Lisa A. DeRoo

Telomere Length, Current Perceived Stress, and Urinary Stress Hormones in Women

Telomeres are repetitive DNA sequences that cap and protect the ends of chromosomes; critically short telomeres may lead to cellular senescence or carcinogenic transformation. Previous findings suggest a link between psychosocial stress, shorter telomeres, and chronic disease risk. This cross-sectional study examined relative telomere length in relation to perceived stress and urinary stress hormones in a sample of participants (n = 647) in the National Institute of Environmental Health Sciences Sister Study, a cohort of women ages 35 to 74 years who have a sister with breast cancer. Average leukocyte telomere length was determined by quantitative PCR. Current stress was assessed using the Perceived Stress Scale and creatinine-adjusted neuroendocrine hormones in first morning urines. Linear regression models estimated differences in telomere length base pairs (bp) associated with stress measures adjusted for age, race, smoking, and obesity. Women with higher perceived stress had somewhat shorter telomeres [adjusted difference of −129bp for being at or above moderate stress levels; 95% confidence interval (CI), −292 to 33], but telomere length did not decrease monotonically with higher stress levels. Shorter telomeres were independently associated with increasing age (−27bp/year), obesity, and current smoking. Significant stress-related differences in telomere length were seen in women ages 55 years and older (−289bp; 95% CI, −519 to −59), those with recent major losses (−420bp; 95% CI, −814 to −27), and those with above-average urinary catecholamines (e.g., epinephrine: −484bp; 95% CI, −709 to −259). Although current perceived stress was only modestly associated with shorter telomeres in this broad sample of women, our findings suggest the effect of stress on telomere length may vary depending on neuroendocrine responsiveness, external stressors, and age. (Cancer Epidemiol Biomarkers Prev 2009;18(2):551–60)

A systematic review of farm safety interventions

OBJECTIVE The main objective of this study was to systematically review the existing evidence for the effectiveness of farm injury prevention interventions. SEARCH STRATEGY We used a systematic approach to search the following electronic databases: MEDLINE, EMBASE, ERIC, PsycInfo, Sociofile, NTIS, Agricola, Expanded Academic Index, Dissertation Abstracts, and Occupational Safety and Health (NIOSHTIC). Proceedings and technical papers of the National Institute for Farm Safety were reviewed. We also checked the references of potentially eligible studies and consulted with experts in the field to identify other relevant information sources. SELECTION CRITERIA Papers had to involve a farm safety intervention to be included in the review. To best characterize the current state of farm safety research, all study designs were accepted, including those without comparison groups and those with absent or inadequate evaluation methods. RESULTS We identified 25 studies for the review. Eleven of the studies involved farm safety education programs, five consisted of multifaceted interventions that included environmental revisions, a farm visit, or both; nine papers described farm safety interventions but did not report results from an evaluation. Farm safety education interventions included safety fairs, day camps; certification programs; workshops; and courses for farm families, youth, and agricultural workers. Multifaceted interventions were targeted to farm operators and generally involved farm safety audits, followed by environmental or equipment changes and/or safety education. Program evaluations assessed changes in safety attitudes, knowledge, and/or behaviors and generally involved pre- and post-test methodology. Only three studies examined changes in the incidence of farm injuries. Of the studies evaluated, most reported positive changes following the interventions. However, limitations in the design of evaluations make the results of many of the studies difficult to interpret. CONCLUSIONS There is a need for more rigorous evaluations of farm safety intervention programs. Suggested study design improvements include randomization of study subjects when appropriate, use of control groups and the objective measurement of outcomes such as behavior change and injury incidence.

