Nurses' Health Study Research Articles

Acetylsalicylic acid and subarachnoid haemorrhage in the Nurses' Health Study.

Acetylsalicylic acid (aspirin) is known to increase the risk of bleeding throughout the body. However, there is also evidence to suggest that acetylsalicylic acid may have a protective role in the formation and rupture of intracranial aneurysms. Previous studies investigating acetylsalicylic acid and subarachnoid haemorrhage (SAH) have so far provided conflicting results. The aim of this study was to analyse the Nurse's Health Study (NHS) using serial assessments to evaluate differences in rates of SAH in those participants taking acetylsalicylic acid and those not taking acetylsalicylic acid while considering dose, frequency, and duration as well as different types of SAH. The Nurse's Health Study (NHS) is a prospective population-based cohort study of female nurses. Information on acetylsalicylic acid was first reported in 1980 until 2016 and included acetylsalicylic acid use, dose, frequency and duration. All stroke cases were classified by physicians. Cox proportional-hazards regression models were used to estimate the hazard ratio (HR) associated with acetylsalicylic acid use. A total of 117,648 NHS participants were eligible for analysis with 357 cases of SAH observed over 4,091,239 years of follow up. There was no association between acetylsalicylic acid use and SAH (HR 1.02 [0.82, 1.28], p=0.85), aneurysmal SAH (1.04 [0.78, 1.39], p=0.78), or idiopathic SAH (HR 0.94 [0.65, 1.34], p=0.72). The number of acetylsalicylic acid tablets per week was associated with SAH (HR 1.03 [1.00, 1.06], p=0.02), specifically fatal SAH (HR 1.04 [1.00, 1.08], p=0.03). There was no association between frequency and SAH (HR 1.06 [0.99, 1.13], p=0.07). There was no evidence to support a protective association between acetylsalicylic acid and either SAH or aneurysmal SAH in female participants. In fact, there was some evidence to suggest increased SAH risk with increased acetylsalicylic acid dose in some but not all analyses. Data are available by request from the Brigham and Women's Hospital, Harvard Medical School, and Harvard T.H. Chan School of Public Health.

Per- and polyfluoroalkyl substances, apolipoproteins and the risk of coronary heart disease in US men and women

BackgroundExisting evidence for associations of per- and polyfluoroalkyl substances (PFASs) with blood lipids, lipoproteins and apolipoproteins (apo), and coronary heart disease (CHD) risk is limited and inconsistent. This study aims to explore associations between plasma PFASs, blood lipoprotein subspecies defined by apolipoproteins, and CHD risk.MethodsA case–control study of CHD was conducted in the Health Professionals Follow-Up Study (HPFS) and Nurses' Health Study (NHS). Among participants initially free of cardiovascular disease at blood collection in 1994 (HPFS) or 1990 (NHS), 101 participants who developed non-fatal myocardial infarction or fatal CHD were identified and confirmed. A healthy control was matched to each case for age, smoking status, and date of blood draw. Plasma levels of perfluorohexane sulfonic acid (PFHxS), perfluorooctanoic acid (PFOA), total perfluorooctane sulfonic acid (PFOS), branched PFOS (brPFOS), linear PFOS (nPFOS), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) were measured. Conditional logistic regression and cubic spline regression models were used to examine associations between baseline PFASs and CHD risk. Linear regression models were applied to study PFAS associations with lipids and their subfractions.ResultsAfter multivariate adjustments, total PFOS, brPFOS and nPFOS were significantly associated with increased risk of developing CHD, and HRs (95% CIs) per log(ng/mL) increment of PFASs were 3.66 (1.36–9.89), 3.68 (1.55–8.76), and 3.01 (1.16–7.86), respectively. Significant positive dose–response relationships were identified for these PFASs (Plinearity = 0.01, 0.002, 0.02, respectively). Other PFASs were not associated with CHD risk. PFNA and PFDA were positively associated with total apoE levels among HDL particles with or without apoC-III. No associations were observed for other PFASs with blood lipid subspecies. Blood lipid subfractions did not explain the association between PFOS and CHD risk.ConclusionsPlasma PFOS and its isomers were positively associated with CHD risk. These findings suggest that PFOS exposure causes public health risks that are greater than hitherto believed.

