Karin B Michels

University of Freiburg, Freiburg, Baden-Württemberg, Germany

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Publications (199)1434.39 Total impact

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    ABSTRACT: The purpose of this study was to evaluate whether antihypertensive medication use, including long-term use, is associated with increased breast cancer incidence in women. We studied 210,641 U.S. registered nurses participating in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHS II). Information on antihypertensive medication use was collected on biennial questionnaires in both cohorts, and breast cancer cases were ascertained during this period. Multivariable-adjusted Cox proportional hazard models were used to estimate relative risks of invasive breast cancer over follow-up (1988-2012 in NHS, 1989-2011 in NHS II) across categories of overall antihypertensive medication use and use of specific classes (diuretics, beta blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors). During follow-up, 10,012 cases of invasive breast cancer developed (6718 cases in NHS and 3294 in the NHS II). Overall, current use of any antihypertensive medication was not associated with breast cancer risk compared with past/never use in NHS (multivariable-adjusted relative risk = 1.00, 95 % CI = 0.95-1.06) or NHS II (multivariable-adjusted relative risk = 0.94, 95 % CI = 0.86-1.03). Furthermore, no specific class of antihypertensive medication was consistently associated with breast cancer risk. Results were similar when we considered hypertensive women only, and when we evaluated consistency and duration of medication use over time. Overall, antihypertensive medication use was largely unrelated to the risk of invasive breast cancer among women in the NHS cohorts.
    Breast Cancer Research and Treatment 02/2015; · 4.47 Impact Factor
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    ABSTRACT: Is sugar-sweetened beverage (SSB) consumption associated with age at menarche? More frequent SSB consumption was associated with earlier menarche in a population of US girls. SSB consumption is associated with metabolic changes that could potentially impact menarcheal timing, but direct associations with age at menarche have yet to be investigated. The Growing up Today Study, a prospective cohort study of 16 875 children of Nurses' Health Study II participants residing in all 50 US states. This analysis followed 5583 girls, aged 9-14 years and premenarcheal at baseline, between 1996 and 2001. During 10 555 person-years of follow-up, 94% (n = 5227) of girls reported their age at menarche, and 3% (n = 159) remained premenarcheal in 2001; 4% (n = 197) of eligible girls were censored, primarily for missing age at menarche. Cumulative updated SSB consumption (composed of non-carbonated fruit drinks, sugar-sweetened soda and iced tea) was calculated using annual Youth/Adolescent Food Frequency Questionnaires from 1996 to 1998. Age at menarche was self-reported annually. The association between SSB consumption and age at menarche was assessed using Cox proportional hazards regression. More frequent SSB consumption predicted earlier menarche. At any given age between 9 and 18.5 years, premenarcheal girls who reported consuming >1.5 servings of SSBs per day were, on average, 24% more likely [95% confidence interval (CI): 13, 36%; P-trend: <0.001] to attain menarche in the next month relative to girls consuming ≤2 servings of SSBs weekly, adjusting for potential confounders including height, but not BMI (considered an intermediate). Correspondingly, girls consuming >1.5 SSBs daily had an estimated 2.7-month earlier menarche (95% CI: -4.1, -1.3 months) relative to those consuming ≤2 SSBs weekly. The frequency of non-carbonated fruit drink (P-trend: 0.03) and sugar-sweetened soda (P-trend: 0.001), but not iced tea (P-trend: 0.49), consumption also predicted earlier menarche. The effect of SSB consumption on age at menarche was observed in every tertile of baseline BMI. Diet soda and fruit juice consumption were not associated with age at menarche. Although we adjusted for a variety of suspected confounders, residual confounding is possible. We did not measure SSB consumption during early childhood, which may be an important window of exposure. More frequent SSB consumption may predict earlier menarche through mechanisms other than increased BMI. Our findings provide further support for public health efforts to reduce SSB