Novel breast cancer susceptibility loci under linkage peaks identified in African ancestry consortia.

BACKGROUND: Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs. METHODS: We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls. We examined associations with overall breast cancer as well as estrogen receptor (ER)-positive and negative subtypes (193,132 SNPs). We replicated associations in the African-ancestry Breast Cancer Genetic Consortium (AABCG). RESULTS: In AA women, we identified two associations on chr12q for overall breast cancer (rs1420647, OR = 1.15, p = 2.50×10-6; rs12322371, OR = 1.14, p = 3.15×10-6), and one for ER-negative breast cancer (rs77006600, OR = 1.67, p = 3.51×10-6). On chr3, we identified two associations with ER-negative disease (rs184090918, OR = 3.70, p = 1.23×10-5; rs76959804, OR = 3.57, p = 1.77×10-5) and on chr16q we identified an association with ER-negative disease (rs34147411, OR = 1.62, p = 8.82×10-6). In the replication study, the chr3 associations were significant and effect sizes were larger (rs184090918, OR: 6.66, 95% CI: 1.43, 31.01; rs76959804, OR: 5.24, 95% CI: 1.70, 16.16). CONCLUSION: The two chr3 SNPs are upstream to open chromatin ENSR00000710716, a regulatory feature that is actively regulated in mammary tissues, providing evidence that variants in this chr3 region may have a regulatory role in our target organ. Our study provides support for breast cancer variant discovery using prioritization based on linkage evidence.

Does COVID-19 Vaccination Disturb Menstrual Cycling?

Coronavirus disease 2019 (COVID-19) vaccines have been reported to have a short-term effect on the menstrual cycle, delaying the onset of the next menses. However, the analytical methods that have been used to study this are subject to a statistical phenomenon called "length-biased sampling" that calls the results into question. Those data are important and should be reanalyzed in an unbiased way.

GADGETS: a genetic algorithm for detecting epistasis using nuclear families.

MOTIVATION: Epistasis may play an etiologic role in complex diseases, but research has been hindered because identification of interactions among sets of single nucleotide polymorphisms (SNPs) requires exploration of immense search spaces. Current approaches using nuclear families accommodate at most several hundred candidate SNPs. RESULTS: GADGETS detects epistatic SNP-sets by applying a genetic algorithm to case-parent or case-sibling data. To allow for multiple epistatic sets, island subpopulations of SNP-sets evolve separately under selection for evident joint relevance to disease risk. The software evaluates the identified SNP-sets via permutation testing and provides graphical visualization. GADGETS correctly identified epistatic SNP-sets in realistically simulated case-parent triads with 10 000 candidate SNPs, far more SNPs than competitors can handle, and it outperformed competitors in simulations with many fewer SNPs. Applying GADGETS to family-based oral-clefting data from dbGaP identified SNP-sets with possible epistatic effects on risk. AVAILABILITY AND IMPLEMENTATION: GADGETS is part of the epistasisGA package at https://github.com/mnodzenski/epistasisGA. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Approaches for Assessing Effects of Exposures on Human Fertility.

BACKGROUND: Fecundability (conception rate per menstrual cycle) varies among non-contracepting couples. Time-to-pregnancy studies can identify exposures contributing to that variability, using three designs: incident cohort, prevalent cohort, and retrospective. Typically, researchers then apply semi-parametric, generalized linear time-to-pregnancy models to data, with either a log or a logit "link," to estimate either a fecundability ratio (FR) or a fecundability odds ratio (FOR). The ongoing-attempt study design can also be informative. METHODS: We consider a different generalized linear model, based on an inverse link. It models the heterogeneity as beta distributed and enables estimation of both the FR and FOR, defined based on population mean fecundabilities, without requiring constancy across attempt time. Under an ongoing-attempt design, the parameter associated with a dichotomous exposure has no clear meaning with a log or a logit link, but under the proposed approach estimates the ratio of the two average times to pregnancy. Basing simulations on conception rates from a large study, we compare the three analytic approaches for confidence interval coverage and power. We also assess the performance of a commonly used method for verifying the constancy of FOR or FR across time. RESULTS: The inverse-link approach had slightly less power than the others, but its estimates maintained nominal confidence interval coverage under nonconstancy. A popular method for testing constancy across time for the FR and FOR had poor power. CONCLUSIONS: The inverse-link analysis offers a useful alternative to the usual methods, with estimation performance that generalizes to the ongoing-attempt design and does not require hard-to-verify constancy assumptions.

