Shannon M. Conroy

Ethnic differences in serum adipokine and C-reactive protein levels: the multiethnic cohort.

Background:Ethnic disparities in metabolic disease risk may be the result of differences in circulating adipokines and inflammatory markers related to ethnic variations in obesity and body fat distribution.Subjects/Methods:In a cross-sectional design, we compared serum levels of leptin, adiponectin, C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in control subjects (321 men and 930 women) from two nested case–control studies conducted within the Multiethnic Cohort Study consisting of whites, Japanese Americans (JA), Latinos, African Americans (AA) and Native Hawaiians (NH). General linear models were applied to evaluate ethnic differences in log-transformed serum biomarker levels before and after adjusting for body mass index (BMI) at cohort entry.Results:In comparison to whites, significant ethnic differences were observed for all biomarkers except TNF-α. JA men and women had significantly lower leptin and CRP levels than whites, and JA women also had lower adiponectin levels. Leptin was significantly higher in AA women (P<0.01), adiponectin was significantly lower in AA men and women (P=0.02 and P<0.001), and CRP and IL-6 were significantly higher in AA men and women. Lower adiponectin (P<0.0001) and CRP (P=0.03) levels were the only biomarkers in NH women that differed from whites; no statistically significant differences were seen for NH men and for Latino men and women. When adjusted for BMI at cohort entry, the differences between the lowest and the highest values across ethnic groups decreased for all biomarkers except adiponectin in men indicating that ethnic differences were partially due to weight status.Conclusions:These findings demonstrate the ethnic variations in circulating adipokine and CRP levels before and after adjustment for BMI. Given the limitation of BMI as a general measure of obesity, further investigation with visceral and subcutaneous adiposity measures are warranted to elucidate ethnicity-related differences in adiposity in relation to disparities in obesity-related disease risk.

Associations between obesity and serum lipid-soluble micronutrients among premenopausal women

Elucidating potential pathways that micronutrients may reduce/promote chronic disease may contribute to our understanding of the underlying etiology of disease and their utility as markers of risk. In the current study, we examined associations of serum lipid-soluble micronutrients with body mass index (BMI). We hypothesized that obesity may differentially influence serum micronutrient levels, thereby affecting risk for chronic disease incidence and mortality. Baseline serum samples from 180 premenopausal women from a nutritional trial were analyzed for leptin, C-reactive protein, 25-hydroxyvitamin D, carotenoids, and tocopherols. Participants were stratified into normal-weight (18.5-24.9), overweight (25-29.9), and obese (>or=30) subgroups by BMI (in kilograms per square meter). Differences in serum biomarkers among BMI subgroups were adjusted for Asian ethnicity and smoking status. As expected, obese individuals had significantly higher serum levels of leptin and C-reactive protein (Ps < .05) compared with normal-weight women. gamma-Tocopherol levels were significantly higher in obese individuals (P < .05), whereas alpha-tocopherol levels did not differ among BMI subgroups. Serum levels of 25-hydroxyvitamin D and carotenoids (except lycopene) were significantly lower in obese than in normal-weight women (Ps < .05). The associations between BMI and carotenoids were independent of dietary intake. The obesity-associated reduction for total provitamin A carotenoids (45%) was approximately 3-fold greater than that observed for non-provitamin A carotenoids (16%). Our results indicate potential influences of obesity on serum levels of lipid-soluble micronutrients and suggest that metabolism of provitamin A carotenoids may contribute to the differences observed.

