Faculty Bibliography

Genome-wide association studies (GWAS) have identified more than 200 risk loci for breast cancer. However, target genes and their encoded proteins in these loci remain largely unknown. In this study, we utilized genetic prediction models for 1349 circulating proteins derived from individuals of African (n = 1871) and European (n = 7213) ancestry to investigate genetically predicted protein levels in association with breast cancer risk among females of African (n = 40,138), Asian (n = 137,677), and European (n = 247,173) ancestry. We identified 51 blood protein biomarkers associated with breast cancer risk, overall or by subtypes, at a false discovery rate (FDR) < 0.05, including 27 proteins encoded by genes located at least 1 Mb away from any of the known risk loci identified in GWAS. Of them, 32 proteins showed significant associations with breast cancer risk at the Bonferroni-corrected significance level (p < 2.45 × 10^-4). Of the 24 proteins located at GWAS-identified risk loci, associations for 14 proteins were significantly attenuated after adjustment for the index risk variant of each respective locus, suggesting that these proteins may be target proteins for the risk loci. Encoding gene expression levels in normal breast tissue could be genetically predicted for 23 of the 51 identified proteins, and 13 encoding genes were associated with breast cancer risk in the same direction (p < .05). Our study identified potential protein targets of GWAS risk loci and biomarkers for breast cancer risk and provided additional insights into breast cancer genetics and etiology.

The gut-liver axis may play an important role in hepatocarcinogenesis. However, limited prospective research has explored associations with liver cancer risk. We conducted a nested case-control study based in 12 prospective cohort studies from across the United States, which included 867 cases of liver cancer and 867 matched controls. We measured bacterial translocation markers, specifically immunoglobulin (Ig) A, IgG, and IgM against lipopolysaccharide and flagellin; soluble CD14 (a co-receptor for lipopolysaccharide); and lipopolysaccharide-binding protein. Multivariable conditional logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) between bacterial translocation marker concentrations per doubling in concentrations and liver cancer risk. Lipopolysaccharide-binding protein concentrations were most strongly associated with higher liver cancer risk (OR per doubling in concentrations: 1.48, 95% CI: 1.23-1.79). Concentrations of anti-flagellin IgA (1.13, 1.01-1.28) and IgG (1.13, 1.01-1.28), anti-lipopolysaccharide IgG (1.20, 1.01-1.42), and soluble CD14 (1.12, 1.01-1.24) were also associated with liver cancer risk. When analyses were separated into hepatocellular carcinoma (HCC, N = 436 cases) and intrahepatic cholangiocarcinoma (ICC, N = 110 cases), no evidence of heterogeneity was observed except for lipopolysaccharide-binding protein concentrations, which were positively associated with HCC (1.77, 1.34-2.33) but not ICC (0.67, 0.37-1.22; p-heterogeneity = .003). Associations did not differ by time to liver cancer diagnosis or other subgroups. These findings support the role of gut barrier dysfunction in hepatocarcinogenesis, necessitating further research to understand the complex interplay among the mechanisms and risk factors disrupting the gut barrier, microbiota, and liver cancer.

Prior research links prenatal exposure to organophosphate (OP) pesticides to adverse health outcomes via molecular mechanisms, such as oxidative stress, neurotransmitter disruption, and mitochondrial dysfunction. This study investigates such mechanisms by assessing the relationships between prenatal OP pesticide exposure and targeted urinary maternal metabolomic profiles using data from the New York University Children's Health and Environment Study (NYU CHES) cohort (n = 890). Urine samples were collected at three time points during pregnancy (T

BACKGROUND:Bile acids are produced in the liver and are important for lipid digestion. Higher circulating bile acid levels, however, have been linked to metabolic disorders, inflammation, and gut microbiota dysbiosis, which have been implicated in liver carcinogenesis. To date, few epidemiological studies have explored the association between circulating bile acids and liver cancer risk. METHODS:We conducted a nested case-control study among 12 prospective cohort studies located in the United States. Fifteen pre-diagnostic circulating bile acids were measured from blood samples among 872 individuals who developed liver cancer and 872 matched control participants. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariable-adjusted conditional logistic regression analysis of circulating bile acid levels and liver cancer risk. RESULTS:Primary conjugated bile acid concentrations were positively associated with higher risk of liver cancer (OR per doubling in concentrations [log2] of glycocholic acid, 95% CI: 1.32, 1.24-1.40; glycochenodeoxycholic acid: 1.33, 1.24-1.43; taurocholic acid: 1.28, 1.22-1.35; and taurchenodeoxycholic acid: 1.32, 1.24-1.39). Secondary conjugated bile acids were also positively associated with liver cancer risk (doubling of concentrations OR ranged from 1.11 to 1.22). Unconjugated bile acid concentrations were generally not associated with liver cancer risk, except lithocholic acid (OR per doubling: 1.27, 1.16-1.39). When analyses were separated into the two main subtypes of liver cancer, hepatocellular carcinoma (HCC; 438 cases/438 controls) and intrahepatic cholangiocarcinoma (ICC; 111 cases/111 controls), significant heterogeneity was observed for primary conjugated bile acid concentrations (all p-values < 0.001) that showed positive significant associations with HCC but not ICC. CONCLUSIONS:These results suggest that bile acids may be important markers of HCC risk and contribute to hepatocarcinogenesis; however, further research using serial measurements is needed.