Urinary phenol concentrations and fecundability and early pregnancy loss.

STUDY QUESTION: Are urinary phenol concentrations of methylparaben, propylparaben, butylparaben, triclosan, benzophenone-3, 2,4-dichlorophenol or 2,5-dichlorophenol associated with fecundability and early pregnancy loss? SUMMARY ANSWER: 2,5-dichlorophenol concentrations were associated with an increased odds of early pregnancy loss, and higher concentrations of butylparaben and triclosan were associated with an increase in fecundability. WHAT IS KNOWN ALREADY: Phenols are chemicals with endocrine-disrupting potential found in everyday products. Despite plausible mechanisms of phenol reproductive toxicity, there are inconsistent results across few epidemiologic studies examining phenol exposure and reproductive function in non-fertility treatment populations. STUDY DESIGN, SIZE, DURATION: Specimens and data were from the North Carolina Early Pregnancy Study prospective cohort of 221 women attempting to conceive naturally from 1982 to 1986. This analysis includes data from 221 participants across 706 menstrual cycles, with 135 live births, 15 clinical miscarriages and 48 early pregnancy losses (before 42 days after the last menstrual period). PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants collected daily first-morning urine specimens. For each menstrual cycle, aliquots from three daily specimens across the cycle were pooled within individuals and analyzed for phenol concentrations. To assess sample repeatability, we calculated intraclass correlation coefficients (ICCs) for each phenol. We evaluated associations between phenol concentrations from pooled samples and time to pregnancy using discrete-time logistic regression and generalized estimating equations (GEE), and early pregnancy loss using multivariable logistic regression and GEE. MAIN RESULTS AND THE ROLE OF CHANCE: ICCs for within-person variability across menstrual cycles in pooled phenol concentrations ranged from 0.42 to 0.75. There was an increased odds of early pregnancy loss with 2,5-dichlorophenol concentrations although the CIs were wide (5th vs 1st quintile odds ratio (OR): 4.79; 95% CI: 1.06, 21.59). There was an increased per-cycle odds of conception at higher concentrations of butylparaben (OR: 1.62; 95% CI: 1.08, 2.44) and triclosan (OR: 1.49; 95% CI: 0.99, 2.26) compared to non-detectable concentrations. No associations were observed between these endpoints and concentrations of other phenols examined. LIMITATIONS, REASONS FOR CAUTION: Limitations include the absence of phenol measurements for male partners and a limited sample size, especially for the outcome of early pregnancy loss, which reduced our power to detect associations. WIDER IMPLICATIONS OF THE FINDINGS: This study is the first to use repeated pooled measures to summarize phenol exposure and the first to investigate associations with fecundability and early pregnancy loss. Within-person phenol concentration variability underscores the importance of collecting repeated samples for future studies. Exposure misclassification could contribute to differences between the findings of this study and those of other studies, all of which used one urine sample to assess phenol exposure. This study also contributes to the limited literature probing potential associations between environmental exposures and early pregnancy loss, which is a challenging outcome to study as it typically occurs before a pregnancy is clinically recognized. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health (award number F31ES030594), the Intramural Research Program of the National Institutes of Health, the National Institute of Environmental Health Sciences (project numbers ES103333 and ES103086) and a doctoral fellowship at the Yale School of Public Health. The authors declare they have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Vitamin D concentrations and breast cancer incidence among Black/African American and non-Black Hispanic/Latina women.

