Benign breast disease and changes in mammographic breast density.

BACKGROUND: Mammographic breast density (MBD) and benign breast disease (BBD) are two of the strongest risk factors for breast cancer. Understanding trends in MBD by age and parity in women with BBD is essential to the clinical management and prevention of breast cancer. METHODS: Using data from the Early Determinants of Mammographic Density (EDMD) study, a prospective follow-up study of women born in 1959-1967, we evaluated MBD in 676 women. We used linear regression with generalized estimating equations to examine associations between self-reported BBD and MBD (percent density, dense area, and non-dense area), assessed through a computer-assisted method. RESULTS: A prior BBD diagnosis (median age at diagnosis 32 years) was reported by 18% of our cohort. The median time from BBD diagnosis to first available study mammogram was 9.4 years (range 1.1-27.6 years). Women with BBD had a 3.44% higher percent MBD (standard error (SE) = 1.56, p-value = 0.03) on their first available mammogram than women without BBD. Compared with parous women without BBD, nulliparous women with BBD and women with a BBD diagnosis prior to first birth had 7-8% higher percent MBD (ß = 7.25, SE = 2.43, p-value< 0.01 and ß = 7.84, SE = 2.98, p-value = 0.01, respectively), while there was no difference in MBD in women with a BBD diagnosis after the first birth (ß = -0.22, SE = 2.40, p-value = 0.93). CONCLUSION: Women with self-reported BBD had higher mammographic breast density than women without BBD; the association was limited to women with BBD diagnosed before their first birth.

Maternal active asthma in pregnancy influences associations between polyunsaturated fatty acid intake and child asthma.

BACKGROUND: Studies evaluating effects of prenatal polyunsaturated fatty acid (PUFA) intake on childhood asthma reveal mixed results. Inconsistencies may result from not accounting for important modifying factors such as maternal asthma or child sex. OBJECTIVE: To evaluate whether associations between prenatal PUFA intake and childhood asthma are modified by prenatal active maternal asthma or child sex in 412 mother-child dyads. METHODS: Energy-adjusted prenatal dietary and supplement intakes of omega-3 (n-3) and omega-6 (n-6) PUFAs were estimated using the Block98 Food Frequency Questionnaire, administered during pregnancy. Mothers reported asthma in children followed prospectively to 4.0 plus or minus 1.7 years. Generalized additive models with smooth terms for PUFA (n-3, n-6, n-6/n-3 ratio) effects were used to investigate associations between PUFAs and child asthma, without prespecifying the form of these relationships, including effect modification by active maternal asthma or child sex. RESULTS: Among mothers (40% Black, 31% Hispanic), 22% had active asthma in pregnancy; 17.5% of children developed asthma. Lower maternal n-3 PUFA intake was significantly associated with risk of childhood asthma (P = .03), in particular among children of mothers with active asthma and low n-3 PUFA intake (P = .01). This inverse association was more apparent in girls (P = .01) compared with boys (P = .30), regardless of maternal asthma status. For n-6 PUFA and the n-6/n-3 ratio, there was a lower risk of childhood asthma in the midrange of intake and increased risk at higher intake (n-6 PUFA P = .10, n-6/n-3 ratio P = .13). CONCLUSION: Consideration of factors that modify effects of prenatal PUFA intake on childhood asthma has implications for designing intervention strategies tailored to impact those at greatest risk.

Data-driven discovery of mid-pregnancy immune markers associated with maternal lifetime stress: results from an urban pre-birth cohort.