Multivitamin use and telomere length in women

BACKGROUND Telomere length may be a marker of biological aging. Multivitamin supplements represent a major source of micronutrients, which may affect telomere length by modulating oxidative stress and chronic inflammation. OBJECTIVE The objective was to examine whether multivitamin use is associated with longer telomeres in women. DESIGN We performed a cross-sectional analysis of data from 586 early participants (age 35-74 y) in the Sister Study. Multivitamin use and nutrient intakes were assessed with a 146-item food-frequency questionnaire, and relative telomere length of leukocyte DNA was measured by quantitative polymerase chain reaction. RESULTS After age and other potential confounders were adjusted for, multivitamin use was associated with longer telomeres. Compared with nonusers, the relative telomere length of leukocyte DNA was on average 5.1% longer among daily multivitamin users (P for trend = 0.002). In the analysis of micronutrients, higher intakes of vitamins C and E from foods were each associated with longer telomeres, even after adjustment for multivitamin use. Furthermore, intakes of both nutrients were associated with telomere length among women who did not take multivitamins. CONCLUSION This study provides the first epidemiologic evidence that multivitamin use is associated with longer telomere length among women.

Obesity and weight gain in adulthood and telomere length.

Obesity and weight gain in adulthood are associated with an increased risk of several cancers. Telomeres play a critical role in maintaining genomic integrity and may be involved in carcinogenesis. Using data from 647 women ages 35 to 74 years in the United States and Puerto Rico (2003-2004), we examined the association between current and past anthropometric characteristics and telomere length in blood. In a multivariate linear regression model, higher current body mass index (BMI) and hip circumference were inversely associated with telomere length. Higher BMI in the 30s was associated with shorter telomere length among women ages ≥40 years (Ptrend < 0.01). Weight gain since the age 30s (Ptrend = 0.07) and weight cycling (Ptrend = 0.04) were also inversely associated with telomere length. When current BMI and BMI at ages 30 to 39 years were considered together, the most marked decrease in telomere length was found for women who had overweight or obese BMI at both time points (mean telomere repeat copy number to single-copy gene copy number ratio = 1.26; 95% confidence interval, 1.21-1.30) compared with women who had normal BMI at both times (mean telomere repeat copy number to single-copy gene copy number ratio = 1.33; 95% confidence interval, 1.30-1.36). These findings support the hypothesis that obesity may accelerate aging, and highlight the importance of maintaining a desirable weight in adulthood. (Cancer Epidemiol Biomarkers Prev 2009;18(3):816–20)

Epigenome-wide Association Study of Breast Cancer Using Prospectively Collected Sister Study Samples

BACKGROUND Previous studies have suggested DNA methylation in blood is a potential epigenetic marker of cancer risk, but this has not been evaluated on a genome-wide scale in prospective studies for breast cancer. METHODS We measured DNA methylation at 27578 CpGs in blood samples from 298 women who developed breast cancer 0 to 5 years after enrollment in the Sister Study cohort and compared them with a random sample of 612 cohort women who remained cancer free. We also genotyped women for nine common polymorphisms associated with breast cancer. RESULTS We identified 250 differentially methylated CpGs (dmCpGs) between case subjects and noncase subjects (false discovery rate [FDR] Q < 0.05). Of these dmCpGs, 75.2% were undermethylated in case subjects relative to noncase subjects. Women diagnosed within 1 year of blood draw had small but consistently greater divergence from noncase subjects than did women diagnosed at more than 1 year. Gene set enrichment analysis identified Kyoto Encyclopedia of Genes and Genomes cancer pathways at the recommended FDR of Q less than 0.25. Receiver operating characteristic analysis estimated a prediction accuracy of 65.8% (95% confidence interval = 61.0% to 70.5%) for methylation, compared with 56.0% for the Gail model and 58.8% for genome-wide association study polymorphisms. The prediction accuracy of just five dmCpGs (64.1%) was almost as good as the larger panel and was similar (63.1%) when replicated in a small sample of 81 women with diverse ethnic backgrounds. CONCLUSIONS Methylation profiling of blood holds promise for breast cancer detection and risk prediction.