consumption. The Growing up Today Study is supported by grant R03 CA 106238. J.L.C. was supported by the Breast Cancer Research Foundation; Training Grant T32ES007069 in Environmental Epidemiology from the National Institute of Environmental Health Sciences, National Institutes of Health; and Training Grant T32HD060454 in Reproductive, Perinatal and Pediatric Epidemiology from the National Institute of Child Health and Human Development, National Institutes of Health. A.L.F. is supported by the American Cancer Society, Research Scholar Grant in Cancer Control. K.B.M. was supported in part by the National Cancer Institute at the National Institutes of Health (Public Health Service grants R01CA158313 and R03CA170952). There are no conflicts of interest to declare. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Human reproduction (Oxford, England). 01/2015;
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    ABSTRACT: Although adult obesity is known to increase endometrial cancer risk, evidence for childhood obesity is limited. We prospectively examined the association between body fatness throughout life and endometrial cancer risk. 47,289 members of the Nurses' Health Study (NHS) and 105,386 of the Nurses' Health Study II (NHS II) recalled their body fatness at ages 5, 10, and 20 using a pictogram. Childhood and adolescent body fatness were derived as the average at ages 5 and 10, and ages 10 and 20, respectively. We obtained adult weight from concurrent questionnaires. We calculated hazard ratios (HR) of endometrial cancer using Cox proportional hazards models. During follow-up, 757 incident cases of endometrial cancer were diagnosed. Body fatness in childhood, at age 10, in adolescence, and at age 20 were positively associated with endometrial cancer risk (HR for ≥ Level 5 versus ≤ Level 2 in adolescence: 1.83 (95% CI 1.41-2.37). After adjusting for most recent BMI, none of the associations persisted. Weight change since age 18 was positively associated with endometrial cancer risk [HR for ≥ 25 kg gain versus stable: 2.54 (95% CI 1.80-3.59). Adult BMI was strongly associated with endometrial cancer risk [HR BMI ≥ 35 kg/m2 versus BMI ≤ 25 kg/m2: 4.13 (95% CI 3.29-5.16)]. In postmenopausal women, the association with BMI was significantly stronger among non-users of hormone therapy. In conclusion, obesity throughout life is positively associated with endometrial cancer risk, with adult obesity one of the strongest risk factors. Maintaining a healthy weight throughout life remains important. This article is protected by copyright. All rights reserved.
    International Journal of Cancer 01/2015; · 6.20 Impact Factor
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    ABSTRACT: Epigenetic regulation of imprinted genes enables monoallelic expression according to parental origin, and its disruption is implicated in many cancers and developmental disorders. The expression of hormone receptors is significant in breast cancer as they are indicators of cancer cell growth rate and determine response to endocrine therapies. We investigated the frequency of aberrant events and variation in DNA methylation at nine imprinted sites in invasive breast cancer and examined the association with estrogen and progesterone receptor status. Breast tissue and blood from patients with invasive breast cancer (n=38) and benign breast disease (n=30) were compared to those from healthy individuals (n=36), matched to the cancer patients by age at diagnosis, ethnicity, BMI, menopausal status, and familial history of cancer. DNA methylation and allele-specific expression were analyzed by pyrosequencing. Tumor-specific methylation changes at IGF2 DMR2 were observed in 59% of cancer patients, IGF2 DMR0 in 38%, DIRAS3 DMR in 36%, GRB10 ICR in 23%, PEG3 DMR in 21%, MEST ICR in 19%, H19 ICR in 18%, KvDMR in 8%, and SNRPN/SNURF ICR in 4%. Variation of methylation was significantly greater in breast tissue from cancer patients than healthy individuals and benign breast disease. Aberrant methylation of three or more sites was significantly associated with negative estrogen-alpha (Fisher's Exact Test, p=0.02) and progesterone-A (p=0.02) receptor status. Aberrant events and increased variation of imprinted gene DNA methylation therefore appear to be frequent in invasive breast cancer and are associated with negative estrogen and progesterone receptor status, without loss of monoallelic expression. This article is protected by copyright. All rights reserved.