CHRNA5-A3-B4, CYP2A6, and DBH genetic associations with smoking cessation throughout adulthood within two longitudinal studies of women.

Genetic studies of smoking cessation have been limited by short-term follow-up or cross-sectional design. Within seven genes (CHRNA3, CHRNA5, CHRNB2, CHRNB4, DRD2, DBH and CYP2A6) influencing biological mechanisms relevant to smoking, this study aimed to identify single nucleotide polymorphisms (SNPs) associated with smoking cessation throughout up to 38-years of follow-up. Participants were from two all-female cohort studies, Nurses' Health Study (NHS) (n = 10,017) and NHS-2 (n = 2,793). For 132 SNPs providing coverage of these genes, genotype associations with the probability of quitting smoking over time were evaluated using generalized estimating equations models. For SNPs reaching nominal statistical significance (p < 0.05) within NHS, NHS-2 was used as the replication cohort to control for multiple testing (false discovery rate (FDR) < 0.05). SNP genotype by smoking intensity (lifetime light versus non-light smoking) interactions were also evaluated. Five SNPs identified in NHS were replicated in NHS-2 with FDR < 0.05. Women with the minor alleles of CHRNA5 SNPs rs637137 [OR = 1.21] and rs503464 [OR = 1.24] had increased odds of cessation. Women with the minor alleles of CYP2A6 SNPs rs56113850 [OR = 0.81] and rs56267346 [OR = 0.82] and DBH SNP rs6479643 [OR = 0.78] had lower odds of cessation throughout adulthood. An interaction with smoking intensity was indicated for three SNPs, CHRNB4 rs4887074, CHRNA3 SNP rs77438700, and CHRNA5 SNP rs76474922. Genetic associations with smoking cessation over decades of follow-up were observed and may guide targeted approaches for smokers most at risk for long-term relapse. This study identified single nucleotide polymorphisms (SNPs) within CHRNA5-A3-B4, CYP2A6, and DBH that were associated with smoking cessation in women over decades of follow-up. This study is the first to examine these genetic associations over years of follow-up. Some associations were novel while others replicated previous findings from short-term studies for the first time. Potential differences in some associations between light and non-light smokers were also observed. Genetic factors associated with long-term smoking behavior may help inform interventions modeled on long-term chronic disease management approaches; specifically, targeted maintenance interventions to sustain abstinence could be implemented among high-risk smokers.

Dietary plant-to-animal protein ratio and risk of cardiovascular disease in 3 prospective cohorts

BackgroundDietary guidelines recommend substituting animal protein with plant protein, however, the ideal ratio of plant-to-animal protein (P:A) remains unknown. ObjectivesWe aimed to evaluate associations between the P:A ratio and incident cardiovascular disease (CVD), coronary artery disease (CAD), and stroke in 3 cohorts. MethodsMultivariable-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) for CVD outcomes among 70,918 females in the Nurses’ Health Study (NHS) (1984–2016), 89,205 females in the NHSII (1991–2017) and 42,740 males from the Health Professionals Follow-up Study (1986–2016). The P:A ratio was based on percent energy from plant and animal protein and assessed using food frequency questionnaires every 4 y. ResultsDuring 30 y of follow-up, 16,118 incident CVD cases occurred. In the pooled multivariable-adjusted models, participants had a lower risk of total CVD [HR: 0.81; 95% confidence interval (CI): 0.76, 0.87; P trend < 0.001], CAD (HR: 0.73; 95% CI: 0.67, 0.79; P trend < 0.001), but not stroke (HR: 0.98; 95% CI: 0.88, 1.09; P trend = 0.71), when comparing highest to lowest deciles of the P:A ratio (ratio: ∼0.76 compared with ∼0.24). Dose–response analyses showed evidence of linear and nonlinear relationships for CVD and CAD, with more marked risk reductions early in the dose-response curve. Lower risk of CVD (HR: 0.72; 95% CI: 0.64, 0.82) and CAD (HR: 0.64; 95% CI: 0.55, 0.75) were also observed with higher ratios and protein density (20.8% energy) combined. Substitution analyses indicated that replacing red and processed meat with several plant protein sources showed the greatest cardiovascular benefit. ConclusionsIn cohort studies of United States adults, a higher plant-to-animal protein ratio is associated with lower risks of CVD and CAD, but not stroke. Furthermore, a higher ratio combined with higher protein density showed the most cardiovascular benefit.

