Health Initiative Observational Study Cohort Research Articles

Frequency of Consuming Breakfast Meals and After-Dinner Snacks Is not Associated with Postmenopausal Breast Cancer Risk: Women’s Health Initiative Observational Study

BackgroundThere has been little investigation into how the timing of meals and eating occasions associates with postmenopausal breast cancer risk. ObjectiveWe examined the association between the frequency of consuming breakfast meals and after-dinner snacks with the risk for postmenopausal breast cancer. MethodsA prospective analysis of 74,825 postmenopausal women aged 49 to 81 y from the Women’s Health Initiative Observational Study cohort. Breakfast and after-dinner snack intake were assessed at year 1 examination. Risk for invasive and in situ breast cancer diagnosed before 28 February 2020 was modeled with multivariable Cox proportional hazards regression models according to breakfast and after-dinner snack consumption frequencies. The models were adjusted for age, self-identified race/ethnicity, education, income, physical activity, smoking, alcohol intake, diet quality score (Healthy Eating Index 2015), energy intake, diabetic status, hormone therapy, and BMI. ResultsDuring the follow-up period, 5313 participants were diagnosed with invasive breast cancer and 1197 participants with in situ breast cancer. Compared with participants who did not eat breakfast, those with daily breakfast consumption was not associated with invasive breast cancer (HR: 1.04; 95% CI: 0.9, 1.19) nor in situ (HR: 1.25; 95% CI: 0.91, 1.74) breast cancer. There were monotonic higher point estimates of in situ breast cancer for each higher category of breakfast intake from 0 to 7 times per week (P-trend = 0.04, Wald test). Compared with consumption of daily after-dinner snacks, avoidance of after-dinner snacks was not associated with invasive breast cancer (HR: 0.97; 95% CI: 0.87, 1.08) nor in situ (HR: 1.12; 95% CI: 0.89, 1.42) breast cancer. ConclusionsThere was no association between intake frequency of breakfast meals or after-dinner snack habits and with risk of breast cancer in postmenopausal women.

Associations of coffee/caffeine consumption with postmenopausal breast cancer risk and their interactions with postmenopausal hormone use.

We investigated the association of coffee and caffeine with breast cancer (BCa) risk, overall and by ER/PR status. We also examined potential interactions of coffee and caffeine with postmenopausal hormone use. Our study included 77,688 postmenopausal participants from the Women's Health Initiative observational study cohort without a history of any cancer at baseline (except non-melanoma skin) and with valid Food Frequency Questionnaire data and complete data on dietary caffeine. Regular coffee (none, 1, 2-3, 4-5, and ≥ 6 cups/day) and caffeine (tertiles) were assessed at baseline. Information on BCa risk factors was collected at baseline. The associations were examined using survival analysis, accounting for death as a competing risk. The median follow-up time for our cohort was 18.3years. During the follow-up, 5005 women developed invasive breast cancer. In multivariable analysis, coffee was not associated with the overall invasive BCa risk. Higher caffeine intake was mildly associated with increased BCa risk (2nd vs. 1st tertile SHR = 1.10, 95% CI 1.03-1.18, 3rd vs. 1st tertile SHR-1.05, 95% CI 0.98-1.13, overall p = 0.03). We found no interaction of coffee/caffeine with postmenopausal hormone use (p interaction = 0.44 and 0.42, respectively). In the exploratory analysis by ER/PR status, we found a positive association of caffeine with ER+ /PR+ BCa (2nd vs. 1st tertile SHR = 1.17, 95% CI 1.07-1.28, 3rd vs. 1st tertile SHR = 1.13, 95% CI 1.03-1.24, overall p = 0.002); no associations were observed for ER-/PR- tumors. Coffee was not associated with the risk of ER+ /PR+ or ER-/PR- tumors. We found no associations of coffee with BCa risk, overall and for ER/PR-defined tumor subtypes. The higher caffeine consumption was mildly and positively associated with the overall BCa risk and with ER+ /PR+ tumors.