    International Journal of Cancer 01/2015; · 6.20 Impact Factor
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    ABSTRACT: Background:Data from previous studies consistently suggest that maternal smoking is positively associated with the risk of obesity later in life. Whether this association persists across generations is unknown. Methods:We investigated the association between grandparent smoking status and grandchild overweight status among 3101 grandmother-mother-child triads in the Nurses’ Health Study II (NHS II), the NHS Mothers’ Cohort Study, and the children of NHS II participants who are in the Growing up Today Study (GUTS). Grandmothers of children provided information on their and their partner’s smoking during pregnancy with the child’s mother. Information on child's weight and height at ages 12 and 17 was obtained by self-report from the GUTS questionnaires. We used logistic regression to estimate odds ratios (ORs) of being overweight or obese, relative to normal weight. Results: Seventy-five percent of grandmothers reportedly did not smoke during pregnancy, while 4% quit during pregnancy, 13% continued smoking up to 14 cigarettes/day, and 7% smoked 15+ cigarettes daily throughout pregnancy. Grand-maternal smoking was not associated with being overweight or obese at age 12 or 17 years, in boys or in girls. After adjusting for multiple covariates, the OR of being overweight or obese relative to normal weight at age 12 years in girls whose grandmothers smoked 15+ cigarettes per day during pregnancy with their mothers was 1.23 (95% CI 0.75-2.01; ptrend = 0.25) and 1.08 (0.65-1.97; ptrend = 0.34) in boys. Grand-paternal smoking was positively associated with being overweight or obese at age 12 years in girls but not boys, and not at age 17 years for either: the OR for being overweight or obese at age 12 years was 1.46 (95% CI 1.07-1.99; ptrend = 0.01) in girls, and 1.26 (95% CI 0.94-1.70; ptrend = 0.11) in boys. After restricting to children of non-smoking mothers, the comparable OR for granddaughter obesity was attenuated and no longer significant [OR 1.35 (95% CI 0.93-1.97; ptrend= 0.10)]. Conclusions: Our findings suggest that grand-maternal smoking is not associated with adolescent overweight status in the grandchild. However, grand-paternal smoking may affect overweight status of the granddaughter, likely through the association between grand-paternal smoking and maternal smoking.
    142nd APHA Annual Meeting and Exposition 2014; 11/2014
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    ABSTRACT: To determine whether use of oral contraceptives is associated with all cause and cause specific mortality.
    BMJ Clinical Research 10/2014; 349:g6356. · 14.09 Impact Factor
  • Epigenomics of Common Diseases, Cambridge, UK; 10/2014
  • Dana Farber/Harvard Cancer Center’s Celebration of Junior Investigators in Cancer Research, Boston, MA; 09/2014
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    Timothy M Barrow, Karin B Michels
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    ABSTRACT: Epigenetic epidemiology includes the study of variation in epigenetic traits and the risk of disease in populations. Its application to the field of cancer has provided insight into how lifestyle and environmental factors influence the epigenome and how epigenetic events may be involved in carcinogenesis. Furthermore, it has the potential to bring benefit to patients through the identification of diagnostic markers that enable the early detection of disease and prognostic markers that can inform upon appropriate treatment strategies. However, there are a number of challenges associated with the conduct of such studies, and with the identification of biomarkers that can be applied to the clinical setting. In this review, we delineate the challenges faced in the design of epigenetic epidemiology studies in cancer, including the suitability of blood as a surrogate tissue and the capture of genome-wide DNA methylation. We describe how epigenetic epidemiology has brought insight into risk factors associated with lung, breast, colorectal and bladder cancer and review relevant research. We discuss recent findings on the identification of epigenetic diagnostic and prognostic biomarkers for these cancers.
    Biochemical and Biophysical Research Communications 08/2014; · 2.28 Impact Factor
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    ABSTRACT: We evaluated the associations of both maternal and paternal smoking during pregnancy with the risk of type 2 diabetes in daughters and explored whether any association was explained by weight at birth or BMI throughout life.