BACKGROUND: Vitamin D may protect against breast cancer. Although Black/African American women and Hispanic/Latina women have lower circulating vitamin D levels than non-Hispanic White women, few studies have examined the association between vitamin D and breast cancer within these racial/ethnic groups. METHODS: The vitamin D-breast cancer association was evaluated using a case-cohort sample of self-identified Black/African American and non-Black Hispanic/Latina women participating in the US-wide Sister Study cohort. Circulating 25-hydroxyvitamin D (25(OH)D) and 24,25-dihydroxyvitamin D (24,25(OH)2D) were measured using liquid chromatography-tandem mass spectrometry in blood samples collected at the baseline from 415 women (290 Black/African American women and 125 non-Black Hispanic/Latina women) who developed breast cancer. These were compared to concentrations in 1545 women (1084 Black/African American women and 461 Hispanic/Latina women) randomly selected from the cohort. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Over a mean follow-up of 9.2 years, women with circulating 25(OH)D concentrations above the clinical cut point for deficiency (20.0 ng/mL) had lower breast cancer rates than women with concentrations ≤ 20 ng/mL (HR, 0.79; 95% CI, 0.61-1.02). The inverse association was strongest among Hispanic/Latina women (HR, 0.52; 95% CI, 0.29-0.93), with a weaker association observed among Black/African American women (HR, 0.89; 95% CI, 0.68-1.18; P for heterogeneity = 0.13). There were no clear differences by menopausal status, follow-up time, estrogen receptor status, or invasiveness. Neither 24,25(OH)2 D nor the 24,25(OH)2 D to 25(OH)D ratio were independently associated with breast cancer risk. CONCLUSIONS: This prospective study supports the hypothesis that vitamin D may be protective against breast cancer incidence in women, including non-Black Hispanic/Latina and Black/African American women. LAY SUMMARY: Vitamin D may protect against breast cancer. Although women of color have lower average vitamin D levels than non-Hispanic White women, few studies have considered the role of race/ethnicity. In a sample of self-identified Black/African American and Hispanic/Latina women, we observed that vitamin D concentrations measured in blood were inversely associated with breast cancer, particularly among Latinas. These findings indicate that vitamin D may protect women against breast cancer, including those in racial/ethnic groups with low average circulating levels.

Inflammation and Conception in a Prospective Time-to-Pregnancy Cohort.

BACKGROUND: Inflammation may contribute to subfertility but this has not been well-explored in large prospective cohort studies. METHODS: We conducted a prospective 12-month cohort study of time to pregnancy in North Carolina, the Time to Conceive study (2010-2016). Participants were 30-44 years old, without a history of infertility (N = 727). We analyzed blood samples with a high sensitivity assay for C-reactive protein (CRP). Women reported their weight, height, and other covariates. We natural log-transformed CRP and examined it (1) linearly, after exploration using restricted cubic splines and (2) in categories based on American Heart Association criteria. We estimated fecundability ratios (FRs) with log-binomial discrete-time-to-pregnancy models. Separate models included an interaction term with body mass index (BMI). RESULTS: The adjusted estimated FR per natural log-unit increase in CRP level was 0.97 (confidence interval [CI] = 0.91, 1.0). The FR (CI) for high CRP (>10 mg/L) compared with low CRP (<1 mg/L) was 0.78 (0.52, 1.2). Compared with normal-weight women with low CRP, women with obesity and high CRP had lower estimated fecundability, but the confidence interval was wide (FR = 0.63; CI = 0.35, 1.1). There was no pattern in the estimated fecundability across levels of CRP within categories of BMI. CONCLUSIONS: There was no evidence of an association between CRP and fecundability either alone or within levels of BMI. Further studies of CRP and fecundability should include higher levels of CRP and additional markers of inflammation.

Gestational Hypertensive Disorders and Maternal Breast Cancer Risk in a Nationwide Cohort of 40,720 Parous Women.

BACKGROUND: Preeclampsia and gestational hypertension are hypothesized to be associated with reduced maternal breast cancer risk, but the epidemiologic evidence is inconclusive. Our objective was to examine associations between gestational hypertensive disorders and breast cancer in a nationwide cohort of women with a family history of breast cancer. METHODS: Women ages 35-74 years who had a sister previously diagnosed with breast cancer, but had never had breast cancer themselves, were enrolled in the Sister Study from 2003 to 2009 (N = 50,884). At enrollment, participants reported diagnoses of eclampsia, preeclampsia, or gestational hypertension in each pregnancy. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between history of a gestational hypertensive disorder and incident invasive breast cancer or ductal carcinoma in situ among 40,720 parous women. We used age as the time scale and adjusted for birth cohort, race-ethnicity, and reproductive, socioeconomic, and behavioral factors. We examined effect measure modification by risk factors for gestational hypertensive disease and breast cancer and assessed possible etiologic heterogeneity across tumor characteristics. RESULTS: The prevalence of gestational hypertensive disease was 12%. During follow-up (mean = 10.9 years), 3,198 eligible women self-reported a breast cancer diagnosis. History of a gestational hypertensive disorder was not associated with breast cancer risk (HR = 1.0; 95% CI = 0.90, 1.1). We did not observe clear evidence of effect measure modification or etiologic heterogeneity. CONCLUSIONS: History of a gestational hypertensive disorder was not associated with breast cancer risk in a cohort of women with a first-degree family history of breast cancer.

Association of dietary and plasma carotenoids with urinary F2-isoprostanes.

