Clarice R. Weinberg’s research while affiliated with National Institute Of Health of Thailand and other places

Reproductive complications tend to recur. The risk of gestational diabetes is much higher in the second pregnancy if it occurred in the first. Such recurrence risks are regarded as reflecting heterogeneity among couples in their inherent risk. Pregnancy complications not only predict their own recurrence but have been shown to be associated with different later health problems like hypertension and heart disease. Epidemiologically considering reproductive history as a risk factor has been challenging, however, because women vary in their number of pregnancies and there’s no obvious way to account for both prior occurrences and prior non-occurrences. We propose a simple empirical Bayes approach, the Beta Approach for Risk Summarization (BARS). We apply BARS to retrospective data reported at enrollment in a large cohort, the Sister Study, to estimate propensity to gestational diabetes, and use that to predict subsequent occurrences of gestational diabetes based on successively updated pregnancy histories. We assess the calibration of our predictive model for gestational diabetes and demonstrate that it works well. We then apply the method to prospective data from the Sister Study, revisiting an earlier paper that linked gestational diabetes to risk of breast cancer, but now using BARS and additional person time.

Background Juvenile idiopathic arthritis (JIA) is an immune-mediated pediatric disease believed to result from a complex interplay of genetic and environmental factors. Genome-wide association studies have enabled calculation of polygenic risk scores (PRS) for JIA. Understanding how the PRS associates with JIA and whether it performs similarly across sexes is essential for its utility in future studies. Methods We studied the relationship between a PRS developed from a previously published genome-wide association study of JIA and JIA in children from the Norwegian Mother, Father and Child Cohort Study (MoBa; total n = 57,630; JIA cases = 238). Generalized linear models (GLM) and generalized additive models (GAM) were used in logistic regression to assess the association. Furthermore, we investigated whether the relationship between PRS and JIA differed by sex by applying GAM models with interaction terms. Results PRS was significantly associated with JIA using both GLM (p< 2e-16) and GAM (p< 2e-16) models, and our results indicated a nonlinear relationship between PRS and JIA (effective degrees of freedom, EDF = 1.96). We found a significant interaction between sex and JIA PRS in relation to JIA (p = 0.017), and indications of a stronger and more logit-nonlinear relationship in females (EDF = 1.82) versus males (EDF = 1.06). Conclusion The relationship between PRS and JIA was slightly logit-nonlinear for females and logit-linear for males. The PRS for JIA can likely be used either as a continuous or discrete variable in analyses, but sex-stratification is recommended for future studies.

Background Depression could affect breast cancer risk; however, epidemiologic findings are mixed. We assessed the association of breast cancer risk with self-reported history of diagnosed depression and time-dependent antidepressant use. Methods We analyzed data from 45,746 women in the Sister Study cohort (2003–2009). Cox proportional hazard regression was used to estimate hazard ratios (HR) for breast cancer. Results During follow-up (mean = 11.7 years), 3,899 breast cancers were diagnosed. There was no association between history of diagnosed depression and risk of breast cancer (HR = 0.98, 95%CI = 0.91–1.06). However, antidepressant use was associated with reduced risk of breast cancer (HR = 0.92, 95%CI = 0.85–1.00). Comparison of antidepressant drug classes revealed a suggestion of an inverse association with selective serotonin reuptake inhibitors (SSRIs, HR = 0.90, 95%CI = 0.81–1.00). Reduction was stronger in those with BMI < 25 (HR = 0.72, 95%CI = 0.59–0.89). Conclusions Depression was not associated with breast cancer risk. We observed a suggestion of a reduction in risk associated with antidepressant use. The analysis evaluating the association by specific drug types, showed a suggestion of a reduction in breast cancer risk associated with use of SSRIs. The negative association with overall antidepressant use and SSRIs, was stronger in those with BMI < 25, which could reflect a dose effect. This was the first study to examine the association between depression, antidepressant use, and breast cancer risk in a large genetic-risk-enriched cohort.