Effects of self-reported age at nonsurgical menopause on time to first fracture and bone mineral density in the Women's Health Initiative Observational Study.

Menopause is a risk factor for fracture; thus, menopause age may affect bone mass and fracture rates. We compared bone mineral density (BMD) and fracture rates among healthy postmenopausal women with varying ages at self-reported nonsurgical menopause. We compared hazard ratios for fractures and differences in BMD among 21,711 postmenopausal women from the Women's Health Initiative Observational Study cohort who had no prior hysterectomy, oophorectomy, or hormone therapy and had varying self-reported ages at menopause (<40, 40-49, or ≥50 y). Before multivariable adjustments, we found no differences in absolute fracture risk among menopause age groups. After multivariable adjustments for known risk factors for fracture, women who underwent menopause before age 40 years had a higher fracture risk at any site compared with women who underwent menopause at age 50 years or older (hazard ratio, 1.21; 95% CI, 1.02 to 1.44; P = 0.03). In a subset with BMD measurements (n = 1,351), whole-body BMD was lower in women who reported menopause before age 40 years than in women who reported menopause at ages 40 to 49 years (estimated difference, -0.034 g/cm; 95% CI, -0.07 to -0.004; P = 0.03) and women who reported menopause at age 50 years or older (estimated difference, -0.05 g/cm; 95% CI, -0.08 to -0.02; P < 0.01). Left hip BMD was lower in women who underwent menopause before age 40 years than in women who underwent menopause at age 50 years or older (estimated difference, -0.05 g/cm; 95% CI, -0.08 to -0.01; P = 0.01), and total spine BMD was lower in women who underwent menopause before age 40 years than in women who underwent menopause at age 50 years or older (estimated difference, -0.11 g/cm; 95% CI, -0.16 to -0.06; P < 0.01) and women who underwent menopause at ages 40 to 49 years (estimated difference, -0.09 g/cm; 95% CI, -0.15 to -0.04; P < 0.01). In the absence of hormone therapy, younger age at menopause may be a risk factor contributing to decreased BMD and increased fracture risk in healthy postmenopausal women. Our data suggest that menopause age should be taken into consideration, along with other osteoporotic risk factors, when estimating fracture risk in postmenopausal women.

Insecticide exposure and farm history in relation to risk of lymphomas and leukemias in the Women's Health Initiative observational study cohort

PurposeRelationships of farm history and insecticide exposure at home or work with lymphohematopoietic (LH) neoplasm risk were investigated in a large prospective cohort of US women. MethodsIn questionnaires, women self-reported history living or working on a farm, personally mixing or applying insecticides, insecticide application in the home or workplace by a commercial service, and treating pets with insecticides. Relationships with non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, plasma cell neoplasms, and myeloid leukemia were investigated using Cox proportional hazard models. Age and farming history were explored as effect modifiers. ResultsThe analysis included 76,493 women and 822 NHL cases. Women who ever lived or worked on a farm had 1.12 times the risk of NHL (95% confidence interval [CI] = 0.95–1.32) compared to those who did not. Women who reported that a commercial service ever applied insecticides in their immediate surroundings had 65% higher risk of CLL/SLL (95% CI = 1.15–2.38). Women aged less than 65 years who ever applied insecticides had 87% higher risk of DLBCL (95% CI = 1.13–3.09). ConclusionsInsecticide exposures may contribute to risk of CLL/SLL and DLBCL. Future studies should examine relationships of LH subtypes with specific types of household insecticides.

Folate-mediated one-carbon metabolism genes and interactions with nutritional factors on colorectal cancer risk: Women's Health Initiative Observational Study.