    Diabetes Care 08/2014; · 8.57 Impact Factor
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    ABSTRACT: Genomic imprinting leads to parent-of-origin specific gene expression and is determined by epigenetic modification of genes. The paternally expressed gene insulin-like growth-factor 2 (IGF2) is located about ~100kb from the maternally expressed non-coding gene H19 on human chromosome 11, and both genes play major roles in embryonic and placental growth. Given adverse gestational environments can influence DNA methylation patterns in extra-embryonic tissues, we hypothesized that prenatal exposure to endocrine disrupting chemicals (EDCs) alters H19 and IGF2 methylation in placenta. Our study was restricted to a total of 196 women co-enrolled in the Predictors of Preeclampsia Study and the Harvard Epigenetic Birth Cohort. First trimester urine concentrations of 8 phenols and 11 phthalate metabolites were measured and used to characterize EDC exposure profiles. We assessed methylation of differentially methylated regions (DMRs) by pyrosequencing of H19, IGF2DMR0, and IGF2DMR2 and correlated values with phenol and phthalate metabolites. We also assessed overall expression and allele-specific expression of H19 and IGF2. We found several significant associations between DNA methylation and additive biomarker measurements. A significant decrease in H19 methylation was associated with high levels of the sum (Σ) of phthalate metabolites and metabolites of low molecular weight (LMW) phthalates. Σphthalate and LMW phthalate concentrations were inversely associated with IGF2DMR0 methylation values. Variation in methylation was not associated with changes in allele-specific expression. However increased deviation of allele-specific expression of H19 was associated with Σdi(2-ethylhexyl) phthalate metabolites and high molecular weight phthalates. Neither methylation nor expression of these imprinted regions had a significant impact on birth length or birth weight. Overall, our study provides new insight into an epigenetic mechanism that occurs following EDC exposure.
    Environmental Research 06/2014; · 3.95 Impact Factor
  • M M Dougan, W C Willett, K B Michels
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    ABSTRACT: Background/Objectives:In animal studies, exposure to multi-vitamins may be associated with obesity in the offspring; however, data in humans is sparse. We therefore examined the association between prenatal vitamin intake during pregnancy and offspring obesity.Subjects/Methods:We investigated the association between prenatal vitamin intake and obesity among 29 160 mother-daughter dyads in the Nurses' Health Study II. Mothers of participants provided information on prenatal vitamin use during pregnancy with the nurse daughter. Information on body fatness at ages 5 and 10, body mass index (BMI) at age 18, weight in 1989 and 2009, waist circumference, and height was obtained from the daughter. Polytomous logistic regression was used to predict BMI in early adulthood and adulthood, and body fatness in childhood. Linear regression was used to predict waist circumference in adulthood.Results:In utero exposure to prenatal vitamins was not associated with body fatness, either in childhood or adulthood. Women whose mothers took prenatal vitamins during pregnancy had a covariate-adjusted odds ratio of being obese in adulthood of 0.99 (95% CI 0.92-1.05, P-value=0.68) compared to women whose mothers did not take prenatal vitamins. Women whose mothers took prenatal vitamins during pregnancy had a covariate-adjusted odds ratio of having the largest body shape at age 5 of 1.02 (95% CI 0.90-1.15, P-value=0.78). In additional analyses, in utero exposure to prenatal vitamins was also unrelated to adult abdominal adiposity.Conclusions:Exposure to prenatal vitamins was not associated with body fatness either in childhood or in adulthood.International Journal of Obesity accepted article preview online, 19 June 2014; doi:10.1038/ijo.2014.107.