Background/Objectives: Iron is necessary for bodily function, but abnormal levels can increase the risk of chronic diseases. Studies of leukocyte telomere length suggest blood iron levels are positively associated with cellular senescence and accelerated aging. However, associations between blood iron and more robust metrics of biological aging, specifically those based on DNA methylation, have not been examined. Methods: In a random sample of women from the Sister Study (n = 1260) with measured serum iron (ferritin, iron, transferrin saturation), we used linear regression models to assess cross-sectional associations between standardized serum iron and three methylation-based biological aging metrics (GrimAgeAccel, PhenoAgeAccel, and DunedinPACE), with and without adjustment for smoking, alcohol, menopause status, education, time since menopause, exercise, and diet. Results: In adjusted models, a one standard deviation increase in serum ferritin was positively associated with higher standardized levels of DunedinPACE, GrimAgeAccel, and PhenoAgeAccel (DunedinPACE: 0.05, (0.00, 0.10); PhenoAgeAccel: 0.06 (0.00, 0.11); GrimAgeAccel: 0.06 (0.01, 0.11)). In contrast, higher serum iron and transferrin saturation were inversely associated with the biological aging metrics (serum iron, DunedinPACE: −0.02, (−0.07, 0.03); PhenoAgeAccel: −0.04 (−0.10, 0.01); GrimAgeAccel: −0.05 (−0.10, −0.01); transferrin saturation (DunedinPACE: −0.01, (−0.06, 0.05); PhenoAgeAccel: −0.01 (−0.06, 0.05); GrimAgeAccel: −0.05 (−0.10, −0.01))). Conclusions: The positive association with ferritin is consistent with the proposed role of oxidative stress in accelerated aging associated with high iron exposure. However, the observed inverse associations with serum iron and transferrin saturation are not consistent with this common explanation, and future studies are needed to examine potential explanations.

Background Among premenopausal women, higher body mass index (BMI) is associated with lower breast cancer risk, although the underlying mechanisms are unclear. Investigating adiposity distribution may help clarify impacts on breast cancer risk. This study was initiated to investigate associations of central and peripheral adiposity with premenopausal breast cancer risk overall and by other risk factors and breast cancer characteristics. Methods We used individual-level data from 14 prospective cohort studies to estimate hazard ratios (HRs) for premenopausal breast cancer using Cox proportional hazards regression. Analyses included 440,179 women followed for a median of 7.5 years (interquartile range: 4.0–11.3) between 1976 and 2017, with 6,779 incident premenopausal breast cancers. Results All central adiposity measures were inversely associated with breast cancer risk overall when not controlling for BMI (e.g. for waist circumference, HR per 10 cm increase: 0.92, 95% confidence interval (CI): 0.90–0.94) whereas in models adjusting for BMI, these measures were no longer associated with risk (e.g. for waist circumference: HR 0.99, 95% CI: 0.95–1.03). This finding was consistent across age categories, with some evidence that BMI-adjusted associations differed by breast cancer subtype. Inverse associations for in situ breast cancer were observed with waist-to-height and waist-to-hip ratios and a positive association was observed for oestrogen-receptor-positive breast cancer with hip circumference (HR per 10 cm increase: 1.08, 95% CI: 1.10–1.14). For luminal B, HER2-positive breast cancer, we observed an inverse association with hip circumference (HR per 10 cm: 0.84, 95% CI: 0.71–0.98), but positive associations with waist circumference (HR per 10 cm: 1.18, 95% CI: 1.03–1.36), waist-to-hip ratio (HR per 0.1 units: 1.29, 95% CI: 1.15–1.45) and waist-to height ratio (HR per 0.1 units: 1.46, 95% CI: 1.17–1.84). Conclusions Our analyses did not support an association between central adiposity and overall premenopausal breast cancer risk after adjustment for BMI. However, our findings suggest associations might differ by breast cancer hormone receptor and intrinsic subtypes.

Introduction Pregnancy involves a double genome, and genetic variants in the mother and her fetus can act together to influence risk for pregnancy complications, adverse pregnancy outcomes, and diseases in the offspring. Large search spaces have hindered the discovery of sets of single nucleotide polymorphisms (SNPs) that act epistatically. Methods Previously, we proposed a method for case-parent studies, called the Genetic Algorithm for Detecting Genetic Epistasis using Triads or Siblings (GADGETS), that can reveal autosomal epistatic SNP-sets in the child’s genome. Here we incorporate maternal SNPs, thereby extending GADGETS to nominate SNP-sets containing offspring loci only, maternal loci only, or both. We use a permutation procedure to impose a preference for epistatic over outcome-related but non-epistatic SNP sets. Our maternal-fetal extension uses case-complement-sibling pairs together with mother-father pairs, exploiting Mendelian transmission and a mating-symmetry assumption. Results In simulations of 1,000 case-parents triads with 10,000 candidate SNPs, GADGETS successfully detected simulated multi-locus effects involving 3-5 SNPs but was somewhat less successful at distinguishing epistatic SNPs from sets of non-epistatic SNPs that each conferred high risk independently. Though the epistasis-mining algorithms MDR-PDT, TrioFS, and EPISFA-LD were originally designed to find epistatic offspring variants, we generalize them to include maternal SNPs and search more broadly. GADGETS outperformed those competitors and could successfully mine a much larger list of candidate SNPs. Applied to dbGaP data, GADGETS nominated several multi-SNP maternal-fetal sets as potentially-interacting risk factors for orofacial clefting. Discussion The extended version of GADGETS can mine for epistasis that involves maternal SNPs.