PURPOSE: Carotenoids may protect against chronic diseases including cancer and cardiometabolic disease by mitigating oxidative stress and/or inflammation. We cross-sectionally evaluated associations between carotenoids and biomarkers of oxidative stress or inflammation. METHODS: From 2003 to 2009, the Sister Study enrolled 50,884 breast cancer-free US women aged 35-74. Post-menopausal participants (n = 512) were randomly sampled to measure carotenoids and biomarkers of oxidative stress. Dietary carotenoid consumption was assessed using a validated 110-item Block 1998 food frequency questionnaire; use of ß-carotene-containing supplements was also assessed. Plasma carotenoids were quantified, adjusting for batch. Urinary markers of lipid peroxidation, 8-iso-prostaglandin F2α (8-iso-PGF2α) and its metabolite (8-iso-PGF2α-M) were also measured. Since the biomarker 8-iso-PGF2α can reflect both oxidative stress and inflammation, we used a modeled 8-iso-PGF2α to prostaglandin F2α ratio approach to distinguish effects reflecting oxidative stress versus inflammation. Multivariable linear regression was used to assess the associations of dietary and plasma carotenoids with the estimated biomarker concentrations. RESULTS: Total plasma carotenoids were inversely associated with 8-iso-PGF2α-M concentrations (P for trend across quartiles = 0.009). Inverse trends associations were also seen for α-carotene and ß-carotene. In contrast, lutein/zeaxanthin showed associations with both 8-iso-PGF2α and 8-iso-PGF2α-M concentrations. The inverse association for total carotenoids appeared to be specific for oxidative stress (chemical 8-iso-PGF2α; Phighest vs. lowest quartile = 0.04 and P for trend across quartiles = 0.02). The pattern was similar for α-carotene. However, lutein/zeaxanthin tended to have a stronger association with enzymatic 8-iso-PGF2α, suggesting an additional anti-inflammatory effect. Supplemental ß-carotene was inversely associated with both 8-iso-PGF2α and 8-iso-PGF2α-M concentrations, as well as with both chemical and enzymatic 8-iso-PGF2α. Dietary carotenoids were not associated with either biomarker. CONCLUSION: Plasma carotenoids and supplemental ß-carotene were associated with lower concentrations of 8-iso-PGF2α metabolite. Plasma carotenoids associations may reflect antioxidant effects.

Genital powder use and risk of uterine cancer: A pooled analysis of prospective studies.

When powder is applied to the genital area, it has the potential to reach internal reproductive organs and promote carcinogenesis by irritating and inflaming exposed tissues. Although many studies have considered the association between genital powder use and ovarian cancer risk, the relationship between genital powder use and uterine cancer is less well-studied. We pooled data from four large, prospective cohorts (the Nurses' Health Study, the Nurses' Health Study II, the Sister Study and the Women's Health Initiative - Observational Study). We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for prespecified confounders. In total, 209 185 women were included, with 37% reporting ever genital powder use. Over a mean 14.5 years of follow-up, 3272 invasive uterine cancers were diagnosed. There was no overall association between ever genital powder use and uterine cancer (HR = 1.01, 95% CI: 0.94-1.09), with little difference observed for frequent (≥1 times/week) vs never use (HR = 1.05, 95% CI: 0.95-1.16; P-for-trend = .46). Long-term use (>20 years; HR = 1.12, 95% CI: 0.96-1.31; P-for-trend = 0.14) was associated with a small, but not statistically significant, increase in risk, compared to never use. There were not clear differences by uterine cancer histologic subtypes or across strata of relevant covariates, including race/ethnicity, follow-up time, menopausal status and body mass index. The results of this large, pooled analysis do not support a relationship between the use of genital powder and uterine cancer, although the positive associations observed for long-term use may merit further consideration.

Metals and Breast Cancer Risk: A Prospective Study Using Toenail Biomarkers.

The role of metals in breast cancer is of interest because of their carcinogenic and endocrine-disrupting capabilities. Evidence from epidemiologic studies remains elusive, and prior studies have not investigated metal mixtures. In a case cohort nested within the Sister Study (enrolled in 2003-2009; followed through September 2017), we measured concentrations of 15 metals in toenails collected at enrollment in a race/ethnicity-stratified sample of 1,495 cases and a subcohort of 1,605 women. We estimated hazard ratios and 95% confidence intervals for each metal using Cox regression and robust variance. We used quantile g-computation to estimate the joint association between multiple metals and breast cancer risk. The average duration of follow-up was 7.5 years. There was little evidence supporting an association between individual metals and breast cancer. An exception was molybdenum, which was associated with reduced incidence of overall breast cancer risk (third tertile vs. first tertile: hazard ratio = 0.82, 95% confidence interval: 0.67, 1.00). An inverse association for antimony was observed among non-Hispanic Black women. Predefined groups of metals (all metals, nonessential metals, essential metals, and metalloestrogens) were not strongly associated with breast cancer. This study offers little support for metals, individually or as mixtures, as risk factors for breast cancer. Mechanisms for inverse associations with some metals warrant further study.