Changes to the maternal inflammatory milieu may be a mechanism through which maternal psychosocial stress is transmitted to the fetus. Research investigating a limited number of immune markers may miss important signals. We take a proteomics approach to investigate maternal lifetime stress and 92 biomarkers of immune system status. Participants were enrolled in an urban, dual-site (Boston, n = 301 and New York City, n = 110) pregnancy cohort. We measured maternal lifetime history of stress and trauma using the validated Life Stressor Checklist-Revised (LSC-R). We measured a panel of 92 immune-related proteins in mid-pregnancy serum using proximity extension assay technology. We leveraged the dual-site study design to perform variable selection and inference within the cohort. First, we used LASSO to select immune markers related to maternal stress among Boston mothers. Then, we performed OLS regression to examine associations between maternal stress and LASSO-selected proteins among New York City mothers. LASSO regression selected 19 immune proteins with non-null coefficients (CCL11, CCL23, CD244, CST5, CXCL1, CXCL5, CXCL10, CX3CL1, FGF-23, IL-5, IL-7, IL-10, IL-17C, MCP-2, MMP-1, SLAMF1, ST1A1, TNF-ß, and TWEAK). Of these, only the chemotactic cytokine CX3CL1 (i.e. fractalkine) was significantly associated with maternal stress among the validation sample (percent change in LSC-R score per 1% increase in relative fractalkine expression: 0.74, 95% confidence interval: 0.19, 1.28). Expanding research suggests fractalkine plays an important role in many aspects of pregnancy and fetal development and is stress-sensitive. We found that maternal lifetime history of stress and trauma was significantly associated with elevated serum fractalkine levels during pregnancy.

Early-Life Growth and Benign Breast Disease.

Using prospective data from the Early Determinants of Mammographic Density study (United States, 1959-2008, n = 1121), we examined the associations between maternal body size, birth size, and infant and early childhood growth during 3 time periods (0-4 months, 4-12 months, and 1-4 years) and benign breast disease (BBD) using multivariable logistic regression with generalized estimating equations. A total of 197 women (17.6%) reported receiving a diagnosis of BBD by a physician. Higher body mass index at age 7 years was inversely associated with BBD risk. Rapid weight gain from age 1 year to 4 years, defined as an increase of least 2 major percentiles (e.g., 5th, 10th, 25th, 50th, 75th, and 95th) relative to stable growth, defined as remaining within 2 percentiles, was also inversely associated with BBD (odds ratio (OR) = 0.51, 95% confidence interval (CI): 0.23, 1.15). In contrast, rapid weight gain in infancy was positively associated with BBD relative to stable growth (from 0 to 4 months, OR = 1.65, 95% CI: 1.04, 2.62; from 4 to 12 months, 1.85, 95% CI: 0.89, 3.85), independent of birth weight, which was not associated with BBD. Our results suggest that patterns of early-life weight gain are important to BBD risk. Thus, susceptibility to BBD, like susceptibility to breast cancer, might start in early life.

Do Birth Weight and Weight Gain During Infancy and Early Childhood Explain Variation in Mammographic Density in Women in Midlife? Results From Cohort and Sibling Analyses.

High birth weight is associated with increased breast cancer risk and, less consistently, with higher mammographic density. In contrast, adolescent body size has been consistently, negatively associated with both MD and breast cancer risk. It is unclear when the direction of these associations changes and whether weight gain in infancy is associated with MD. We evaluated the associations of birth weight and postnatal weight (measured at 4 months, 1 year, and 4 years) by absolute and velocity measures (relative within-cohort percentile changes) with adult mammographic density, assessed using a computer-assisted thresholding program (Cumulus), using linear regression models with generalized estimating equations to account for correlation between siblings in the Early Determinants of Mammographic Density study (1959-2008; n = 700 women with 116 sibling sets; mean age = 44.1 years). Birth weight was positively associated with dense area (per 1-kg increase, ß = 3.36, 95% confidence interval (CI): 0.06, 6.66). Weight gains from 0 months to 4 months and 1 year to 4 years were negatively associated with dense area (for 10-unit increase in weight percentile, ß = -0.65, 95% CI: -1.23, -0.07, and ß = -1.07, 95% CI: -1.98, -0.16, respectively). Findings were similar in the sibling subset. These results support the hypothesis that high birth weight is positively associated with increased breast density and suggest that growth spurts starting in early infancy reduce mammographic dense area in adulthood.

Maternal Lifetime Trauma and Birthweight: Effect Modification by In Utero Cortisol and Child Sex.