    International journal of obesity (2005) 06/2014; · 5.22 Impact Factor
  • Society for Epidemiologic Research Annual Conference, Seattle, WA; 06/2014
  • Society for Epidemiologic Research Annual Conference, Seattle, WA; 06/2014
  • Jenny L Carwile, Walter C Willett, Karin B Michels
    Journal of Nutrition 05/2014; 144(5):791-2. · 4.23 Impact Factor
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    ABSTRACT: Despite the high prevalence of depression, anxiety, and use of antidepressant medications during pregnancy, there is much uncertainty around the impact of high levels of distress or antidepressant medications on the developing fetus. These intrauterine exposures may lead to epigenetic alterations to the DNA during this vulnerable time of fetal development, which may have important lifetime health consequences. In this study we investigated patterns of genome-wide DNA methylation using the Illumina Infinium Human Methylation450 BeadChip in the umbilical cord blood of neonates exposed to non-medicated maternal depression or anxiety (n = 13), or selective serotonin reuptake inhibitors (SSRIs) during pregnancy (n = 22), relative to unexposed neonates (n = 23). We identified 42 CpG sites with significantly different DNA methylation levels in neonates exposed to non-medicated depression or anxiety. CpG site methylation was not different in neonates exposed to SSRIs relative to the controls, after adjusting for multiple comparisons. In neonates exposed either to non-medicated maternal depression or SSRIs, the vast majority of CpG sites displayed lower DNA methylation relative to the controls, but differences were very small. A gene ontology analysis suggests significant clustering of the top genes associated with non-medicated maternal depression/anxiety, related to regulation of transcription, translation, and cell division processes (e.g., negative regulation of translation in response to oxidative stress, regulation of mRNA export from the nucleus, regulation of stem cell division). While the functional consequences of these findings are yet to be determined, these small DNA methylation differences may suggest a possible role for epigenetic processes in the development of neonates exposed to non-medicated maternal depression/anxiety.
    Epigenetics: official journal of the DNA Methylation Society 04/2014; 9(7). · 5.11 Impact Factor
  • American Association for Cancer Research Annual Meeting, San Diego, CA; 04/2014
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    ABSTRACT: Bisulfite treatment of DNA introduces methylation-dependent sequence changes through selective chemical conversion of nonmethylated cytosine to uracil and serves as pretreatment step for the majority of DNA methylation analysis methods.
    Medical Epigenetics. 02/2014; Med Epigen(2):28–36.
  • Harvard School of Public Health Reproductive Health Symposium, Boston, MA; 01/2014
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    Alexandra M Binder, Karin B Michels
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    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.
    BMC Bioinformatics 12/2013; 14(1):353. · 2.67 Impact Factor

Publication Stats

6k Citations
1,434.39 Total Impact Points

Institutions

  • 2014
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
  • 1996–2014
    • Harvard Medical School
      • • Department of Medicine
      • • Department of Obstetrics, Gynecology, and Reproductive Biology
      Boston, Massachusetts, United States
  • 2012
    • National Cancer Institute (USA)
      • Hormonal and Reproductive Epidemiology
      베서스다, Maryland, United States
    • Erasmus MC
      Rotterdam, South Holland, Netherlands
  • 1998–2012
    • Brigham and Women's Hospital
      • • Department of Medicine
      • • Department of Obstetrics and Gynecology
      Boston, MA, United States
  • 2011
    • Columbia University
      • Department of Epidemiology
      New York City, New York, United States
    • University of North Carolina at Chapel Hill
      • Department of Obstetrics and Gynecology
      North Carolina, United States
    • Partners HealthCare
      Boston, Massachusetts, United States
  • 1994–2011
    • Harvard University
      • • Department of Epidemiology
      • • Department of Nutrition
      Boston, MA, United States
  • 2010
    • Karolinska Institutet
      • Institutionen för medicin, Huddinge
      Solna, Stockholm, Sweden
  • 2009
    • Universitätsklinikum Freiburg
      Freiburg an der Elbe, Lower Saxony, Germany
  • 2008
    • University of Toronto
      Toronto, Ontario, Canada
  • 2005
    • University of Cambridge
      • Cambridge Institute of Public Health
      Cambridge, England, United Kingdom
  • 2000
    • Statens Serum Institut
      • Department of Epidemiology Research
      Copenhagen, Capital Region, Denmark
  • 1999
    • University of California, Los Angeles
      • Department of Epidemiology
      Los Angeles, CA, United States
    • Massachusetts Department of Public Health
      Boston, Massachusetts, United States