Novel metabolomic predictors of incident colorectal cancer in men and women.

Metabolomic profiles may influence colorectal cancer (CRC) development. Few studies have performed pre-diagnostic metabolome-wide analyses with CRC risk. We conducted a nested case-control study among women (Nurses' Health Study (NHS)) and men (Health Professionals Follow-up Study (HPFS)) who provided blood between 1989 and 1995. Over 22.9 years, 684 (409 NHS, 275 HPFS) incident CRC cases occurred and were matched 1:1 to controls. Liquid chromatography-mass spectrometry (LC-MS) identified 255 plasma metabolites after quality control. Cohort-specific and combined metabolite association analyses were performed using conditional logistic regression. Metabolite set enrichment analysis (MSEA) was used to identify differential abundance in metabolite classes. Weighted Correlation Network Analysis (WGCNA) provided modules of covarying metabolites, which were tested for CRC association. MSEA identified specific acylcarnitines associated with higher CRC risk and triacylglycerols with lower CRC risk among women and men. Further, phosphatidylcholines were associated with a higher risk of CRC among men. In an analysis restricted to CRC cases diagnosed two years after blood draw, myristoleic acid (OR = 1.37; 95%CI = 1.15-1.62; FDR = 0.072) and C60:12 triacylglycerol (OR = 0.75; 95%CI = 0.64-0.88; FDR = 0.072 were associated with CRC risk in women. WGCNA identified amino acids associated with CRC in men, fatty acid esters (carnitines) with distal CRC in men, and triradylcglycerols inversely associated with CRC in women. We identified pre-diagnostic CRC-associated metabolites with distinct sex-specific profiles. These results provide insight into CRC etiopathogenesis and have implications for risk prediction strategies.

Consumption of aspartame and risk of breast cancer in the Nurses' Health Studies.

Debate persists regarding the potential carcinogenicity of aspartame as suggested by experimental studies. Therefore, we prospectively evaluated whether aspartame consumption is associated with breast cancer risk in the Nurses' Health Study (NHS) and Nurses' Health study II (NHSII). We used Cox models to calculate HRs and 95% CIs. During up to 30 years of follow-up with 4-yearly assessments of intake, we documented 10,814 invasive breast cancer cases. Overall, there was no association between aspartame consumption and invasive breast cancer risk (HR per 200 mg/day [approximately one 12 oz serving of diet soda] = 1.00 (95% CI 0.98, 1.03). We observed similar lack of associations after excluding cases occurring in the first 10 years of follow-up (n = 3,125) (HR per 200 mg/day 1.00, 95% CI 0.97, 1.03). In these cohorts, aspartame consumption did not increase breast cancer risk.

Plasma C-peptide mammographic features and risk of breast cancer

Our study in the Nurses’ Health Study (NHS) and NHS2, a nested case-control study with 1260 cases and 2221 controls, investigated the association between C-peptide levels, mammographic density (MD) parameters, V (a measure of gray scale variation), and breast cancer (BC) risk. We also examined how C-peptide and BC risk vary across quartiles of mammographic features. Linear and logistic regressions were used to study the associations between C-peptide and MD parameters, and breast cancer. C-peptide was inversely associated with percent MD and positively with non-dense area, but no associations were found with dense area and V measure. C-peptide was associated with an increased risk of invasive BC risk (top vs. bottom quartile, odds ratio = 1.46, 95% CI: 1.12–1.91). No multiplicative interactions were found between C-peptide, MD parameters, and BC risk. Our results suggest a positive association between C-peptide and BC risk, and MD parameters do not seem to modify this association.