OBJECTIVES: To evaluate associations between maternal lifetime traumatic stress and offspring birthweight and examine modifying effects of third trimester cortisol and fetal sex. STUDY DESIGN: Analyses included 314 mother-infant dyads from an ethnically mixed pregnancy cohort. Maternal lifetime trauma was reported via the Life Stressor Checklist-Revised. Fenton birthweight for gestational age z-scores (BWGA-z) were calculated. A 3-cm scalp-nearest maternal hair segment collected at birth was assayed to reflect cumulative third trimester cortisol secretion. Multivariable regression was used to investigate associations between maternal lifetime trauma and BWGA-z and examine 2- and 3-way interactions with cortisol and fetal sex. Because subjects with low or high cortisol levels could represent susceptible populations, varying coefficient models that relax the linearity assumption on cortisol level were used to assess the modification of maternal lifetime trauma associations with BWGA-z as a function of cortisol. RESULTS: Women were primarily minorities (41% Hispanic, 26% black) with ≤12 years education (63%); 63% reported ≥1 traumatic event. Prenatal cortisol modified the association between maternal lifetime trauma and birthweight. Women with higher lifetime trauma and increased cortisol had significantly lower birthweight infants in males; among males exposed to the 90th percentile of cortisol, a 1-unit increase in trauma score was associated with a 0.19-unit decrease in BWGA-z (95% CI, -0.34 to -0.04). Associations among females were nonsignificant, regardless of cortisol level. CONCLUSIONS: These findings underscore the need to consider complex interactions among maternal trauma, disrupted in utero cortisol production, and fetal sex to fully elucidate intergenerational effects of maternal lifetime trauma.

Hair product use, age at menarche and mammographic breast density in multiethnic urban women.

BACKGROUND: Select hair products contain endocrine disrupting chemicals (EDCs) that may affect breast cancer risk. We hypothesize that, if EDCs are related to breast cancer risk, then they may also affect two important breast cancer risk factors: age at menarche and mammographic breast density. METHODS: In two urban female cohorts (N = 248): 1) the New York site of the National Collaborative Perinatal Project and 2) the New York City Multiethnic Breast Cancer Project, we measured childhood and adult use of hair oils, lotions, leave-in conditioners, root stimulators, perms/relaxers, and hair dyes using the same validated questionnaire. We used multivariable relative risk regression models to examine the association between childhood hair product use and early age at menarche (defined as <11 years of age) and multivariable linear regression models to examine the association between childhood and adult hair product use and adult mammographic breast density. RESULTS: Early menarche was associated with ever use of childhood hair products (RR 2.3, 95% CI 1.1, 4.8) and hair oil use (RR 2.5, 95% CI 1.2, 5.2); however, additional adjustment for race/ethnicity, attenuated associations (hair products RR 1.8, 95% CI 0.8, 4.1; hair oil use RR 2.3, 95% CI 1.0, 5.5). Breast density was not associated with adult or childhood hair product or hair oil use. CONCLUSIONS: If confirmed in larger prospective studies, these data suggest that exposure to EDCs through hair products in early life may affect breast cancer risk by altering timing of menarche, and may operate through a mechanism distinct from breast density.

Early life socioeconomic environment and mammographic breast density.