Mammographic density and hormone receptor expression in breast cancer: The Multiethnic Cohort Study

BACKGROUND It is unclear whether mammographic breast density, a strong risk factor for breast cancer, predicts subtypes of breast cancer defined by estrogen receptor (ER) and/or progesterone receptor (PR) expression. METHODS In a nested case-control study, we compared the breast density of 667 controls and 607 breast cancer cases among women of Caucasian, Japanese, and Native Hawaiian ancestry in the Hawaii component of the Multiethnic Cohort Study. A reader blinded to disease status performed computer assisted density assessment on prediagnostic mammograms. Receptor status was obtained from the statewide Hawaii Tumor Registry. Tumors were classified into ER+PR+ (n=341), ER-PR- (n=50), ER+PR-/ER-PR+ (n=64), and unstaged/unknown (n=152). Mean percent density values were computed for women with more than one mammogram. Polytomous logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) while adjusting for confounders. RESULTS Mean percent density was significantly greater for ER+PR+ but not for ER-PR- tumors compared to controls after adjusting for age: 37.3%, 28.9% versus 29.4%, respectively. The overall OR per 10% increase in percent density were similar for ER+PR+ and ER+PR-/ER-PR+ tumors: 1.26 (95% CI 1.17-1.36) and 1.23 (95% CI 1.07-1.42), respectively. However, percent density was not found to be a predictor for ER-PR- tumors (OR 1.00, 95% CI 0.84-1.18). The results did not differ by ethnicity, nor by menopausal status, parity, or HRT use. CONCLUSIONS Our findings indicate that within a multiethnic population, women with higher breast density have an increased risk for ER+PR+ but not ER-PR- tumors.

Non-Hodgkin Lymphoma and circulating markers of inflammation and adiposity in a nested case-control study: The Multiethnic Cohort

Background: Because immune dysfunction is thought to underlie the development of non-Hodgkin lymphoma (NHL), obesity and chronic inflammation may be involved in its etiology. We examined the association of prediagnostic inflammatory markers and adipokines with NHL risk. Methods: We conducted a nested case–control analysis (272 cases and 541 matched controls) within the Multiethnic Cohort. Luminex technology was used to measure a 10-plex panel of cytokines, ELISA assays for adipokines, and an autoanalyzer for C-reactive protein (CRP). ORs and 95% confidence intervals (CI) for tertiles of analytes were estimated by conditional logistic regression. Results: After a median time of 2.7 years from phlebotomy to diagnosis, interleukin (IL)-10 was significantly related to NHL risk (ORT3 vs. T1 = 3.07; 95%CI, 2.02–4.66; Ptrend < 0.001). TNF-α and IL-8 showed borderline elevated risks, whereas IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, and CRP were not associated with NHL. Leptin but not adiponectin was related to NHL risk (ORT3 vs. T1 = 0.48; 95%CI, 0.30–0.76; Ptrend < 0.001). Adjustment for body mass index did not substantially affect the risk estimates. Stratification by subtype indicated significant associations with IL-10 and leptin for follicular but not for diffuse large B-cell lymphoma. Excluding cases diagnosed less than 1 year after phlebotomy attenuated all associations. Conclusions: IL-10 was the only cytokine and leptin the only adipokine associated with NHL, but due to the short follow-up time, preclinical effects cannot be excluded. Impact: Although markers of inflammation and adiposity may provide new insights into the etiology of NHL, they need to be assessed many years before clinical diagnosis. Cancer Epidemiol Biomarkers Prev; 22(3); 337–47. ©2012 AACR.

Mammographic density as a predictor of breast cancer survival: the Multiethnic Cohort

IntroductionMammographic density, a strong predictor for breast cancer incidence, may also worsen prognosis in women with breast cancer. This prospective analysis explored the effect of prediagnostic mammographic density among 607 breast cancer cases diagnosed within the Hawaii component of the Multiethnic Cohort (MEC).MethodsFemale MEC participants, aged ≥ 50 years at cohort entry, diagnosed with primary invasive breast cancer, and enrolled in a mammographic density case-control study were part of this analysis. At cohort entry, anthropometric and demographic information was collected by questionnaire. Tumor characteristics and vital status were available through linkage with the Hawaii Tumor Registry. Multiple digitized prediagnostic mammograms were assessed for mammographic density using a computer-assisted method. Cox proportional hazards regression was applied to examine the effect of mammographic density on breast cancer survival while adjusting for relevant covariates.ResultsOf the 607 cases, 125 were diagnosed as in situ, 380 as localized, and 100 as regional/distant stage. After a mean follow-up time of 12.9 years, 27 deaths from breast cancer and 100 deaths from other causes had occurred; 71 second breast cancer primaries were diagnosed. In an overall model, mammographic density was not associated with breast cancer-specific survival (HR = 0.95 per 10%; 95%CI: 0.79-1.15), but the interaction with radiotherapy was highly significant (p = 0.006). In stratified models, percent density was associated with a reduced risk of dying from breast cancer (HR = 0.77; 95%CI: 0.60-0.99; p = 0.04) in women who had received radiation, but with an elevated risk (HR = 1.46; 95% CI: 1.00-2.14; p = 0.05) in patients who had not received radiation. High breast density predicted a borderline increase in risk for a second primary (HR = 1.72; 95% CI: 0.88-2.55; p = 0.15).ConclusionsAssessing mammographic density in women with breast cancer may identify women with a poorer prognosis and provide them with radiotherapy to improve outcomes.