Investigations of folate-mediated one-carbon metabolism (FOCM) genes and gene-nutrient interactions with respect to colorectal cancer (CRC) risk are limited to candidate polymorphisms and dietary folate. This study comprehensively investigated associations between genetic variants in FOCM and CRC risk and whether the FOCM nutrient status modified these associations. Two hundred eighty-eight candidate and tagging single-nucleotide polymorphisms (SNPs) in 30 FOCM genes were genotyped for 821 incident CRC case-control matched pairs in the Women's Health Initiative Observational Study cohort. FOCM biomarkers (red blood cell [RBC] folate, plasma folate, pyridoxal-5'-phosphate [PLP], vitamin B12, and homocysteine) and self-reported alcohol consumption were measured at the baseline. Conditional logistic regression was implemented; effect modification was examined on the basis of known enzyme-nutrient relations. Statistically significant associations were observed between CRC risk and functionally defined candidate SNPs of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1; K134R), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR; P450R), and PR domain containing 2 with ZNF domain (PRDM2; S450N) and a literature candidate SNP of thymidylate synthase (TYMS; g.676789A>T; nominal P < .05). In addition, suggestive associations were noted for tagging SNPs in cystathionine-β-synthase (CBS), dihydrofolate reductase (DHFR), DNA (cytosine-5-)-methyltransferase 3β (DNMT3B), methionine adenosyltransferase I α (MAT1A), MTHFD1, and MTRR (nominal P < .05; adjusted P, not significant). Significant interactions between nutrient biomarkers and candidate polymorphisms were observed for 1) plasma/RBC folate and folate hydrolase 1 (FOLH1), paraoxonase 1 (PON1), transcobalamin II (TCN2), DNMT1, and DNMT3B; 2) plasma PLP and TYMS TS3; 3) plasma B12 and betaine-homocysteine S-methyltransferase 2 (BHMT2); and 4) homocysteine and methylenetetrahydrofolate reductase (MTHFR) and alanyl-transfer RNA synthetase (AARS). Genetic variants in FOCM genes are associated with CRC risk among postmenopausal women. FOCM nutrients continue to emerge as effect modifiers of genetic influences on CRC risk.

Birth weight and subsequent risk of cancer

Background: We aimed to determine the association between self-reported birth weight and incident cancer in the Women's Health Initiative Observational Study cohort, a large multiethnic cohort of postmenopausal women. Methods: 65,850 women reported their birth weight by category (<6lbs, 6–7lbs 15oz, 8–9lbs 15oz, and ≥10lbs). All self-reported, incident cancers were adjudicated by study staff. We used Cox proportional hazards regression to estimate crude and adjusted hazard ratios (aHR) for associations between birth weight and: (1) all cancer sites combined, (2) gynecologic cancers, and (3) several site-specific cancer sites. Results: After adjustments, birth weight was positively associated with the risk of lung cancer (p=0.01), and colon cancer (p=0.04). An inverse trend was observed between birth weight and risk for leukemia (p=0.04). A significant trend was not observed with breast cancer risk (p=0.67); however, women born weighing ≥10lbs were less likely to develop breast cancer compared to women born between 6lbs-7lbs 15oz (aHR 0.77, 95% CI 0.63, 0.94). Conclusion: Birth weight category appears to be significantly associated with the risk of any postmenopausal incident cancer, though the direction of the association varies by cancer type.

Cytokines in serum in relation to future non‐Hodgkin lymphoma risk: Evidence for associations by histologic subtype

Specific associations for lymphoma in the general population suggest that chronic immune dysfunction/dysregulation may be associated with the development of B-cell non-Hodgkin lymphoma (NHL). Furthermore, polymorphisms in several cytokine genes have been associated with increased lymphoma risk, most consistently with genes for TNF and IL10. To evaluate the hypothesis that prediagnostic circulating cytokine levels would be associated with increased B-cell lymphoma risk, we conducted a nested case-control study within the Women's Health Initiative Observational Study cohort involving 491 B-cell NHL cases and 491 controls. Levels of eleven cytokines, including IL1β, IL2, IL4, IL5, IL6, IL10, IL12, IL13, TNF, IFNγ and GM-CSF, were measured using a Luminex suspension bead-based multiplexed array in prediagnostic serum samples collected a median of 6 years prior to the lymphoma diagnosis. We observed a modestly increased risk of all B-cell NHL in women with increased levels of the cytokines TNF and IL10 (OR1.22, CI 1.07-1.38 and OR 1.09, CI 1.04-1.15, respectively, per doubling in the serum cytokine concentration) and this association showed some variation according to histologic subtype. The increased risk was strongest for those neoplasms diagnosed in close proximity to the blood draw for some histologic subtypes but not others, suggesting a component of reverse causation. Further study will be required to better understand how genetic polymorphisms in TNF and IL10 genes may interact with circulating cytokine levels and states of chronic immune dysfunction/stimulation to contribute to the risk of B-cell NHL.