BACKGROUND: Early life social environment may influence breast cancer through shaping risk factors operating in early life, adolescence and adulthood, or may be associated with breast cancer risk independent of known risk factors. We investigated the associations between early life socioeconomic status (SES) and mammographic density, a strong risk factor for breast cancer, and the extent to which these associations were independent of risk factors across the lifecourse. METHODS: We used data from an adult follow-up study of two U.S. birth cohorts of women (average age = 43 years) with prospectively collected data starting during the pregnancy of the mother and continuing through early childhood of the offspring. We collected data on factors in later life periods through computer-assisted interviews with the offspring as adults, and obtained routine clinical mammograms for measurement of percent density and dense and nondense breast areas using a computer assisted method. We used generalized estimating equation models for multivariable analysis to account for correlated data for sibling sets within the study sample (n = 700 composed of 441 individuals and 127 sibling sets). RESULTS: Highest vs. lowest family income level around the time of birth was associated with smaller dense breast area after adjustment for early life factors (e.g., birthweight, maternal smoking during pregnancy) and risk factors in later life periods, including adult body mass index (BMI) and adult SES (ß = -8.2 cm2, 95% confidence interval [CI]: -13.3, -3.2). Highest vs. lowest parental educational attainment was associated with higher percent density in models that adjusted for age at mammogram and adult BMI (e.g., ß = 4.8, 95% CI = 0.6, 9.1 for maternal education of college or higher degree vs. less than high school), but the association was attenuated and no longer statistically significant after further adjustment for early life factors. There were no associations between early life SES indicators and non-dense area after adjustment for adult BMI. Neither adult education nor adult income was statistically significantly associated with any measure of mammographic density after adjusting for age and adult BMI. CONCLUSIONS: We did not observe consistent associations between different measures of early life SES and mammographic density in adulthood.

Alcohol intake from early adulthood to midlife and mammographic density.

PURPOSE: Moderate alcohol consumption (15 g/day) has been consistently associated with increased breast cancer risk; however, the association between alcohol and mammographic density, a strong marker of breast cancer risk, has been less consistent. Less is known about the effect of patterns of alcohol intake across the lifecourse. METHODS: Using the Early Determinants of Mammographic Density study, an adult follow-up of women born in two US birth cohorts (n = 697; Collaborative Perinatal Project in Boston and Providence sites and the Childhood Health and Development Studies in California), we examined the association between alcohol intake in early adulthood (ages 20-29 years) and at time of interview and mammographic density (percent density and total dense area). We report the difference between nondrinkers and three levels of alcohol intake. We considered confounding by age at mammogram, body mass index, geographic site, race/ethnicity, and reproductive characteristics. RESULTS: Seventy-nine percent of women reported ever consuming alcohol. Compared to nondrinkers in early adulthood, we observed an inverse association between >7 servings/week and percent density in fully adjusted models (ß = -5.1, 95% CI -8.7, -1.5; p for trend = <0.01). Associations with dense area were inverse for the highest category of drinking in early adulthood but not statistically significant (p for trend = 0.15). Compared to noncurrent drinkers, the association for current intake of >7 servings/week and percent density was also inverse (ß = -3.1, 95% CI -7.0, 0.8; p for trend = 0.01). In contrast, moderate alcohol intake (>0-≤7 servings/week) in either time period was positively associated with dense area; but associations were not statistically significant in fully adjusted models. CONCLUSIONS: Our study does not lend support to the hypothesis that the positive association between alcohol intake and breast cancer risk is through increasing mammographic density.

The association of alcohol consumption with mammographic density in a multiethnic urban population.

BACKGROUND: Alcohol consumption is associated with higher breast cancer risk. While studies suggest a modest association between alcohol intake and mammographic density, few studies have examined the association in racial/ethnic minority populations. METHODS: We assessed dense breast area and total breast area from digitized film mammograms in an urban cohort of African American (42%), African Caribbean (22%), white (22%), and Hispanic Caribbean (9%) women (n = 189, ages 40-61). We examined the association between alcohol intake and mammographic density (percent density and dense area). We used linear regression to examine mean differences in mammographic density across alcohol intake categories. We considered confounding by age, body mass index (BMI), hormone contraceptive use, family history of breast cancer, menopausal status, smoking status, nativity, race/ethnicity, age at first birth, and parity. RESULTS: Fifty percent currently consumed alcohol. Women who consumed >7 servings/week of alcohol, but not those consuming ≤7 servings/week, had higher percent density compared to nondrinkers after full adjustments (servings/week >7 ß = 8.2, 95% Confidence Interval (CI) 1.8, 14.6; ≤7 ß = -0.5, 95% CI -3.7, 2.8). There was a positive association between high alcohol intake and dense area after full adjustments (servings/week >7 ß = 5.8, 95% CI -2.7, 14.2; ≤7 ß = -0.1, 95% CI -4.4, 4.2). We did not observe race/ethnicity modification of the association between alcohol intake and percent density. In women with a BMI of <25 kg/m(2), drinkers consuming >7 servings/week of alcohol had a = 17% increase in percent density compared to nondrinkers (95% CI 5.4, 29.0) and there was no association in women with a BMI ≥ 25 kg/m(2) (BMI ≥ 25-30 kg/m(2) > 7 ß = 5.1, 95% CI -8.5, 18.7 and BMI > 30 kg/m(2) > 7 ß = 0.5, 95% CI -6.5, 7.5) after adjusting for age and BMI (continuous). CONCLUSION: In a racially/ethnically diverse cohort, women who consumed >7 servings/week of alcohol, especially those with a BMI < 25 kg/m(2), had higher percent density.