Association of Intrauterine and Early-Life Exposures with Diagnosis of Uterine Leiomyomata by 35 Years of Age in the Sister Study

Background Early-life exposures to hormonally active compounds and other factors may affect later response to estrogen or progesterone and hence may influence development of uterine leiomyomata (fibroids). Objectives We evaluated associations of in utero and early-life exposures, including soy formula, with self-report of physician-diagnosed fibroids by 35 years of age. Methods Our study included 19,972 non-Hispanic white women who were 35–59 years of age when they enrolled in the Sister Study in 2003–2007. We estimated risk ratios (RRs) and 95% confidence intervals (CIs) using log-binomial regression models for fibroid associations with adjustment for participant’s age and education, maternal age at participant’s birth, birth order, and childhood family income. Results Greater risk of early fibroid diagnosis was associated with soy formula during infancy (RR = 1.25; 95% CI, 0.97–1.61), maternal prepregnancy diabetes (RR = 2.05; 95% CI, 1.16–3.63), low childhood socioeconomic status (RR = 1.28; 95% CI, 1.01–1.63), and gestational age at birth (RR = 1.64; 95% CI, 1.27–2.13, for being born at least 1 month early). In utero diethylstilbestrol (DES) exposure was also associated with early fibroid diagnosis (RR = 1.42; 95% CI, 1.13–1.80), but this association was driven by women reporting probable rather than definite exposure. Conclusions There are plausible biological pathways by which these early-life factors could promote fibroid pathogenesis. This is the first epidemiologic study to evaluate such exposures, with the exception of in utero DES, in relation to fibroid risk, and replication of findings in other populations is needed.

Accuracy and reliability of self-reported weight and height in the Sister Study

OBJECTIVE To assess the accuracy and reliability of self-reported weight and height and identify the factors associated with reporting accuracy. DESIGN Analysis of self-reported and measured weight and height from participants in the Sister Study (2003-2009), a nationwide cohort of 50 884 women aged 35-74 years in the USA with a sister with breast cancer. SETTING Weight and height were reported via computer-assisted telephone interview (CATI) and self-administered questionnaires, and measured by examiners. SUBJECTS Early enrolees in the Sister Study. There were 18 639 women available for the accuracy analyses and 13 316 for the reliability analyses. RESULTS Using weighted kappa statistics, comparisons were made between CATI responses and examiner measures to assess accuracy and CATI and questionnaire responses to assess reliability. Polytomous logistic regression evaluated factors associated with over- or under-reporting. Compared with measured values, agreement was 96 % for reported height (±1 inch (±2·5 cm); weighted κ = 0·84) and 67 % for weight (±3 lb (±1·36 kg); weighted κ = 0·92). Obese women (BMI ≥ 30 kg/m2) were more likely than normal-weight women to under-report weight by ≥5 % and underweight women (BMI < 18·5 kg/m2) were more likely to over-report. Among normal-weight and overweight women (18·5 kg/m2 ≤ BMI < 30 kg/m2), weight cycling and lifetime weight difference ≥50 lb (≥22·68 kg) were associated with over-reporting. CONCLUSIONS US women in the Sister Study were reasonably reliable and accurate in reporting weight and height. Women with normal-range BMI reported most accurately. Overweight and obese women and those with weight fluctuations were less accurate, but even among obese women, few under-reported their weight by >10 %.

Serum microRNA expression as an early marker for breast cancer risk in prospectively collected samples from the Sister Study cohort