Age at menarche by birth cohort: A pooled analysis of half a million women in Asia

ObjectivesTo evaluate changes in the age at menarche in Asian populations. Study designRetrospective cohort study. MethodsWe included 548,830 women from six countries in Asia. The data were sourced from 20 cohorts participating in the Asia Cohort Consortium (ACC) and two additional cohort studies: Japan Multi-institutional Collaborative Cohorts (J-MICC), and Japan Nurse Health Study (JNHS) with data on age at menarche. Joinpoint regression was used to evaluate changes in age at menarche by birth year and by country. ResultsThe study includes data from cohorts in six Asian countries namely, China, Iran, Japan, Korea, Malaysia and Singapore. Birth cohorts ranged from 1873 to 1995. The mean age of menarche was 14.0 years with a standard deviation (SD) of 1.4 years, ranged from 12.6 to 15.5 years. Over 100 years age at menarche showed an overall decrease in all six countries. China showed a mixed pattern of decrease, increase, and subsequent decrease from 1926 to 1960. Iran and Malaysia experienced a sharp decline between about 1985 and 1990, with APC values of −4.48 and −1.24, respectively, while Japan, South Korea, and Singapore exhibited a nearly linear decline since the 1980s, notably with an APC of −3.41 in Singapore from 1993 to 1995. ConclusionsOverall, we observed a declining age at menarche, while the pace of the change differed by country. Additional long-term observation is needed to examine the contributing factors of differences in trend across Asian countries. The study could serve as a tool to strengthen global health campaigns.

Circulating Estrogen Metabolites and Risk of Breast Cancer among Postmenopausal Women in the Nurses' Health Study.

Estradiol and estrone are well-established risk factors for postmenopausal breast cancer (BC). Experimental evidence suggests that specific estrogen metabolites, produced via irreversible hydroxylation of estrone and estradiol at the 2- or 16-position may independently influence carcinogenesis. We performed a nested case-control study of BC (328 BC cases; 639 controls) among postmenopausal women within the Nurses' Health Study (NHS)to examine the role of estrogens and estrogen metabolites (jointly referred to as EM). Plasma concentrations of each EM (unconjugated+conjugated forms) were measured by liquid chromatography-tandem mass spectrometry. Multivariable conditional logistic regression, adjusting for BC risk factors, estimated relative risks (RR) and 95% confidence intervals (CI) of BC across quintiles of individual EM, EM pathways, and pathway ratios. Associations by estrogen/progesterone receptor (ER/PR) status were analyzed by unconditional logistic regression. Estradiol and estrone were strongly associated with increased BC risk [estradiol: RRQ5v.Q1 (95% CI)=2.64 (1.64-4.26), estrone: 2.78 (1.74-4.45); both p-trends<0.001]. The 2-hydroxylation pathway was strongly associated with risk [RRQ5v.Q1=3.09 (1.81-5.27), p-trend<0.001], and remained so after adjusting for unconjugated estradiol [RRQ5v.Q1=2.23 (1.25-3.96), p-trend=0.01]. While the 16-hydroxylation pathway was modestly associated with risk [RRQ5v.Q1=1.62 (1.03-2.54), p-trend=0.01], the association was attenuated after unconjugated estradiol adjustment [RRQ5v.Q1=1.24 (0.77-1.99), p-trend=0.19]. Similar positive associations with the 2-pathway and 16-pathway were observed for ER+/PR+ and ER-/PR- tumors. In this cohort of postmenopausal women, 2-hydroxylation of estrone and estradiol was associated with increased BC risk, independent of unconjugated estradiol. These results highlight the need to revisit the role of estrogen metabolism in BC etiology and prevention.