Impact of folic acid fortification on global DNA methylation and one-carbon biomarkers in the Women's Health Initiative Observational Study cohort

DNA methylation is an epigenetic mechanism that regulates gene expression and can be modified by one-carbon nutrients. The objective of this study was to investigate the impact of folic acid (FA) fortification of the US food supply on leukocyte global DNA methylation and the relationship between DNA methylation, red blood cell (RBC) folate, and other one-carbon biomarkers among postmenopausal women enrolled in the Women's Health Initiative Observational Study. We selected 408 women from the highest and lowest tertiles of RBC folate distribution matching on age and timing of the baseline blood draw, which spanned the pre- (1994–1995), peri- (1996–1997), or post-fortification (1998) periods. Global DNA methylation was assessed by liquid chromatography-tandem mass spectrometry and expressed as a percentage of total cytosine. We observed an interaction (P = 0.02) between fortification period and RBC folate in relation to DNA methylation. Women with higher (vs. lower) RBC folate had higher mean DNA methylation (5.12 vs. 4.99%; P = 0.05) in the pre-fortification period, but lower (4.95 vs. 5.16%; P = 0.03) DNA methylation in the post-fortification period. We also observed significant correlations between one-carbon biomarkers and DNA methylation in the pre-fortification period, but not in the peri- or post-fortification period. The correlation between plasma homocysteine and DNA methylation was reversed from an inverse relationship during the pre-fortification period to a positive relationship during the post-fortification period. Our data suggest that (1) during FA fortification, higher RBC folate status is associated with a reduction in leukocyte global DNA methylation among postmenopausal women and; (2) the relationship between one-carbon biomarkers and global DNA methylation is dependent on folate availability.

Investigation of epstein-barr virus as a potential cause of B-cell non-Hodgkin lymphoma in a prospective cohort.

We hypothesized that poor control of Epstein-Barr virus (EBV) infection, leading to reactivation of the virus, increases the risk of non-Hodgkin lymphoma (NHL) in the general population of primarily immunocompetent persons. We conducted a case-control study nested within the Women's Health Initiative Observational Study cohort in which we measured antibodies to EBV antigens [immunoglobulin G (IgG) to viral capsid antigen (VCA), nuclear antigen (EBNA1), and early antigen-diffuse (EA-D)] and EBV DNA load in prediagnostic samples of 491 B-cell NHL cases and 491 controls. We found no association with established EBV infection, based on seropositivity for VCA. Seropositivity for EBNA1 was associated with decreased risk of B-cell NHL, overall [OR = 0.5; 95% confidence interval (CI), 0.3-0.8] and for each of the histologic subtypes examined. Increased risk of chronic lymphocytic leukemia (CLL) and related subtypes was observed with higher levels of EBV DNA and antibody to EA-D, both markers reflective of reactivation. These associations were strongest for cases with the shortest time interval between blood draw and diagnosis. In balance, these results do not provide strong evidence of EBV playing a causal role in B-cell NHL in general population women. The associations we observed may reflect increased risk of NHL with underlying immune impairment or could be due to reverse causation. Further characterization of the subtype-specific association with CLL is warranted. Exclusion of cases with preclinical disease markers (such as monoclonal B-lymphocytosis for CLL) may help rule out reverse causation in future studies.