Leptin, Adiponectin, and Obesity among Caucasian and Asian Women

Ethnic differences in adipose tissue distribution may contribute to different chronic disease risks across ethnic groups, and adipokines may mediate the risk. In a cross-sectional study, we examined ethnic differences in adipokines and inflammatory markers as related to body mass index (BMI) among 183 premenopausal women with Caucasian and Asian ancestry. General linear models were used to estimate adjusted mean levels of leptin, adiponectin, interleukin-6, and C-reactive protein (CRP). Asian women had significantly lower serum levels of leptin, adiponectin, and CRP than Caucasian participants (P ≤ .01) across all levels of BMI. Among overweight and obese women, Asians showed a stronger association of CRP with leptin (β = 1.34 versus β = 0.64) and with adiponectin (β = −0.95 versus β = −0.75) than Caucasians. Compared to Caucasians of similar BMI, Asians may experience a higher chronic disease risk due to lower levels of adiponectin despite their lower levels of leptin.

Estrogen Levels in Nipple Aspirate Fluid and Serum during a Randomized Soy Trial

Background: On the basis of hypothesized protective effect, we examined the effect of soy foods on estrogens in nipple aspirate fluid (NAF) and serum, possible indicators of breast cancer risk. Methods: In a crossover design, we randomized 96 women who produced 10 μL or more NAF to a high- or low-soy diet for 6 months. During the high-soy diet, participants consumed 2 soy servings of soy milk, tofu, or soy nuts (∼50 mg of isoflavones per day); during the low-soy diet, they maintained their usual diet. Six NAF samples were obtained using a FirstCyte aspirator. Estradiol (E2) and estrone sulfate (E1S) were assessed in NAF and estrone (E1) in serum only, using highly sensitive radioimmunoassays. Mixed-effects regression models accounting for repeated measures and left-censoring limits were applied. Results: Mean E2 and E1S were lower during the high-soy than the low-soy diet (113 vs. 313 pg/mL and 46 vs. 68 ng/mL, respectively) without reaching significance (P = 0.07); the interaction between group and diet was not significant. There was no effect of the soy treatment on serum levels of E2 (P = 0.76), E1 (P = 0.86), or E1S (P = 0.56). Within individuals, NAF and serum levels of E2 (rs = 0.37; P < 0.001) but not of E1S (rs = 0.004; P = 0.97) were correlated. E2 and E1S in NAF and serum were strongly associated (rs = 0.78 and rs = 0.48; P < 0.001). Conclusion: Soy foods in amounts consumed by Asians did not significantly modify estrogen levels in NAF and serum. Impact: The trend toward lower estrogen levels in NAF during the high-soy diet counters concerns about adverse effects of soy foods on breast cancer risk. Cancer Epidemiol Biomarkers Prev; 20(9); 1815–21. ©2011 AACR.