Association between Inflammatory Dietary Pattern and Mammographic Features

BackgroundThe empirical dietary inflammation pattern score (EDIP), which measures the ability of the diet to regulate chronic inflammation, is associated with both higher adiposity and breast cancer (BC) risk. Mammographic density (MD) is an important risk factor for BC. ObjectiveWe examined the associations between EDIP and mammographic features overall and stratified by menopausal status, and assessed the extent to which these associations are mediated by adiposity. MethodsWe included 4145 participants without BC in the Nurses’ Health Study (NHS) and NHSII. Cumulative average EDIP was assessed by food frequency questionnaires every 4–6 y. We assessed MD parameters (percent MD, dense area, and nondense area) and V (measure of grayscale variation). MD parameters were square-root transformed. Multivariable-adjusted linear regression models were used to analyze the associations between EDIP score and MD parameters. Baron and Kenny’s regression method was used to assess the extent to which the associations of EDIP and mammographic traits were mediated by BMI. ResultsIn multivariable-adjusted models, EDIP was significantly inversely associated with percent MD [top compared with bottom quartile, β = –0.57; 95% confidence interval (CI): –0.78, –0.36]. Additional adjustment for BMI attenuated the association (β = –0.15; 95% CI: –0.34, 0.03), with 68% (β = 0.68, 20; 95% CI: 0.54, 0.86) mediation via BMI. In addition, EDIP was positively associated with nondense area after adjusting for BMI and other covariates. No associations were observed for dense area and V measure. Results were similar when stratified by menopausal status. ConclusionsEDIP score was inversely associated with percent MD and positively associated with nondense area, and these associations were largely mediated by BMI.

Germline polygenic risk scores are associated with immune gene expression signature and immune cell infiltration in breast cancer

The tumor immune microenvironment (TIME) plays key roles in tumor progression and response to immunotherapy. Previous studies have identified individual germline variants associated with differences in TIME. Here, we hypothesize that common variants associated with breast cancer risk or cancer-related traits, represented by polygenic risk scores (PRSs), may jointly influence immune features in TIME. We derived 154 immune traits from bulk gene expression profiles of 764 breast tumors and 598 adjacent normal tissue samples from 825 individuals with breast cancer in the Nurses' Health Study (NHS) and NHSII. Immunohistochemical staining of four immune cell markers were available for a subset of 205 individuals. Germline PRSs were calculated for 16 different traits including breast cancer, autoimmune diseases, type 2 diabetes, ages at menarche and menopause, body mass index (BMI), BMI-adjusted waist-to-hip ratio, alcohol intake, and tobacco smoking. Overall, we identified 44 associations between germline PRSs and immune traits at false discovery rate q<0.25, including 3 associations with q<0.05. We observed consistent inverse associations of inflammatory bowel disease (IBD) and Crohn disease (CD) PRSs with interferon signaling and STAT1 scores in breast tumor and adjacent normal tissue; these associations were replicated in a Norwegian cohort. Inverse associations were also consistently observed for IBD PRS and B cell abundance in normal tissue. We also observed positive associations between CD PRS and endothelial cell abundance in tumor. Our findings suggest that the genetic mechanisms that influence immune-related diseases are also associated with TIME in breast cancer.

Environmental mixtures and body mass index in two prospective US-based cohorts of female nurses

We estimated the joint effect of particulate matter ≤ 2.5 µm in diameter (PM2.5), nitrogen dioxide (NO2), seasonal temperature, noise, greenness, light at night, and neighborhood socioeconomic status (NSES) on body mass index (BMI) in a mixture context among 194,966 participants from the Nurses’ Health Study (NHS) and Nurses’ Health Study II (NHSII) over 30 years. BMI was calculated from self-reported weight and height. Single- and multi-exposure generalized estimating equations models were used to estimate the difference in BMI per interquartile range (IQR) increase of environmental factors, and quantile g-computation methods were used to estimate joint associations. In both cohorts, we consistently observed positive associations of BMI with PM2.5 and NO2 concentrations as well as negative associations with light at night and NSES regardless modeling approach. A positive association with noise was only observed in NHS. Negative associations with greenness and winter temperature were only observed in NHSII. Overall, the changes in BMI per quintile increase in all eight exposures were −0.11 (−0.13, −0.08) in NHS and −0.39 (−0.41, −0.37) in NHSII, which were largely driven by air pollution and nighttime noise (18–45 %) in the positive direction and NSES (>70 %) in the negative direction. Future intervention on environmental factors, especially reducing PM2.5, NO2 and noise or improving the NSES, might be helpful to lower BMI.

Metabolomic profiles of incident gallstone disease

Background and aimsGallstone disease affects ≥40 million people in the USA and accounts for health costs of ≥$4 billion a year. Risk factors such as obesity and metabolic syndrome are...