Serum Fatty Acids and Incidence of Ischemic Stroke Among Postmenopausal Women

Although studies have linked types of fatty acids with coronary heart disease, data on individual fatty acids and risk of ischemic stroke are limited. We aimed to examine the associations between serum fatty acid concentrations and incidence of ischemic stroke and its subtypes. We conducted a prospective case-control study nested in the Women's Health Initiative Observational Study cohort of postmenopausal US women aged 50 to 79 years. Between 1993 and 2003, incident cases of ischemic stroke were matched 1:1 to controls on age, race, and length of follow-up (964 matched pairs). Conditional logistic regression was used to estimate odds ratios and 99.9% confidence intervals (CI) for ischemic stroke and its subtypes. The multivariable-adjusted odds ratios and 99.9% CI of ischemic stroke associated with a 1-SD increment in serum fatty acid concentration were 1.38 (99.9% CI, 1.05-1.83) for linoelaidic acid (18:2tt, SD=0.04%), 1.27 (99.9% CI, 1.06-1.51) for palmitic acid (16:0, SD=2.74%), 1.20 (99.9% CI, 1.01-1.43) for oleic acid (18:1n9, SD=2.32%), 0.72 (99.9% CI, 0.59-0.87) for docosapentaenoic acid (22:5n3, SD=0.18%), 0.72 (99.9% CI, 0.59-0.87) for docosahexaenoic acid (22:6n3, SD=0.91%), and 0.81 (99.9% CI, 0.67-0.98) for arachidonic acid (20:4n6, SD=2.02%). These associations were generally consistent for atherothrombotic and lacunar stroke but not cardioembolic stroke. These findings suggest that individual serum trans, saturated, and monounsaturated fatty acids are positively associated with particular ischemic stroke subtypes, whereas individual n3 and n6 polyunsaturated fatty acids are inversely associated.

B vitamin intakes and incidence of colorectal cancer: results from the Women’s Health Initiative Observational Study cohort

The role of one-carbon metabolism nutrients in colorectal carcinogenesis is not fully understood. Associations might be modified by mandated folic acid (FA) fortification or alcohol intake. We investigated associations between intakes of folate, riboflavin, vitamin B-6, and vitamin B-12 and colorectal cancer (CRC) in the Women's Health Initiative Observational Study, stratified by time exposed to FA fortification and alcohol intake. A total of 88,045 postmenopausal women were recruited during 1993-1998; 1003 incident CRC cases were ascertained as of 2009. Quartiles of dietary intakes were compared; HRs and 95% CIs were estimated by Cox proportional hazards models. Dietary and total intakes of vitamin B-6 in quartile 4 compared with quartile 1 (HR: 0.80; 95% CI: 0.66, 0.97 and HR: 0.80; 95% CI: 0.66, 0.99, respectively) and total intakes of riboflavin (HR: 0.81; 95% CI: 0.66, 0.99) were associated with reduced risk of CRC overall and of regionally spread disease. In current drinkers who consumed <1 drink (13 g alcohol)/wk, B vitamin intakes were inversely associated with CRC risk (P-interaction < 0.05). Dietary folate intake was positively associated with CRC risk among women who had experienced the initiation of FA fortification for 3 to <9 y (P-interaction < 0.01). Vitamin B-6 and riboflavin intakes from diet and supplements were associated with a decreased risk of CRC in postmenopausal women. Associations of B vitamin intake were particularly strong for regional disease and among women drinkers who consumed alcohol infrequently. Our study provides new evidence that the increased folate intake during the early postfortification period may have been associated with a transient increase in CRC risk.

Markers of B-cell activation in relation to risk of non-Hodgkin lymphoma.