Health-related quality of life outcomes among breast cancer survivors.

BACKGROUND: Data from a nationwide sample of US breast cancer survivors were used to examine associations between patient characteristics (breast cancer clinical features, prognostic factors, and treatments) and health-related quality of life (HRQOL). Associations between postdiagnosis HRQOL and mortality were then evaluated. METHODS: The authors identified female breast cancer survivors (n = 2453) from the Sister Study or Two Sister Study who were at least 1 year from breast cancer diagnosis and who had responded to a survivorship survey in 2012. HRQOL was assessed with the Patient-Reported Outcomes Measurement Information System (PROMIS) Global 10 measures. Multivariable linear regression was used to assess predictors associated with HRQOL. Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between HRQOL and all-cause mortality. RESULTS: HRQOL, assessed an average of 4.9 years after the cancer diagnosis (standard deviation of 1.9 years), was negatively associated with a higher cancer stage at diagnosis; a higher comorbidity score at the survey; experience of surgical complications; dissatisfaction with breast surgery; and experience of any recent recurrence, metastasis, or secondary malignancy. Since the completion of the survey, there were 85 deaths (3.5%) during a mean follow-up of 4 years (standard deviation of 0.5 years). In multivariate models, decreases in PROMIS physical T scores and mental T scores were associated with increased mortality (HR for physical T scores, 1.08; 95% CI, 1.05-1.11; HR for mental T scores, 1.03; 95% CI, 1.01-1.06). CONCLUSIONS: Prognostic and cancer treatment-related factors affect HRQOL in breast cancer survivors and may inform targeted survivorship care. PROMIS global health measures may offer additional insights into patients' well-being and mortality risk. LAY SUMMARY: Findings from a study suggest that prognostic and cancer treatment-related factors affect health-related quality of life (HRQOL) in breast cancer survivors and that poor HRQOL may increase the mortality risk. The evaluation of HRQOL is important because it may hold potential as a tool for optimizing survivorship care.

Early-life Farm Exposure and Ovarian Reserve in a US Cohort of Women.

BACKGROUND: In a previous exploratory study, we reported lower concentrations of the ovarian reserve biomarker anti-Müllerian hormone (AMH) in adulthood with prenatal farm exposure. We now examine this association as well as childhood farm exposure using enrollment data from the Sister Study, a large US cohort of women. METHODS: We collected prenatal and childhood farm exposure data by questionnaire and telephone interview. However, serum AMH data were available only for a nested subset: premenopausal women ages 35-54 subsequently diagnosed with breast cancer (n = 418 cases) and their matched controls (n = 866). To avoid potential bias from restricting analyses to only premenopausal controls, we leveraged the available cohort data. We used data from both premenopausal cases and controls as well as postmenopausal women ages 35-54 (n = 3,526) (all presumed to have undetectable AMH concentrations) and applied weights to produce a sample representative of the cohort ages 35-54 (n = 17,799). The high proportion of undetectable AMH concentrations (41%) was addressed using reverse-scale Cox regression. An adjusted hazard ratio (HR) <1.0 indicates that exposed individuals had lower AMH concentrations than unexposed individuals. RESULTS: Prenatal exposure to maternal residence or work on a farm was associated with lower AMH concentrations (HR 0.66; 95% confidence intervals [CI] = 0.48 to 0.90). Associations between childhood farm residence exposures and AMH were null or weak, except childhood contact with pesticide-treated livestock or buildings (HR 0.69; 95% CI = 0.40 to 1.2). CONCLUSIONS: Replication of the prenatal farm exposure and lower adult AMH association raises concern that aspects of prenatal farm exposure may result in reduced adult ovarian reserve.

Community-Based Testing Sites for SARS-CoV-2 - United States, March 2020-November 2021.

