Modifiable Factors and Incident Gout Across Ethnicity Within a Large Multiethnic Cohort of Older Adults.

OBJECTIVE: Gout disproportionately affects older Pacific Islander and Black populations relative to White populations. However, the ethnic-specific determinants remain understudied within these groups, as well as within other ethnicities. We examined gout incidence and associations with behavioral factors, including diet, alcohol, and smoking, within a large multiethnic population of older adults from the Multiethnic Cohort Study, which linked prospective cohort data to Medicare gout claims between 1999-2016. METHODS: Using samples of Black (n = 12,370), Native Hawaiian (n = 6459), Japanese (n = 29,830), Latino (n = 17,538), and White (n = 26,067) participants, we conducted multiple Cox regressions, producing hazard ratios (HRs) and 95% CIs. RESULTS: Relative to White individuals, Native Hawaiians had the highest risk of gout (HR 2.21, 95% CI 2.06-2.38), followed successively by Black and Japanese participants, whereas Latino individuals had a lower risk of gout (HR 0.78, 95% CI 0.73-0.83). Alcohol use was associated with an increased risk, with significantly greater effects observed among Japanese participants drinking ≥ 3 drinks per day (HR 1.46, 95% CI 1.27-1.66), or > 5 beers per week (HR 1.29, 95% CI 1.17-1.43), compared to White individuals (Pinteraction < 0.001). Former smokers with ≥ 20 pack-years had an increased risk (HR 1.14, 95% CI 1.06-1.22). Higher dietary quality was associated with a decreased gout risk, with the largest effect observed among White participants (HRQ5vsQ1 0.84, 95% CI 0.79-0.90), whereas vitamin C was weakly associated with a decreased risk of gout only among Japanese individuals (HR 0.91, 95% CI 0.85-0.98). CONCLUSION: Overall, notable ethnic differences were observed in both gout risk and associations with modifiable behavioral factors. Our findings offer crucial insights that may improve precision in preventing and managing gout.

Association of serum levels of antioxidant micronutrients with mortality in US adults: National Health and Nutrition Examination Survey 1999-2002.

OBJECTIVE: To examine associations between serum antioxidant levels and mortality (all-cause, cancer and CVD) among US adults. DESIGN: We examined the risk of death from all-cause and cause-specific mortality associated with serum antioxidant (vitamin E and carotenoids) and vitamin A levels using Cox regression models to estimate hazards ratios (HR) and 95 % CI. SETTING: The National Health and Nutrition Examination Survey (NHANES) 1999-2002 was followed up through 31 December 2015. PARTICIPANTS: The NHANES 1999-2002 cohort included 8758 participants aged ≥ 20 years. Serum carotenoid levels were only assessed for the 1999-2000 cycle. Therefore, sample size for each assessed antioxidant ranged from 4633 to 8758. RESULTS: Serum vitamin E level was positively associated with all-cause mortality (HR = 1·22, 95 % CI 1·04, 1·43, highest v. lowest quartile). No other antioxidants were associated with mortality in overall analysis. In race/ethnicity-specific analyses, high vitamin E and α-tocopherol levels were associated with increased risk of all-cause mortality among non-Hispanic Whites. Among non-Hispanic Blacks, serum α-tocopherol level was associated with decreased risk of cancer mortality (HR = 0·30, 95 % CI 0·12, 0·75, third v. first quartile) and total carotenoid levels with reduced risk of CVD mortality (HR = 0·26; 95 % CI 0·07, 0·97, second v. lowest quartile). Hispanics with high ß-carotene levels had reduced risk of CVD mortality. CONCLUSIONS: Serum antioxidant levels may be related to mortality; these associations may differ by race/ethnicity and appeared to be non-linear for all-cause and cause-specific mortality. Further studies are needed to confirm our results.

The Potential Physiological Role of γ-Tocopherol in Human Health: A Qualitative Review.

Chronic aging-related diseases result in the greatest burden to the health care system, yet there is little agreement on optimal levels of vitamins or the functional significance of many other dietary molecules in disease prevention. This review presents accumulated information regarding the role of γ-tocopherol in the prevention of nitrogen oxide-mediated damage and its impact on aging-related diseases. γ-Tocopherol is ubiquitous in the diet and levels appear to be physiologically regulated such that levels rise in response to inflammation and deficiencies in certain key vitamins. The unique antioxidant properties of γ-tocopherol, whereby DNA-damaging nitrogen dioxide is rapidly converted to nitric oxide, suggest a mechanistic justification for a functional role in the prevention of DNA damage over time. Data from cell, animal, and human studies indicate that γ-tocopherol appears to have significant beneficial effects, protecting cells from inflammatory damage; however, interpretation of epidemiologic studies is complex due to the paradoxical rise in levels of γ-tocopherol in response to known etiologic risk factors. Current knowledge of its antioxidant mechanism of action, apparent physiological regulation, and impact on various enzymatic pathways suggests γ-tocopherol may have a functional role in maintaining human health. Its utility as a biomarker and the consequences of its deficiency deserve further study.

Association of serum γ-tocopherol levels with mortality: the Multiethnic Cohort Study.