B-cell activation biomarkers have been associated with increased risk of non-Hodgkin lymphoma (NHL) in HIV-infected populations. However, whether a similar association may exist in general populations has not been established. We conducted a case-control study within the Women's Health Initiative Observational Study cohort to measure the B-cell activation biomarkers sCD23, sCD27, sCD30, sCD44, and CXCL13 in serum samples collected an average of 6 years before NHL diagnosis in 491 cases and 491 controls. Using logistic regression to estimate odds ratios, we observed strong associations between NHL and markers for all B-cell NHL and for major subtypes. Women with marker levels in the highest-versus-lowest quartile categories of CD23, CD27, CD30, or CXCL13 were at 2.8- to 5.5-fold increased risk of B-NHL. In addition, there were significant trends of risk with increasing levels of these markers present. Associations were strongest for cases with shortest lag times between blood draw and diagnosis (<3 years). However, there were also significant associations for cases with the longest prediagnostic lag (9 to 13 years). Taken together, our findings indicate a prominent role for B-cell activation among postmenopausal women in the etiology of B-cell NHL and/or in processes reflective of early disease development as early as 9 years before diagnosis.

Menopausal Hormone Therapy and Coronary Heart Disease: Reconciling Divergent Findings from Observational Studies and Clinical Trials

Randomized clinical trials of menopausal hormone therapy have shown increased risks of coronary heart disease in the first few years after randomization, and neutral or increased risk over the full trial period. These results diverge substantially from the protective associations of menopausal hormone use with coronary heart disease found in observational studies. In common with many other studies, conventional analyses in the Women’s Health Initiative Observational Study cohort of estrogen plus progestin users showed an association with reduced risk of coronary heart disease even after adjustment for potential confounders. However, upon allowing risk to vary by time since initiation, the hazard ratios did not differ significantly from those observed in the clinical trial. In analyses combining clinical trial and observational data the hazard ratios were 1.58 (1.12, 2.24) within the first 2 years after initiation, 1.19 (0.87, 1.63) between 2 and 5 years, and 0.63 (0.59, 1.26) after 5 years. Similar analyses for estrogen alone also reconciled trial and observational data. These findings were confirmed in novel re-analyses of the Nurses’ Health Study when investigators for the first time included outcomes occurring in the interval between the biennial study cycles. The key towards understanding the underestimation of coronary heart disease in observational studies of menopausal hormone therapy appears to lie in the time-dependent nature of coronary heart disease risk rather than differences in study populations. Observational studies typically do not capture early events in current users and the data mostly reflect the experience of long-term users who have survived the early risk, while clinical trials by design capture early events very efficiently and mainly reflect short-term use.

Predictors of Change in Pain and Physical Functioning Among Post-Menopausal Women With Recurrent Pain Conditions in the Women’s Health Initiative Observational Cohort

Pain complaints are commonly reported symptoms among postmenopausal women and can have significant effects on health-related quality of life. We sought to identify medical and psychosocial factors that predict changes in pain and overall physical functioning over a 3-year period among postmenopausal women with recurrent pain conditions. We examined data from postmenopausal women age 50 to 79 with recurrent pain conditions (low back pain, neck pain, headache or migraines, or joint pain or stiffness) over a 3-year period using the Women’s Health Initiative Observational Study Cohort (N = 67,963). Multinomial logistic regression models controlling for demographic and clinical characteristics were used to identify baseline predictors of change in the SF-36 subscales for pain and physical functioning between baseline and 3-year follow-up. Body mass index (BMI) was associated with worsening of pain (OR [95% CI] 1.54 [1.45-1.63] for BMI ≥30) and physical functioning (1.83 [1.71-1.95] for BMI ≥30). A higher reported number of nonpain symptoms, higher medical comorbidity, and a positive screen for depression (1.13 [1.05-1.22] for worsened pain) were also associated with worsening of pain and physical functioning. Baseline prescription opioid use was also associated with lack of improvement in pain (OR .42, 95% CI .36-.49) and with worsened physical functioning (1.25 [1.04-1.51]). Perspective This study presents prospective data on change in pain and physical functioning in postmenopausal women over a 3-year period. Our results suggest depression, nonpain physical symptoms, obesity, and possibly opioid treatment are associated with worse long-term pain outcomes in this population.