Association between childhood abuse and risk of post-COVID-19 conditions: Results from three large prospective cohort studies

BackgroundSignificant early life adversities, such as childhood sexual and physical/emotional abuse, are associated with risk of poor health outcomes but are understudied risk factors for post-COVID-19 conditions. In this prospective study, we examined the associations between combined exposure to sexual and physical/emotional abuse during childhood with risk of post-COVID-19 conditions in adulthood. Additionally, we explored the extent to which lifestyle, health-related and psychological factors explain this association. MethodsWe used data from three large, ongoing cohorts: Nurses’ Health Study (NHS)-II, NHS3, and the Growing Up Today Study. Between April 2020 and November 2021, participants responded to periodic COVID-19 surveys. Participants were included if they responded to a questionnaire about childhood abuse, subsequently tested positive for SARS-CoV-2 infection and responded to questions about post-COVID-19 conditions. Childhood sexual abuse was measured before the COVID-19 pandemic with the Sexual Maltreatment Scale of the Parent-Child Conflict Tactics Scale, and physical/emotional abuse was measured with the Physical and Emotional Abuse Subscale of the Childhood Trauma Questionnaire. Post-COVID-19 conditions, defined as COVID–19–related symptoms lasting 4 weeks or longer (e.g., fatigue, dyspnea), were self-reported in the final COVID-19 questionnaire in November 2021. Sexual abuse and physical/emotional abuse were examined separately and jointly in relation to post-COVID-19 conditions. Data on key lifestyle (e.g., cigarette smoking), health-related (e.g., asthma, diabetes), and psychological factors (e.g., depression and anxiety) were obtained. ResultsOf 2851 participants, the mean age (range) was 55.8 (22.0–75.0) years; 2789 (97.8 %) were females, and 2750 (96.5 %) were whites. We observed a dose-dependent relationship between severity of childhood abuse and post-COVID conditions (p-trend:<0.0001); participants with severe versus no childhood abuse had a 42 % higher subsequent risk of post-COVID conditions [relative risk (95 % confidence interval): 1.42 (1.25 to 1.61)]. Key lifestyle, health-related, and psychological factors mediated 25.5 % of this association. Both sexual and physical/emotional abuse, were independently associated with post-COVID conditions. ConclusionsIn this prospective study of 2851 participants, childhood abuse was significantly associated with increased risk of post-COVID conditions. Biological pathways connecting childhood abuse with subsequent risk of post-COVID conditions should be investigated.

Chronicles of racial discrimination: redlining’s influence on hypertension risk in women – Nurses Health Study II (1989 – 2019)

Chronicles of racial discrimination: redlining’s influence on hypertension risk in women – Nurses Health Study II (1989 – 2019)

Herpes zoster and long-term risk of subjective cognitive decline

BackgroundHerpes zoster (HZ), commonly known as “shingles,” may contribute to cognitive decline through mechanisms such as neuroinflammation or direct neuronal injury. However, evidence on the longitudinal association between HZ and cognitive decline is conflicting and whether the risk differs by APOE ε4-carrier status has not been studied; prospective cohort studies on the association between HZ vaccination and cognitive decline are also lacking.MethodsWe included 149,327 participants from three large cohorts—the Nurses’ Health Study (NHS), NHSII, and Health Professionals Follow-Up Study (HPFS)—to prospectively examine the association between HZ and subsequent subjective cognitive decline (SCD). Poisson regression was used to estimate the multivariable-adjusted relative risk (MVRR) of a 3-unit increment in SCD score according to years since HZ compared with participants with no history of HZ.ResultsCompared with individuals with no history of HZ, the MVRR (95% CI) of a 3-unit increment in SCD score was significantly and independently higher among individuals with a history of HZ, but the duration of time since HZ when the elevated risk of SCD was statistically significant differed among the cohorts. In NHS, HZ was associated with higher long-term risk of SCD; compared with individuals with no history of HZ, the MVRR (95% CI) of a 3-unit increment in SCD score was 1.14 (1.01, 1.32) for ≥ 13 years since HZ. In NHS II, HZ was associated with higher risk of SCD in both the short-term [MVRR 1.34 (1.18, 1.53) for 1–4 years] and long-term [MVRR 1.20 (1.08, 1.34) for ≥ 13 years since HZ]. In HPFS, an elevated risk of SCD was suggested across all time points. Among the subset of participants with information on APOE ε4, there was a suggestion that the association differed by APOE ε4 carrier status, but the results were not consistent between women and men. Among the subset of women with information on HZ vaccination, there was a suggestion that the long-term risk of SCD may be greater among women who were not vaccinated against HZ.ConclusionsData from three large independent cohorts of women and men showed that HZ was associated with higher long-term risk of SCD, and the risk may differ by APOE ε4-carrier status.