Immediately following the March 13, 2020 declaration of COVID-19 as a national emergency (1), the U.S. government began implementing national testing programs for epidemiologic surveillance, monitoring of frontline workers and populations at higher risk for acquiring COVID-19, and identifying and allocating limited testing resources. Effective testing supports identification of COVID-19 cases; facilitates isolation, quarantine, and timely treatment measures that limit the spread of SARS-CoV-2 (the virus that causes COVID-19); and guides public health officials about the incidence of COVID-19 in a community. A White House Joint Task Force, co-led by the Department of Health and Human Services (HHS) and the Federal Emergency Management Agency (FEMA), created the Community-Based Testing Sites (CBTS) program working with state and local partners (2). This report describes the timeline, services delivered, and scope of the CBTS program. During March 19, 2020-April 11, 2021, the CBTS program conducted 11,661,923 SARS-CoV-2 tests at 8,319 locations across the United States and its territories, including 402,223 (3.5%) administered through Drive-Through Testing, 10,129,142 (86.9%) through Pharmacies+ Testing, and 1,130,558 (9.7%) through Surge Testing programs. Tests administered through the CBTS program yielded 1,176,959 (10.1%) positive results for SARS-CoV-2. Among tested persons with available race data,* positive test results were highest among American Indian or Alaska Native (14.1%) and Black persons (10.4%) and lowest among White persons (9.9%), Asian persons (7.3%), and Native Hawaiian or Other Pacific Islanders (6.4%). Among persons with reported ethnicity, 25.3% were Hispanic, 15.9% of whom received a positive test result. Overall, 82.0% of test results were returned within 2 days, but the percentage of test results returned within 2 days was as low as 40.7% in July 2020 and 59.3% in December 2020 during peak testing periods. Strong partnerships enabled a rapid coordinated response to establish the federally supported CBTS program to improve access to no-charge diagnostic testing, including for frontline workers, symptomatic persons and close contacts, and persons living in high-prevalence areas. In April 2021, the CBTS Pharmacies+ Testing and Surge Testing programs were expanded into the Increasing Community Access to Testing (ICATT) program. As of November 12, 2021, the CBTS and ICATT programs conducted approximately 26.6 million tests with approximately 10,000 active testing sites. Although the CBTS program represented a relatively small portion of overall U.S. SARS-CoV-2 testing, with its successful partnerships and adaptability, the CBTS program serves as a model to guide current community-based screening, surveillance, and disease control programs, and responses to future public health emergencies.

Associations of periodontal disease and tooth loss with all-cause and cause-specific mortality in the Sister Study.

AIM: Studies have found that periodontal disease and tooth loss are associated with increased mortality; however, associations with cause-specific mortality and all-cause mortality within specific subgroups have not been thoroughly investigated. MATERIALS AND METHODS: We examined the association of self-reported periodontal disease and disease/decay-related tooth loss with subsequent all-cause and cause-specific mortality in the Sister Study, a prospective cohort study of 50,884 women aged 35-74 years at baseline, whose sister was diagnosed with breast cancer. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the associations were calculated with adjustment for relevant confounders. RESULTS: With a mean follow-up of 10.9 years (range 0.1-14.3), 2058 women died. Participants with periodontal disease had a slightly higher rate of all-cause mortality (HR = 1.08, 95% CI 0.98-1.19), while participants with tooth loss had an increased rate of all-cause mortality (HR = 1.15, 95% CI 1.05-1.26). For cause-specific mortality, women with tooth loss had increased rates of death from circulatory system diseases, respiratory system diseases, and endocrine/metabolic diseases. Results varied in stratified models, but no heterogeneity across strata was found. CONCLUSIONS: In this large prospective study, periodontal disease and tooth loss were associated with all-cause and certain specific cause-specific mortality outcomes.

Do Genetic Variants Modify the Effect of Smoking on Risk of Preeclampsia in Pregnancy?