The Volume of Nipple Aspirate Fluid Is Not Affected by 6 Months of Treatment with Soy Foods in Premenopausal Women

Based on the hypothesis that soy food consumption may influence breast tissue activity, we examined its effect on the production of nipple aspirate fluid (NAF), a possible indicator of breast cancer risk. Of 310 premenopausal women screened, 112 (36%) produced at least 10 μL of NAF, the minimum for study participation. In a crossover design, we randomized 96 women to 2 groups who, in reverse order, consumed a high-soy diet with 2 soy servings/d (1 serving = 177 mL soy milk, 126 g tofu, or 23 g soy nuts) and a low-soy diet with <3 servings/wk of soy for 6 mo each separated by a 1-mo washout period. During each diet period, 3 NAF samples were obtained (baseline and 3 and 6 mo) using a FirstCyte Aspirator and 4 urine samples (baseline and 1, 3, and 6 mo) were analyzed for isoflavonoids by liquid chromatography tandem MS. Adherence to the study protocol according to 24-h dietary recalls and urinary isoflavonoid excretion was high. The drop-out rate was 15% (n = 14); 82 women completed the intervention. The 2 groups produced similar mean NAF volumes at baseline (P = 0.95) but differed in age and previous soy intake and in their response to the intervention (P = 0.03). In both groups, NAF volume decreased during the first 3 mo of the high-soy diet period and returned to baseline at 6 mo, but there was no effect of the high-soy diet on NAF volume (P = 0.50 for diet; P-interaction = 0.21 for diet with time). Contrary to an earlier report, soy foods in amounts consumed by Asians did not increase breast tissue activity as assessed by NAF volume.

Metabolic syndrome and mammographic density: The Study of Women's Health Across the Nation

The metabolic syndrome (MetS) is associated with an increase in breast cancer risk. In our study, we evaluated whether the MetS was associated with an increase in percent mammographic density (MD), a breast cancer risk factor. We used linear regression and mixed models to examine the cross‐sectional and longitudinal associations of the MetS and components of the MetS to percent MD in 790 premenopausal and early perimenopausal women enrolled in the Study of Womens Health Across the Nation (SWAN). In cross‐sectional analyses adjusted for body mass index (BMI), modest inverse associations were observed between percent MD and the MetS [β = −2.5, standard error (SE) = 1.9, p = 0.19], abdominal adiposity (β = −4.8, SE = 1.9, p = 0.01) and raised glucose (β = −3.7, SE = 2.4, p = 0.12). In longitudinal models adjusted for covariates including age and BMI, abdominal adiposity (β = 0.34, SE = 0.17, p = 0.05) was significantly positively associated with slower annual decline in percent MD with time. In conclusion, our results do not support the hypothesis that the MetS increases breast cancer risk via a mechanism reflected by an increase in percent MD.

Mammographic density and risk of breast cancer by adiposity: An analysis of four case-control studies

The association of mammographic breast density with breast cancer risk may vary by adiposity. To examine effect modification by body mass index (BMI), the authors standardized mammographic density data from four case‐control studies (1994–2002) conducted in California, Hawaii and Minnesota and Gifu, Japan. The 1,699 cases and 2,422 controls included 45% Caucasians, 40% Asians and 9% African‐Americans. Using ethnic‐specific BMI cut points, 34% were classified as overweight and 19% as obese. A single reader assessed density from mammographic images using a computer‐assisted method. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) while adjusting for potential confounders. Modest heterogeneity in the relation between percent density and breast cancer risk across studies was observed (pheterogeneity = 0.08). Cases had a greater age‐adjusted mean percent density than controls: 31.7% versus 28.5%, respectively (p <0.001). Relative to <20 percent density, the ORs for >35 were similar across BMI groups whereas the OR for 20‐35 was slightly higher in overweight (OR = 1.69, 95% CI: 1.28, 2.24) and obese (OR = 1.62, 95% CI: 1.12, 2.33) than in normal weight women (OR = 1.49, 95% CI: 1.11, 2.01). Furthermore, limited evidence of effect modification by BMI of the OR per 10% increase in percent density (pinteraction = 0.06) was observed, including subgroup analyses by menopausal status and in analyses that excluded women at the extremes of the BMI scale. Our findings indicate little, if any, modification by BMI of the effects of breast density on breast cancer risk.