Abstract PR-05: Biomarkers of inflammation predict colorectal cancer risk among women: Results from the Women's Health Initiative Observational Study (WHI-OS) cohort

Abstract Introduction: There is strong evidence that chronic inflammation plays a role in colorectal carcinogenesis. Despite this, epidemiological studies that have investigated this association using C-reactive protein (CRP) as an inflammatory biomarker have reported conflicting results, especially among women. Limitations of previous studies include the small number of cases and the fact that CRP measurements were performed at only one point in time. Likewise, no previous study has investigated the association of serum amyloid A (SAA), a related marker of inflammation, and colorectal cancer (CRC) risk. We investigated the associations of CRP and SAA with CRC risk, using repeat assessments, in a case-control study nested within the Women's Health Initiative Observational Study cohort (WHI-OS). We also explored the impact of changes in the two biomarkers (from baseline to 3rd year of follow-up) on CRC risk. Methods: The WHI-OS is a prospective cohort study that enrolled 93,676 post-menopausal women between 1993 and 1998 at 40 U.S. clinical institutions. We identified 988 women with CRC and matched 988 cancer-free control women based on age (±3 years), clinical center, race/ethnicity, and time of blood draw (±6 months). CRP and SAA measurements were performed at baseline and during the 3rd year of follow-up. Conditional logistic regression models were used to estimate the multivariate-adjusted odds ratios and 95% confidence intervals (OR, 95% CI) of CRC (adjusted for age, body mass index, post-menopausal hormone use (HRT) and previous history of colonoscopy). Results: Elevated CRP, but not SAA concentrations were positively associated with CRC risk. Women in the highest quintiles of CRP and SAA concentrations had an odds ratios of 1.28 (95% CI 0.94–1.76, p-trend=0.03) and 1.19 (95% CI 0.88–1.62, p-trend=0.17) respectively, compared to women in the lowest quintiles. Women who had high levels of both biomarkers had increased risk of colorectal cancer (OR=1.35, 95% CI 1.06–1.73, p-value=0.02), particularly colon cancer (OR=1.49, 95% CI 1.13–1.97, p-value=0.005) compared to those with low concentrations. Neither CRP nor SAA was positively associated with rectal cancer risk in any of the analyses. There was a non-significant increased risk of CRC (OR 1.31, 95% CI 0.91–1.89, p-trend=0.14) among women who had the largest increase in CRP concentration (from baseline to 3rd year of follow-up), while the risk associated with changes in SAA concentration was close to unity (OR 1.05 95% CI 0.73–1.49, p-trend 0.94). The associations between CRP and CRC risk were not modified by HRT use. Conclusions: Our study supports the hypothesis that inflammation is associated with colorectal carcinogenesis and that CRP and SAA used together may better predict CRC risk than either used alone. Citation Information: Cancer Prev Res 2011;4(10 Suppl):PR-05.

Fish Intake and the Risk of Incident Heart Failure

Background— Whether fish or the fatty acids they contain are independently associated with risk for incident heart failure (HF) among postmenopausal women is unclear. Methods and Results— The baseline Women's Health Initiative Observational Study cohort consisted of 93 676 women ages 50 to 79 years of diverse ethnicity and background, of which 84 493 were eligible for analyses. Intakes of baked/broiled fish, fried fish, and omega-3 fatty acid (eicosapentaenoic acid+docosahexaenoic acid, α-linolenic acid), and trans-fatty acid were determined from the Women's Health Initiative food frequency questionnaire. Baked/broiled fish consumption was divided into 5 frequency categories: &lt;1/mo (referent), 1 to 3/mo, 1 to 2/wk, 3 to 4/wk, ≥5/wk. Fried fish intake was grouped into 3 frequency categories: &lt;1/mo (referent), 1–3/mo, and ≥1/wk. Associations between fish or fatty acid intake and incident HF were determined using Cox models adjusting for HF risk factors and dietary factors. Baked/broiled fish consumption (≥5 servings/wk at baseline) was associated with a hazard ratio of 0.70 (95% confidence interval, 0.51 to 0.95) for incident HF. In contrast, fried fish consumption (≥1 serving/wk at baseline) was associated with a hazard ratio of 1.48 (95% confidence interval, 1.19 to 1.84) for incident HF. No significant associations were found between eicosapentaenoic acid+docosahexaenoic acid, α-linolenic acid, or trans-fatty acid intake and incident HF. Conclusions— Increased baked/broiled fish intake may lower HF risk, whereas increased fried fish intake may increase HF risk in postmenopausal women.