OBJECTIVE:Research into risk factors for subjective cognitive complaints (SCCs) may offer insight into the etiology and prevention of Alzheimer's disease. Ultra-processed foods (UPFs) contain food additives that improve palatability and processed raw materials. Evidence is limited on the role of mid-life UPF intake in the development of late-life SCCs. METHODS:We included 5119 participants who responded to the 2018 or 2020 follow-up of the New York University Women's Health Study, a prospective cohort of 14,274 women recruited in New York City, United States, in 1985-91. Data on diet were collected at baseline using a validated modified Block food frequency questionnaire. Energy-adjusted total intake of UPFs and subgroups of UPFs, defined following the nova guidelines, were estimated using the residual method. RESULTS:The odds ratios (ORs) and 95 % confidence intervals (CIs) for reporting ≥2 SCCs were 1.15 (0.94-1.39), 1.06 (0.87-1.30), 1.20 (0.99-1.46), and 1.24 (1.02-1.51) for women in the 2nd, 3rd, 4th, and 5th quintiles of energy-adjusted UPF intake, respectively, compared to those in the bottom quintile (p-trend = 0.02). The associations were similar in sensitivity analyses using Multiple Imputation and Inverse Probability Weighting to account for potential selection bias. CONCLUSIONS:Higher UPF intakes in midlife were associated with higher odds of late-life SCCs in women.

BACKGROUND/UNASSIGNED:Per- and polyfluoroalkyl substances (PFAS) have been associated with numerous deleterious health outcomes including liver damage. However, whether exposure to PFAS is associated with liver cancer risk remains unclear. METHODS/UNASSIGNED:percentile incremental increase. RESULTS/UNASSIGNED:percentile increase:0.68, 0.50-0.92; p-interaction=0.005). Analyses separating liver cancer subtypes, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma, showed no evidence of heterogeneity, although associations were stronger but not significant for HCC. No evidence of interaction was observed by time to diagnosis, time period of blood draw, body mass index, alcohol intake, ethnicity, or diabetes status. CONCLUSIONS/UNASSIGNED:In the largest study to date, none of the measured circulating PFAS were associated with liver cancer risk; however, PFOA associations appeared to differ by sex and further research is needed to explore these apparent differences by sex. https://doi.org/10.1289/EHP16980.

INTRODUCTION/BACKGROUND:Maintaining oral health during pregnancy is essential for women's health, yet awareness of and access to dental care among pregnant women in China remain limited. OBJECTIVES/OBJECTIVE:We aim to assess the knowledge, attitudes, and dental care-seeking behaviors of pregnant women in 2 regions of China and identify the key factors predicting prenatal dental care utilization. METHODS:Data were collected via an online survey from pregnant women recruited through convenience sampling at 2 hospitals in Beijing municipality and Haikou city, Hainan province. The survey included knowledge, attitudes, and sociopsychological factors that may influence dental care utilization. Principal component analysis and multivariate logistic regression were applied to assess the roles of knowledge and attitudes in prenatal dental care utilization. RESULTS:A total of 248 participants completed the survey. Among them, 39.92% consulted a dentist when experiencing dental issues, while 63.31% consulted any health care professional, including dentists and obstetricians. Participants from Hainan were significantly less likely to consult a dentist as compared with those from Beijing (odds ratio [OR], 0.01; 95% CI, 0.00 to 0.40). Regular dental care before pregnancy (principal component 1) was associated with lower odds of consulting a dentist (OR, 0.58; 95% CI, 0.37 to 0.92) and any health care professional (OR, 0.56; 95% CI, 0.35 to 0.92). Perceived severity of untreated dental issues (principal component 6) increased the odds of consulting a dentist (OR, 1.69; 95% CI, 1.22 to 2.33) and a health care professional (OR, 1.66; 95% CI, 1.21 to 2.30). CONCLUSION/CONCLUSIONS:Geographic location and perceptions regarding dental care during pregnancy significantly influenced dental care-seeking behaviors among pregnant women. Women in less developed regions such as Hainan sought less dental care, while those aware of untreated dental risks were more likely to seek treatment. These findings highlight the importance of targeted interventions to address regional disparities and gaps in knowledge.Knowledge Transfer Statement:This study highlights key factors influencing prenatal dental care utilization among pregnant women in China, emphasizing regional disparities and the impact of knowledge and perceptions on care-seeking behaviors. Women in less developed regions, such as Hainan, were significantly less likely to consult a dentist or other health care professional as compared with women in Beijing. In addition, prior regular dental care was associated with lower odds of seeking treatment during pregnancy, and awareness of the severity of untreated dental issues increased the likelihood of seeking care. These findings underscore the need for targeted interventions to improve oral health education and access to prenatal dental care, particularly in underserved areas.