An Empirical Dietary Pattern Associated With the Gut Microbial Features in Relation to Colorectal Cancer Risk

Background & AimsEpidemiologic evidence for dietary influence on colorectal cancer (CRC) risk through the gut microbiome remains limited. MethodsLeveraging 307 men and 212 women with stool metagenomes and dietary data, we characterized and validated a sex-specific dietary pattern associated with the CRC-related gut microbial signature (CRC Microbial Dietary Score [CMDS]). We evaluated the associations of CMDS with CRC risk according to Fusobacterium nucleatum, pks+Escherichia coli, and enterotoxigenic Bacteroides fragilis (ETBF) status in tumor tissue using Cox proportional hazards regression in the Health Professionals Follow-up Study (1986-2018), Nurses’ Health Study (NHS) (1984-2020), and NHS II (1991-2019). ResultsThe CMDS was characterized by high industrially processed foods and low unprocessed fiber-rich foods intakes. In 259,200 participants, we documented 3,854 incident CRC cases over 6,467,378 person-years of follow-up. CMDS was associated with a higher risk of CRC (Ptrend<0.001), with a multivariable hazard ratio (HRQ5vs.Q1) of 1.25 (95%CI, 1.13-1.39). The association remained after adjusting for previously established dietary patterns, e.g., the Western and prudent diets. Notably, the association was stronger for tumoral F. nucleatum-positive (HRQ5vs.Q1, 2.51; 95%CI, 1.68-3.75; Ptrend<0.001) (Pheterogeneity=0.03, positivity vs. negativity), pks+E. coli-positive (HRQ5vs.Q1, 1.68; 95%CI, 0.84-3.38; Ptrend=0.005) (Pheterogeneity=0.01, positivity vs. negativity), and ETBF-positive CRC (HRQ5vs.Q1, 2.06; 95%CI, 1.10-3.88; Ptrend=0.016) (Pheterogeneity=0.06, positivity vs. negativity), compared with their negative counterparts. ConclusionsCMDS was associated with increased CRC risk, especially for tumors with detectable F. nucleatum, pks+E. coli, and ETBF in tissue. Our findings support a potential role of the gut microbiome underlying the dietary effects on CRC.

Short-term exposures to temperature and risk of sudden cardiac death in women: A case-crossover analysis in the Nurses' Health Study.

Sudden cardiac death (SCD) is a major source of mortality and is the first manifestation of heart disease for most cases. Thus, there is a definite need to identify risk factors for SCD that can be modified on the population level. Short-term exposures to temperature have been implicated as a potential risk factor. Our objective was to determine if short-term temperature exposures were associated with increased risk of SCD in a US-based time-stratified case-crossover study. A total of 465 cases of SCD were identified among participants of the prospective Nurses' Health Study (NHS). Control days were selected from all other matching days of the week within the same month as the case day. Average ambient temperature on the current day (Lag0) and preceding 27 days (Lags1-27) was determined at the residence level using 800-m resolution estimates. Conditional logistic distributed lag nonlinear models (DLNMs) were used to assess the relative risk (RR) of the full range of temperature exposures over the lag period. Warmer exposures in the days before event and colder temperatures 21-28 days prior were associated with increased risks of SCD. These results were driven by associations in regions other than the Northeast and among married women. Both warm and cold ambient temperatures are suggestively associated with risks of SCD among middle-aged and older women living across the United States.

