, methylation levels were comparable between infants with WFA≤85th and those with WFA>85th percentile.
Our findings suggest that IGF2 plasticity may be mechanistically important in early childhood overweight or obese status. If confirmed in larger studies, findings suggest aberrant DNA methylation at sequences regulating imprinted genes may be useful identifiers of children at risk for early obesity.
Obesity; Breast Feeding; Child; DNA Methylation; Epigenetics; Genetic; Insulin-Like Growth Factor II
Folate metabolism, with its importance to DNA repair, provides a promising region for genetic investigation of lung cancer risk. This project investigates genes (MTHFR, MTR, MTRR, CBS, SHMT1, TYMS), folate metabolism related nutrients (B vitamins, methionine, choline, and betaine) and their gene-nutrient interactions.
We analyzed 115 tag single nucleotide polymorphisms (SNPs) and 15 nutrients from 1239 and 1692 non-Hispanic white, histologically-confirmed lung cancer cases and controls, respectively, using stochastic search variable selection (a Bayesian model averaging approach). Analyses were stratified by current, former, and never smoking status.
Rs6893114 in MTRR (odds ratio [OR] = 2.10; 95% credible interval [CI]: 1.20–3.48) and alcohol (drinkers vs. non-drinkers, OR = 0.48; 95% CI: 0.26–0.84) were associated with lung cancer risk in current smokers. Rs13170530 in MTRR (OR = 1.70; 95% CI: 1.10–2.87) and two SNP*nutrient interactions [betaine*rs2658161 (OR = 0.42; 95% CI: 0.19–0.88) and betaine*rs16948305 (OR = 0.54; 95% CI: 0.30–0.91)] were associated with lung cancer risk in former smokers. SNPs in MTRR (rs13162612; OR = 0.25; 95% CI: 0.11–0.58; rs10512948; OR = 0.61; 95% CI: 0.41–0.90; rs2924471; OR = 3.31; 95% CI: 1.66–6.59), and MTHFR (rs9651118; OR = 0.63; 95% CI: 0.43–0.95) and three SNP*nutrient interactions (choline*rs10475407; OR = 1.62; 95% CI: 1.11–2.42; choline*rs11134290; OR = 0.51; 95% CI: 0.27–0.92; and riboflavin*rs8767412; OR = 0.40; 95% CI: 0.15–0.95) were associated with lung cancer risk in never smokers.
This study identified possible nutrient and genetic factors related to folate metabolism associated with lung cancer risk, which could potentially lead to nutritional interventions tailored by smoking status to reduce lung cancer risk.