Repetitive element DNA methylation levels in white blood cell DNA from sisters discordant for breast cancer from the New York site of the Breast Cancer Family Registry.

Global decreases in DNA methylation, particularly in repetitive elements, have been associated with genomic instability and human cancer. Emerging, though limited, data suggest that in white blood cell (WBC) DNA levels of methylation, overall or in repetitive elements, may be associated with cancer risk. We measured methylation levels of three repetitive elements [Satellite 2 (Sat2)], long interspersed nuclear element-1 (LINE-1) and Alu) by MethyLight, and LINE-1 by pyrosequencing in a total of 282 breast cancer cases and 347 unaffected sisters from the New York site of the Breast Cancer Family Registry (BCFR) using DNA from both granulocytes and total WBC. We found that methylation levels in all markers were correlated between sisters (Spearman correlation coefficients ranged from 0.17 to 0.55). Sat2 methylation was statistically significantly associated with increased breast cancer risk [odds ratio (OR) = 2.09, 95% confidence interval (CI) = 1.09-4.03; for each unit decrease in the natural log of the methylation level, OR = 2.12, 95% CI = 0.88-5.11 for the lowest quartile compared with the highest quartile]. These associations were only observed in total WBC but not granulocyte DNA. There was no association between breast cancer and LINE-1 and Alu methylation. If replicated in larger prospective studies, these findings support that selected markers of epigenetic changes measured in WBC, such as Sat2, may be potential biomarkers of breast cancer risk.

Prenatal and childhood environmental tobacco smoke exposure and age at menarche.

Previous studies have reported mixed results regarding the association between age at menarche and environmental tobacco smoke exposure, both prenatally and during early childhood; however, few studies have had data available during both time periods. The present study examined whether exposure to prenatal tobacco smoke (PTS) via maternal smoking during pregnancy or childhood environmental tobacco smoke (ETS) was associated with age at menarche in a multi-ethnic birth cohort. With the uniquely available prospectively collected data on body size and growth at birth and in early life, we further examined whether the association between PTS and ETS exposure and age at menarche was mediated by these variables. From 2001 to 2006, we recruited 262 women born between 1959 and 1963 who were enrolled previously in a New York City site of the National Collaborative Perinatal Project. Mothers who smoked during pregnancy vs. those who did not were more likely to be White, younger, have more education and have lower birthweight babies. Daughters with heavy PTS exposure (≥ 20 cigarettes per day) had a later age at menarche (>12 years vs. ≤ 12 years), odds ratio (OR) =2.1 [95% confidence interval (CI) 0.9, 5.0] compared with daughters with no PTS. Daughters exposed to only childhood ETS had a later age at menarche, OR=2.1 [95% CI 1.0, 4.3], and those exposed to PTS and ETS combined had a statistically significant later age at menarche, OR=2.2 [95% CI 1.1, 4.6] compared with daughters with no PTS and no ETS. These results did not change after further adjustment for birthweight and postnatal growth suggesting that exposure to PTS and ETS is associated with later age at menarche even after considering possible relationships with growth.

Placental morphometry in relation to daughters' percent mammographic breast density at midlife.