The Clinical Usefulness of a Glaucoma Polygenic Risk Score in 4 Population-Based European Ancestry Cohorts

ObjectiveWe used a polygenic risk score (PRS) to identify high-risk groups for primary open-angle glaucoma (POAG) within population-based cohorts. DesignSecondary analysis of four prospective population-based studies. ParticipantsWe included four European-ancestry cohorts: the United States (US) based Nurses’ Health Study (NHS), NHS2, and the Health Professionals Follow-up Study, and the Rotterdam Study (RS) in the Netherlands. The US cohorts included female nurses and male health professionals aged 55+ years. The RS included residents aged 45 years or older living in Rotterdam, the Netherlands. MethodsPRS weights were estimated by applying the Lassosum method on imputed genotype and phenotype data from the UK-Biobank. This resulted in 144,020 variants, single nucleotide polymorphism (SNPs) and indels, with non-zero betas that we used to calculate a PRS in the target populations. Using multivariable Cox proportional hazard models, we estimated the relationship between the standardized PRS and relative risk for POAG. Additionally, POAG prediction was tested by calculating these models’ concordance (Harrell’s C-statistic). Finally, we assessed the association between PRS tertiles and glaucoma-related traits. Main Outcome MeasuresThe relative risk for POAG and Harrell’s C-statistic (the equivalent of an area-under-the-curve for longitudinal models). ResultsAmong 1,046 cases and 38,809‬ controls, the relative risk (95% confidence interval) for POAG for participants in the highest PRS quintile was 3.99 (3.08, 5.18) in the US cohorts, and 4.89 (2.93, 8.17) in the Rotterdam Study, compared with participants with median genetic risk (3rd quintile). In restricted cubic spline analyses, the relation between continuous PRS and POAG risk increased exponentially in the US and Rotterdam cohorts (Pspline<0.05). Combining age, sex, intraocular pressure >25 mmHg, and family history resulted in a meta-analyzed concordance of 0.75 (0.73, 0.75). Adding the PRS to this model improved the concordance to 0.82 (0.80, 0.84). In a meta-analysis of all cohorts, cases in the highest tertile had a larger cup-disc ratio at diagnosis, by 0.11 (0.07, 0.15), and a 2.07-fold increased risk of requiring glaucoma surgery (1.19, 3.60). ConclusionsIncorporating a PRS into a POAG predictive model improves identification concordance from 0.75 up to 0.82, supporting its potential for guiding more cost-effective screening strategies.

Risk of colorectal cancer and adenoma after an appendectomy: results from three large prospective cohort studies and meta-analysis.

The relationship between appendectomy and subsequent colorectal cancer risk remains unclear, and no study has examined its association with colorectal adenoma. We used data from three prospective cohorts: Health Professionals Follow-up Study, Nurses' Health Study (NHS), and NHSII. Appendectomy history was self-reported at baseline. Colorectal cancer risk was analyzed with Cox proportional hazard models among 224,109 participants followed up to 32years. Colorectal adenoma risk was evaluated among 157,490 participants with at least one lower gastrointestinal endoscopy during follow-up with logistic regression models accounting for repeated observations. We also performed a meta-analysis of cohort studies that examined association between appendectomy and colorectal cancer risk. We documented 3,384 colorectal cancers, 13,006 conventional adenomas, and 11,519 serrated polyps during the follow-up period. Compared to participants without appendectomy, those whoreported appendectomy history were not at higher risk of colorectal (HR [95% CI], 0.92 [0.84-1.00]), colon (0.92 [0.83-1.01]), or rectal (0.85 [0.70-1.03]) cancer. Similarly, appendectomy history was not associated with higher risk of conventional adenoma (OR [95% CI], 1.00 [0.97-1.02]), serrated polyp (0.97 [0.94-1.00]), or high-risk adenoma (0.96 [0.92-1.01]). The meta-analysis showed appendectomy was associated with a higher risk of colorectal cancer within a short time after the procedure (1.68 [1.01-2.81]), while the long-term risk was slightly inverse (0.94 [0.90-0.97]). We found no evidence of an association between appendectomy history and long-term risk of colorectal cancer or its precursors. The observed higher risk of colorectal cancer right after appendectomy in the first few years is likely due to reverse causation.