Background Blood DNA methylation (DNAm) profiles have been used to show that changes in circulating leukocyte composition occur during breast cancer development, suggesting that peripheral immune system alterations are markers of breast cancer risk. Blood DNAm profiles have recently been used to predict plasma protein concentrations (“Protein EpiScores”), but their associations with breast cancer risk have not been examined in detail. Methods Whole blood DNAm profiles were obtained for a case-cohort sample of participants in the Sister Study and used to calculate 109 Protein EpiScores. Of the 4,479 women included, 2,151 (48%) were diagnosed with breast cancer within 15 years of their baseline blood draw (median time to diagnosis: 8.6 years; 1,673 invasive cancer and 478 ductal carcinomas in situ). Protein EpiScores associations with breast cancer incidence were estimated using weighted Cox regression models, overall and stratified by time and participant characteristics. Results Protein EpiScores for RARRES2, IGFBP4, and CCL21 were positively associated with invasive breast cancer risk (hazard ratios from 1.17 to 1.24), while those for F7, SELL, CXCL9, CD48, and IL19 were inversely associated (hazard ratios from 0.82 to 0.86) (all FDR < 0.10). Eight immune response-related Protein EpiScores (CXCL9, CD48, FCGR3B, CXCL11, CCL21, CRTAM, VCAM1, GZMA) were associated with invasive cancers diagnosed within five years of enrollment. Protein EpiScore associations were consistently stronger for estrogen receptor-negative tumors. Conclusions Several Protein EpiScores, including many related to immune response, were associated with breast cancer risk, highlighting novel changes to the peripheral immune system that occur during breast cancer development.

Study question: Is being born of a young mother associated with worse gynecologic health, as indicated by a bilateral oophorectomy or hysterectomy before age 40? Summary answer: Daughters of mothers younger than 25 did not have reduced parity but did have a higher risk of having bilateral oophorectomy or hysterectomy before age 40, particularly if their mother was younger than 20 years at their birth. What is known already: Three recent studies have reported lower fecundability among daughters of mothers younger than 20 years; adverse socioeconomic conditions may explain part of that association. Study design, size, duration: This study reports cumulative, primarily retrospective, accrual of outcomes up to age 40 among 41 450 women recruited into the US-based Sister Study between 2003 and 2009. Participants/materials, setting, methods: The analysis sample included women ≥41 years at the time of the latest follow-up and <66 years at recruitment. Using log-binomial regression, we estimated adjusted relative risks (RRs) of having major gynecologic surgery (bilateral oophorectomy or hysterectomy) before age 40 by age of the participant's mother (G1) when she gave birth to the participant (G2). All models were adjusted for father's age at G2's birth, daughter's self-identified race/ethnicity, and year of birth. We assessed possible effect modification by stratifying the analyses by self-reported G2's family income level during childhood (poor-low, medium-high) and G2's educational level (categorized as below bachelor's degree and bachelor's degree or higher) and, in the following step, by G2's age at first birth. Main results and the role of chance: Compared with daughters born to mothers aged 30-34, daughters of mothers <20 and 20-24 years had an RR of 1.74 (95% CI 1.51, 2.00) and 1.35 (1.22, 1.50), respectively, of major gynecologic surgery before age 40. Although lower childhood income, G2 education, and giving birth before age 25 were strongly associated with outcome risk, the RRs changed little after accounting for those factors. Limitations, reasons for caution: This is a descriptive study of a proxy indicator of poor gynecologic health. Furthermore, all information was self-reported and, for nearly all women, recalled after the event. The measures used for socioeconomic status may have been insufficient. Wider implications of the findings: Daughters of younger mothers did not have reduced parity but appeared to have a higher risk of major gynecologic surgery before age 40. This study adds to prior evidence that daughters of young mothers have worse gynecologic health. Study funding/competing interest(s): This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005, Z01-ES102245, and Z01-ES103086). The authors report no conflict of interest. Trial registration number: N/A.