Intrauterine and early-life exposures, including intrauterine smoke exposures and infant growth are associated with mammographic breast density (MBD), a strong breast cancer risk factor. We investigated whether placental morphometry, which is affected by intrauterine smoke exposure and also influences infant growth, predicts %MBD at ages 37-47. In 247 daughters in the Child Health and Development Studies, we found that larger placental surface area and placental thickness were associated with lower %MBD (-0.32 per cm2, 95% CI -0.6, -0.05; -37.8 per 0.5 cm, 95% CI= -73.3, -2.3 respectively) independent of mothers' smoking, age, weight, parity and daughters' birthweight and age at mammogram. We also observed a positive interaction between placental surface area and thickness (p < 0.05) such that the highest breast dense area was observed for offspring with the thickest and largest placentas. Factors that impact placental morphometry, in addition to in utero smoke exposure, may influence adult breast architecture and breast cancer risk.

In utero DDT exposure and breast density before age 50.

Prior studies in the Child Health and Development Studies (CHDS) found in utero exposure to the pesticide, dichlorodiphenyltrichloroethane (DDT), increased breast cancer risk by age 52. Mammographic density is considered a primary risk factor for breast cancer. We conducted a study of 309 daughters from the CHDS to examine in utero DDT exposure and mammographic density in midlife. Among daughters with high (>75th percentile) exposure to p,p'-Dichlorodiphenyldichloroethylene (DDE), p,p'-DDT was significantly correlated with increased dense area and percent density regardless of her body mass in midlife. In the subset of women with lower (<75th percentile) p,p-DDE, p,p'-DDT was associated with increased non-dense breast area. This was explained by adjustment for midlife BMI suggesting that p,p'-DDT may be obesogenic. In aggregate our findings indicate that early life p,p'-DDT exposure impacts breast density in a complex way that depends on the hosts biological ability to sequester and process DDT and levels of exposure.

Validity of self-reported birth weight by adult women: sociodemographic influences and implications for life-course studies.

Life-course epidemiologic studies frequently obtain data on perinatal and childhood factors through adult self-report. Data from a prospective US birth cohort of 262 women, born between 1959 and 1963 (average age at adult follow-up, 41.8 years), were used to assess the validity of self-reported birth weight category by sociodemographic characteristics. The effect of reporting error on the associations of birth weight with childhood and adult body mass index was evaluated by comparing the estimates of associations from linear regression analyses. The level of agreement between the birth weight category reported by 85% of the participants and the birth weight recorded at the time of birth was moderate to good (sensitivity = 73%, weighted kappa = 0.67). The validity varied by birth weight category (sensitivity range = 58%-81% for the lowest and highest birth weight category, respectively) and was highest for participants who were white, of lower childhood family income, and born to older mothers. Despite this moderate to good validity, the associations of birth weight with childhood and adult body mass index were attenuated and no longer statistically significant when self-reported birth weight was used. In conclusion, birth weight reported in middle adult life is measured with error, limiting its utility for detecting modest associations with health in later life periods.

Birth weight, postnatal growth, and age at menarche.

Larger body size in childhood is correlated with earlier age at menarche; whether birth and infant body size changes are also associated with age at menarche is less clear. The authors contacted female participants enrolled in the New York site of the US National Collaborative Perinatal Project born between 1959 and 1963 (n = 262). This racially and ethnically diverse cohort (38% white, 40% African American, and 22% Puerto Rican) was used to investigate whether maternal (body size, pregnancy weight gain, age at menarche, smoking) and birth (birth weight, birth length, placental weight) variables and early infant body size changes were associated with age at menarche even after considering later childhood body size. Higher percentile change in weight from ages 4 months to 1 year was associated with earlier age at menarche even after adjustment for later childhood growth (beta = -0.15, 95% confidence interval: -0.27, -0.02 years per 10-percentile change in weight from ages 4 months to 1 year). The association was in the same direction for all 3 racial/ethnic groups but was largest for the white group. These New York Women's Birth Cohort Adult Follow-up data (2001-2006) suggest that infant weight gain, in addition to childhood weight gain, may be associated with earlier age at menarche.