Resistin, but Not Adiponectin and Leptin, Is Associated With the Risk of Ischemic Stroke Among Postmenopausal Women

Adipose tissue is considered an endocrine organ that secretes adipokines, which possibly mediate the effects of obesity on the risk of cardiovascular disease. However, there are yet limited prospective data on the association between circulating adipokine levels and the risk of ischemic stroke. We aimed to examine the associations of 3 adipokines (adiponectin, leptin, and resistin) with the risk of ischemic stroke. We conducted a prospective nested case-control study (972 stroke cases and 972 matched control subjects) within the Women's Health Initiative Observational Study cohort. The control subjects were matched to cases on age, race/ethnicity, date of study enrollment, and follow-up time. Adipokine levels were associated with established stroke risk factors such as obesity and systolic blood pressure. Adjusted for body mass index, the ORs for incident ischemic stroke comparing the highest (Quartile 4) with the lowest quartile (Quartile 1) were 0.81 (95% CI, 0.61 to 1.08; P trend=0.068) for adiponectin, 1.15 (95% CI, 0.83 to 1.59; P trend=0.523) for leptin, and 1.57 (95% CI, 1.18 to 2.08; P trend=0.002) for resistin. The association for resistin remained significant even after accounting for established stroke risk factors (OR, 1.39; 95% CI, 1.01 to 1.90; P trend=0.036). Further adjustment for markers for inflammation, angiogenesis, and endothelial function also did not affect our results. Circulating levels of resistin, but not those of adiponectin or leptin, are associated with an increased risk of incident ischemic stroke in postmenopausal women, independent of obesity and other cardiovascular disease risk factors.

Sleep Duration and Risk of Ischemic Stroke in Postmenopausal Women

Many studies have shown a U-shape association between sleep duration and mortality, but epidemiological evidence linking cardiovascular diseases with habitual sleep patterns is limited and mixed. We conducted a prospective study on 93 175 older women (aged 50 to 79 years) in the Women's Health Initiative Observational study cohort to examine the risk of ischemic stroke in relation to self-reported sleep duration. Cox models were used to investigate the putative associations, adjusting for multiple sociodemographic and lifestyle factors, depression, snoring, sleepiness symptoms, and other cardiovascular disease-related clinical characteristics. At baseline, 8.3% of subjects had reported their sleep duration as <or=5 hours per night and 4.6% reported long duration of sleep (>or=9 hours/night). After an average of 7.5 years of follow-up, 1166 cases of ischemic stroke had occurred. Multivariable-adjusted relative risk (RR) and 95% CI for ischemic stroke (using a sleep time of 7 hours/night as the reference) were 1.14 (0.97, 1.33), 1.24 (1.04, 1.47), and 1.70 (1.32, 2.21) for women reporting <or=6, 8, and >or=9 hours of sleep. A modestly stronger association with sleep duration <or=6 hours per night (RR, 1.22; 1.03, 1.44) was noted among women without prevalent cardiovascular disease at baseline. Our analyses also reveal that the adverse effect of long sleep is likely independent of the increased risk for ischemic stroke associated with frequent snoring and sleepiness (RR, 1.31; 1.00, 1.72). Habitual sleep patterns are important neurobehavioral determinants of risk for ischemic stroke in postmenopausal women. The underlying neurobiology and mechanistic mediators for the putative adverse effect of long sleep (>or=9 hours/night) need further elucidation.