OBJECTIVE: Maternal smoking is associated with as much as a 50% reduced risk of preeclampsia, despite increasing risk of other poor pregnancy outcomes that often co-occur with preeclampsia, such as preterm birth and fetal growth restriction. Researchers have long sought to understand whether this perplexing association is biologically based, or a result of noncausal mechanisms. We examined whether smoking-response genes modify the smoking-preeclampsia association to investigate potential biological explanations. STUDY DESIGN: We conducted a nested case-control study within the Norwegian Mother, Father and Child Birth Cohort (1999-2008) of 2,596 mother-child dyads. We used family-based log-linear Poisson regression to examine modification of the maternal smoking-preeclampsia relationship by maternal and fetal single nucleotide polymorphisms involved in cellular processes related to components of cigarette smoke (n = 1,915 with minor allele frequency ≥10%). We further investigated the influence of smoking cessation during pregnancy. RESULTS: Three polymorphisms showed overall (p < 0.001) multiplicative interaction between smoking and maternal genotype. For rs3765692 (TP73) and rs10770343 (PIK3C2G), protection associated with smoking was reduced with two maternal copies of the risk allele and was stronger in continuers than quitters (interaction p = 0.02 for both loci, based on testing 3-level smoking by 3-level genotype). For rs2278361 (APAF1) the inverse smoking-preeclampsia association was eliminated by the presence of a single risk allele, and again the trend was stronger in continuers than in quitters (interaction p = 0.01). CONCLUSION: Evidence for gene-smoking interaction was limited, but differences by smoking cessation warrant further investigation. We demonstrate the potential utility of expanded dyad methods and gene-environment interaction analyses for outcomes with complex relationships between maternal and fetal genotypes and exposures. KEY POINTS: · Maternal and fetal genotype may differentially influence preeclampsia.. · Smoking-related genes did not strongly modify smoking-preeclampsia association.. · Smoking cessation reduced strength of gene by smoking interactions..

Perinatal and postnatal exposures and risk of young-onset breast cancer.

BACKGROUND: Perinatal factors have been associated with some adult health outcomes, but have not been well studied in young-onset breast cancer. We aimed to evaluate the association between young-onset breast cancer and perinatal exposures and to explore etiologic heterogeneity in the relationship between associated perinatal factors and estrogen receptor status of the tumor. METHODS: We addressed this in a sister-matched case-control study. Cases were women who had been diagnosed with ductal carcinoma in situ or invasive breast cancer before the age of 50. Each case had a sister control who was free of breast cancer up to the same age at which her case sister developed the disease. The factors considered were self-reported and included the mother's preeclampsia in that pregnancy, mother's smoking in that pregnancy, gestational hypertension, prenatal diethylstilbestrol use, and gestational diabetes, as well as low birth weight (less than 5.5 pounds), high birth weight (greater than 8.8 pounds), short gestational length (less than 38 completed weeks), and being breastfed or being fed soy formula. RESULTS: In conditional logistic regression analyses, high birth weight (odds ratio [OR] = 1.59, 95% confidence interval [CI] 1.07-2.36) and preeclampsia (adjusted OR = 1.92, CI 0.824-4.5162) were positively associated with risk. The association with preeclampsia was stronger when the analysis was restricted to invasive breast cancer (OR = 2.87, CI 1.08-7.59). We also used case-only analyses to assess etiologic heterogeneity for estrogen receptor (ER)-positive versus estrogen receptor-negative cancer. Women who were born to a preeclamptic pregnancy and later developed young-onset breast cancer were at increased odds for the ER-negative type (OR = 2.27; CI 1.05-4.92). CONCLUSION: These results suggest that being born to a preeclamptic pregnancy may increase risk for young-onset breast cancer, especially for the ER-negative subtype.

Metals and trace elements in relation to body mass index in a prospective study of US women.

BACKGROUND: Epidemiologic studies on the association between metals and body mass index (BMI) have been cross-sectional and have demonstrated inconsistent associations. Our study prospectively examined whether metals measured at baseline were associated with later BMI. We considered metals individually and as joint exposure to pre-defined metal groupings. METHODS: We measured concentrations of 16 metals in toenails collected at baseline (2003-2009) in a subset of 1221 women from the Sister Study. We calculated BMI from height and weight reported on a follow-up questionnaire an average of 5.2 years (range = 3.5-8.3) after baseline. Multivariable linear regression was used to estimate ß coefficients and 95% confidence intervals (CIs) for associations between BMI and individual metals (with estimates given per interquartile range (IQR) increase or in quartiles). Quantile g-computation was used to examine joint associations between groups of metals and BMI. Groups considered were (1) all metals combined, and metals classified as (2) non-essential or (3) essential. RESULTS: In individual metal models we found that, with the exception of cobalt, no single metal was strongly related to BMI. In our mixture analyses, a quartile increase in all non-essential metals was associated with higher BMI (ß = 0.32; 95%CI: 0.00, 0.63 kg/m2), whereas essential metals were suggestively associated with lower BMI (ß = -0.25; 95%CI: 0.58, 0.07 kg/m2). CONCLUSIONS: In this population of women who were, on average, overweight, essential metals were jointly associated with slightly healthier, lower BMI whereas non-essential metals were jointly associated with slightly higher, unhealthier BMI, after controlling for other health indicators and predictors of metals exposures.