Alcohol intake over the life course and mammographic density.

Alcohol intake is one of the few modifiable risk factors for breast cancer. Current alcohol intake has been associated with mammographic density, a strong intermediate marker of breast cancer risk, though few studies have examined the effect of both current and average lifetime alcohol intake. We interviewed 262 participants from a New York birth cohort (born 1959-1963) and obtained mammograms from 163 (71.5% of participants with a mammogram). We collected information on alcohol intake by beverage type separately for each decade of life. We used multivariable linear models to assess the associations between current and average lifetime alcohol intake and mammographic density using a quantitative measure of density from digitized images. Overall, current alcohol intake was more strongly associated with mammographic density than average lifetime alcohol intake; compared with nondrinkers, those with current intake of seven or more servings per week had on average 12.3% (95% CI: 4.3, 20.4) higher density, adjusted for average lifetime alcohol intake, age, and body mass index. We observed a consistent inverse association for red wine intake and mammographic density, suggesting that the positive association between mammographic density and overall alcohol intake was driven by other types of alcoholic beverages. Our findings support an association between current alcohol intake and increased mammographic density independent of the effect of average lifetime alcohol intake. If replicated, our study suggests that reducing current alcohol consumption, particularly beer and white wine intake, may be a means of reducing mammographic density regardless of intake earlier in life.

Epidemiology of Cow's Milk Allergy.

Immunoglobulin E (IgE)-mediated cow's milk allergy (CMA) is one of the most common food allergies in infants and young children. CMA can result in anaphylactic reactions, and has long term implications on growth and nutrition. There are several studies in diverse populations assessing the epidemiology of CMA. However, assessment is complicated by the presence of other immune-mediated reactions to cow's milk. These include non-IgE and mixed (IgE and non-IgE) reactions and common non-immune mediated reactions, such as lactose intolerance. Estimates of prevalence and population-level patterns are further complicated by the natural history of CMA (given its relatively high rate of resolution) and variation in phenotype (with a large proportion of patients able to tolerate baked cow's milk). Prevalence, natural history, demographic patterns, and long-term outcomes of CMA have been explored in several disparate populations over the past 30 to 40 years, with differences seen based on the method of outcome assessment, study population, time period, and geographic region. The primary aim of this review is to describe the epidemiology of CMA. The review also briefly discusses topics related to prevalence studies and specific implications of CMA, including severity, natural course, nutritional impact, and risk factors.

Genomic DNA methylation among women in a multiethnic New York City birth cohort.

One plausible mechanism for the environment to alter cancer susceptibility is through DNA methylation. Alterations in DNA methylation can lead to genomic instability and altered gene transcription. Genomic DNA methylation levels have been inversely associated with age, suggesting that factors throughout life may be associated with declines in DNA methylation. Using information from a multiethnic New York City birth cohort (born between 1959 and 1963), we examined whether genomic DNA methylation, measured in peripheral blood mononuclear cells, was associated with smoking exposure and other epidemiologic risk factors across the life course. Information on prenatal and childhood exposures was collected prospectively through 1971, and information on adult exposures and blood specimens were collected in adulthood from 2001 to 2007. Methylation levels of leukocyte DNA were determined using a [(3)H]-methyl acceptance assay where higher values of disintegrations per minute per microgram DNA indicate less DNA methylation. Genomic methylation of leukocyte DNA differed by ethnicity (66% of Blacks, 48% of Whites, and 29% of Hispanics were above the median level of disintegrations per minute per microgram DNA; P = 0.03). In multivariable modeling, DNA methylation was statistically significantly associated with maternal smoking during pregnancy, longer birth length, later age at menarche, nulliparity, and later age at first birth. These data, if replicated in larger samples, suggest that risk factors across the life course may be associated with DNA methylation in adulthood. Larger studies and studies that measure within-individual changes in DNA methylation over time are a necessary next step.