BACKGROUND:The relationship between body mass index (BMI) changes across the lifespan and cognitive health in later life remains unclear. This study evaluated the association between BMI changes from midlife to late-life and subsequent subjective cognitive complaints (SCCs) in women. METHODS:We analysed data from 5160 women in the New York University Women's Health Study, a prospective cohort with over 30 years of follow-up. BMI was calculated using self-reported height and weight at baseline and follow-up. SCCs were assessed using a validated questionnaire in 2018-2020. Odds ratios (ORs) for reporting ≥2 SCCs were estimated using unconditional logistic regression. RESULTS:BMI at specific life stages was not significantly associated with SCC risk. BMI changes from midlife to late-life were associated with SCC risk. Compared to women with stable BMI (≤5% change), moderate BMI loss (5.1-10% decrease) was associated with higher odds of ≥2 SCCs (OR: 1.23, 95% CI: 1.02-1.48), large BMI gain (>10% increase) was associated with lower odds of ≥2 SCCs (OR: 0.81, 95% CI: 0.67-0.97). These findings were consistent across sensitivity analyses, including varying age cut-offs and excluding BMI changes occurring 5-10 years before late-life. CONCLUSIONS:Our findings emphasize the importance of considering lifelong weight changes in assessing cognitive health risks. In particular, significant weight loss from midlife to late-life may serve as a potential indicator of cognitive decline in older adults. Further research is needed to elucidate the underlying mechanisms of this association and to explore effective interventions for mitigating cognitive health risks.

BACKGROUND:Incidence of premenopausal breast cancer (BC) has risen in recent years, though most existing BC prediction models are not generalizable to young women due to underrepresentation of this age group in model development. METHODS:Using questionnaire-based data from 19 prospective studies harmonized within the Premenopausal Breast Cancer Collaborative Group (PBCCG), representing 783,830 women, we developed a premenopausal BC risk prediction model. The data were split into training (2/3) and validation (1/3) datasets with equal distribution of cohorts in each. In the training dataset variables were chosen from known and hypothesized risk factors: age, age at menarche, age at first birth, parity, breastfeeding, height, BMI, young adulthood BMI, recent weight change, alcohol consumption, first-degree family history of BC, and personal history of benign breast disease (BBD). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox proportional hazards regression using age as time scale, stratified by cohort. Given that complete information on all risk factors was not available in all cohorts, coefficients were estimated separately in groups of cohorts with the same available covariate information, adjusted to account for the correlation between missing and non-missing variables and meta-analyzed. Absolute risk of BC (in situ or invasive) within 5 years, was determined using country-, age-, and birth cohort-specific incidence rates. Discrimination (area under the curve, AUC) and calibration (Expected/Observed, E/O) were evaluated in the validation dataset. We compared our model with a literature-based model for women < 50 years (iCARE-Lit). RESULTS:Selected model risk factors were age at menarche, parity, height, current and young adulthood BMI, family history of BC, and personal BBD history. Predicted absolute 5-year risk ranged from 0% to 5.7%. The model overestimated risk on average [E/O risk = 1.18 (1.14-1.23)], with underestimation of risk in lower absolute risk deciles and overestimation in upper absolute risk deciles [E/O 1st decile = 0.59 (0.58-0.60); E/O 10th decile = 1.48 (1.48-1.49)]. The AUC was 59.1% (58.1-60.1%). Performance was similar to the iCARE-Lit model. CONCLUSION/CONCLUSIONS:In this prediction model for premenopausal BC, the relative contribution of risk factors to absolute risk was similar to existing models for overall BC. The discriminatory ability was nearly identical (< 1% difference in AUC) to the existing iCARE-Lit model developed in women under 50 years. The inability to improve discrimination highlights the need to investigate additional predictors to better understand premenopausal BC risk.

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.