Breast Cancer Risk After Recent Childbirth: A Pooled Analysis of 15 Prospective Studies.

Background: Parity is widely recognized as protective for breast cancer, but breast cancer risk may be increased shortly after childbirth. Whether this risk varies with breastfeeding, family history of breast cancer, or specific tumor subtype has rarely been evaluated. Objective: To characterize breast cancer risk in relation to recent childbirth. Design: Pooled analysis of individual-level data from 15 prospective cohort studies. Setting: The international Premenopausal Breast Cancer Collaborative Group. Participants: Women younger than 55 years. Measurements: During 9.6 million person-years of follow-up, 18 826 incident cases of breast cancer were diagnosed. Hazard ratios (HRs) and 95% CIs for breast cancer were calculated using Cox proportional hazards regression. Results: Compared with nulliparous women, parous women had an HR for breast cancer that peaked about 5 years after birth (HR, 1.80 [95% CI, 1.63 to 1.99]) before decreasing to 0.77 (CI, 0.67 to 0.88) after 34 years. The association crossed over from positive to negative about 24 years after birth. The overall pattern was driven by estrogen receptor (ER)-positive breast cancer; no crossover was seen for ER-negative cancer. Increases in breast cancer risk after childbirth were pronounced when combined with a family history of breast cancer and were greater for women who were older at first birth or who had more births. Breastfeeding did not modify overall risk patterns. Limitations: Breast cancer diagnoses during pregnancy were not uniformly distinguishable from early postpartum diagnoses. Data on human epidermal growth factor receptor 2 (HER2) oncogene overexpression were limited. Conclusion: Compared with nulliparous women, parous women have an increased risk for breast cancer for more than 20 years after childbirth. Health care providers should consider recent childbirth a risk factor for breast cancer in young women. Primary Funding Source: The Avon Foundation, the National Institute of Environmental Health Sciences, Breast Cancer Now and the UK National Health Service, and the Institute of Cancer Research.

Association of Powder Use in the Genital Area With Risk of Ovarian Cancer.

Importance: The relationship between use of powder in the genital area and ovarian cancer is not established. Positive associations reported in case-control studies have not been confirmed in cohort studies. Objective: To estimate the association between use of powder in the genital area and ovarian cancer using prospective observational data. Design, Setting, and Participants: Data were pooled from 4 large, US-based cohorts: Nurses' Health Study (enrollment 1976; follow-up 1982-2016; n = 81 869), Nurses' Health Study II (enrollment 1989; follow-up 2013-2017; n = 61 261), Sister Study (enrollment 2003-2009; follow-up 2003-2017; n = 40 647), and Women's Health Initiative Observational Study (enrollment 1993-1998; follow-up 1993-2017; n = 73 267). Exposures: Ever, long-term (≥20 years), and frequent (≥1/week) use of powder in the genital area. Main Outcomes and Measures: The primary analysis examined the association between ever use of powder in the genital area and self-reported incident ovarian cancer. Covariate-adjusted hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models. Results: The pooled sample included 252 745 women (median age at baseline, 57 years) with 38% self-reporting use of powder in the genital area. Ten percent reported long-term use, and 22% reported frequent use. During a median of 11.2 years of follow-up (3.8 million person-years at risk), 2168 women developed ovarian cancer (58 cases/100 000 person-years). Ovarian cancer incidence was 61 cases/100 000 person-years among ever users and 55 cases/100 000 person-years among never users (estimated risk difference at age 70 years, 0.09% [95% CI, -0.02% to 0.19%]; estimated HR, 1.08 [95% CI, 0.99 to 1.17]). The estimated HR for frequent vs never use was 1.09 (95% CI, 0.97 to 1.23) and for long-term vs never use, the HR was 1.01 (95% CI, 0.82 to 1.25). Subgroup analyses were conducted for 10 variables; the tests for heterogeneity were not statistically significant for any of these comparisons. While the estimated HR for the association between ever use of powder in the genital area and ovarian cancer risk among women with a patent reproductive tract was 1.13 (95% CI, 1.01 to 1.26), the P value for interaction comparing women with vs without patent reproductive tracts was .15. Conclusions and Relevance: In this analysis of pooled data from women in 4 US cohorts, there was not a statistically significant association between use of powder in the genital area and incident ovarian cancer. However, the study may have been underpowered to identify a small increase in risk.