IntroductionMicroRNAs (miRNAs) are small, non-coding, single-stranded RNAs between 18-22 nucleotides long that regulate gene expression. Expression of miRNAs is altered in tumor compared to normal tissue; there is some evidence that these changes may be reflected in the serum of cancer cases compared to healthy individuals. This has yet to be examined in a prospective study where samples are collected before diagnosis.MethodsWe used Affymetrix arrays to examine serum miRNA expression profiles in 410 participants in the Sister Study, a prospective cohort study of 50,884 women. All women in the cohort had never been diagnosed with breast cancer at the time of enrollment. We compared global miRNA expression patterns in 205 women who subsequently developed breast cancer and 205 women who remained breast cancer-free. In addition within the case group we examined the association of miRNA expression in serum with different tumor characteristics, including hormone status (ER, PR, and HER-2) and lymph node status.ResultsOverall, 414 of 1,105 of the human miRNAs on the chip were expressed above background levels in 50 or more women. When the average expression among controls was compared to cases using conditional logistic regression, 21 miRNAs were found to be differentially expressed (P≤.05). Using qRT-PCR on a small, independent sample of 5 cases and 5 controls we verified overexpression of the 3 highest expressing miRNAs among cases, miR-18a, miR-181a, and miR-222; the differences were not statistically significant in this small set. The 21 differentially expressed miRNAs are known to target at least 82 genes; using the gene list for pathway analysis we found enrichment of genes involved in cancer-related processes. In a separate case-case analyses restricted to the 21 miRNAs, we found 7 miRNAs with differential expression for women whose breast tumors differed by HER-2 expression, and 10 miRNAs with differential expression by nodal status.ConclusionsmiRNA levels in serum show a number of small differences between women who later develop cancer versus those who remain cancer-free.

Eating patterns and nutritional characteristics associated with sleep duration.

OBJECTIVE To identify major meal and snack eating patterns, and examine their relationships with sleep duration. DESIGN The analyses included 27 983 participants in a prospective cohort study of women aged 35 to 74 years in the USA or Puerto Rico. RESULTS The principal component analysis of eight meal and snack frequency items at different times across the day yielded two major eating patterns: (i) eating during conventional eating hours (defined as times from breakfast to dinner); and (ii) dominance of snacks over meals. Comparing the identified eating patterns among women with varying sleep duration (<5, 5-5·9, 6-6·9, 7-7·9, 8-8·9, 9-9·9 and ≥10 h daily), the tendency for eating during conventional eating hours decreased with decreasing sleep duration: adjusted mean score of -0·54 (95% CI -0·68, -0·41) in women sleeping for <5 h daily v. 0·08 (95% CI 0·06, 0·11) among those with 7-7·9 h of sleep daily. The extent of snack dominance over meals increased in women with shorter sleep. Women with long (≥10 h) sleep duration had eating patterns similar to those with short (<6 h) sleep duration. Lower tendency for eating during conventional eating hours and greater snack dominance over meals were also related to higher intakes of fat and sweets for energy and lower intakes of fruits and vegetables. CONCLUSIONS Disrupted eating patterns and diet of poor nutritional quality may exacerbate the development of obesity and metabolic diseases in habitual short and very long sleepers.

First-Trimester Maternal Alcohol Consumption and the Risk of Infant Oral Clefts in Norway: A Population-based Case-Control Study

Although alcohol is a recognized teratogen, evidence is limited on alcohol intake and oral cleft risk. The authors examined the association between maternal alcohol consumption and oral clefts in a national, population-based case-control study of infants born in 1996-2001 in Norway. Participants were 377 infants with cleft lip with or without cleft palate, 196 with cleft palate only, and 763 controls. Mothers reported first-trimester alcohol consumption in self-administered questionnaires completed within a few months after delivery. Logistic regression was used to calculate odds ratios and 95% confidence intervals, adjusting for confounders. Compared with nondrinkers, women who reported binge-level drinking (>or=5 drinks per sitting) were more likely to have an infant with cleft lip with or without cleft palate (odds ratio = 2.2, 95% confidence interval: 1.1, 4.2) and cleft palate only (odds ratio = 2.6, 95% confidence interval: 1.2, 5.6). Odds ratios were higher among women who binged on three or more occasions: odds ratio = 3.2 for cleft lip with or without cleft palate (95% confidence interval: 1.0, 10.2) and odds ratio = 3.0 for cleft palate only (95% confidence interval: 0.7, 13.0). Maternal binge-level drinking may increase the risk of infant clefts.