BACKGROUND/OBJECTIVES: γ-Tocopherol has unique properties that protect against nitrogen oxide-mediated cellular damage. To elucidate the potential role of γ-tocopherol in the aging process, we examined the associations of serum γ-tocopherol levels with all-cause and cause-specific mortality. SUBJECTS/METHODS: Among participants in the biorepository subcohort of the Multiethnic Cohort Study, pre-cancer diagnostic serum γ-tocopherol levels were measured in a subset of 3904 men and 4461 women. Of these, 22.7% of men and 13.5% of women died during a mean follow-up time of 9.6 ± 2.6 years. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for mortality associated with γ-tocopherol were estimated by Cox proportional hazards regression. RESULTS: Positive associations of serum γ-tocopherol with all-cause, cancer, and cardiovascular disease mortality (CVD) (Ptrend < 0.05) were detected after adjusting for age, race/ethnicity, and serum cholesterol levels. The respective HRs (95% CIs) for the highest versus the lowest sex-specific γ-tocopherol quartile were 1.43 (1.17-1.74), 1.79 (1.22-2.64), and 1.52 (1.10-2.11) for men and 1.58 (1.25-2.00), 1.59 (1.05-2.41), and 1.59 (1.07-2.37) for women. Associations remained significant for all-cause mortality among women after further adjusting for smoking variables and history of cancer, CVD, diabetes, and hypertension at cohort entry (highest vs. lowest γ-tocopherol quartile: HR = 1.38; 95% CI = 1.08-1.75; Ptrend = 0.005). Overall, associations with all-cause mortality were consistent across race/ethnicity and were significant in three of ten sex-specific racial/ethnic groups in the fully adjusted models, with no interactions between ethnicity and γ-tocopherol. CONCLUSIONS: The positive association between γ-tocopherol and mortality suggests a potential physiological role for γ-tocopherol in response to pathological conditions.

Association Between Occupational Exposure to Pesticides and Cardiovascular Disease Incidence: The Kuakini Honolulu Heart Program.

Background Previously, Kuakini Honolulu Heart Program researchers reported that occupational exposure to pesticides was significantly associated with total mortality. The current study examines occupational exposure to pesticides in relation to incident cardiovascular disease, defined as coronary heart disease or cerebrovascular accident. Methods and Results With the Occupational Safety Health Administration exposure scale used as an estimate of exposure, statistical analyses were performed on a cohort of 7557 Japanese-American men from the Kuakini Honolulu Heart Program. Hazard ratios for cardiovascular disease incidence were calculated for various levels of pesticide exposure using Cox proportional hazards models. In the first 10 years of follow-up, a positive association was observed between age-adjusted cardiovascular disease incidence and high levels of pesticide exposure (hazard ratio=1.46, 95% CI=1.10-1.95, P=0.009). This relationship remained significant after adjustment for other cardiovascular disease risk factors (hazard ratio=1.42, 95% CI=1.05-1.92, P=0.021). No significant association for coronary heart disease or cerebrovascular accident incidence with pesticide exposure was observed when examined separately, possibly due to a smaller number of events. Conclusions These findings suggest that occupational exposure to pesticides may play a role in the development of cardiovascular diseases. The results are novel, as the association between occupational exposure to pesticides and cardiovascular disease incidence has not been examined previously in this unique cohort.

Late life insulin resistance and Alzheimer's disease and dementia: The Kuakini Honolulu heart program.

INTRODUCTION: Recent findings outline negative effects of brain insulin signaling on memory due to hyperinsulinemia. We investigated the association between insulin resistance (IR) with AD and dementia. METHODS: Later life Japanese men (N = 1544, mean age = 79.9 years) with normal cognitive function were followed from exam 4 to 5 of the Kuakini Honolulu Asia Aging Study. Subjects underwent physical exams, blood draws, and neuropsychological testing. IR status was determined at exam 4 using the McAuley and HOMA indices. Subjects with prevalent diabetes and dementia were excluded. Incident dementia and AD cases were determined at exam 5. RESULTS: IR was associated with decreased odds of AD and dementia using both IR indices. Carriers of the APOE ε4 allele had 15% increased odds of AD and dementia. DISCUSSION: Our findings provide insight regarding possible inverse relationship between IR and AD in elderly Japanese men, and support biologic studies showing short term hyperinsulinemia improves memory and cognitive function.

Diet quality measured by four a priori-defined diet quality indices is associated with lipid-soluble micronutrients in the Multiethnic Cohort Study (MEC).

BACKGROUND/OBJECTIVES: This study examined the long-term relation of lipid-soluble micronutrients with diet quality as assessed by four a priori-defined dietary patterns. SUBJECTS/METHODS: In a prospective design, nutritional biomarkers (carotenoids, tocopherols, retinol, and coenzyme Q10) were measured using a validated HPLC-based assay. General linear models were applied to obtain covariate-adjusted means of biomarkers for tertiles of four a priori diet quality indices: Healthy Eating Index (HEI) 2010, Alternative HEI (AHEI) 2010, Alternate Mediterranean Diet Score (aMED), and Dietary Approaches to Stop Hypertension (DASH). For a subcohort of 8367 participants within the Multiethnic Cohort (MEC), diet was assessed by a validated quantitative food frequency questionnaire in 1993-96 and serum was collected in 2001-06. RESULTS: Participants with the highest diet-quality scores had significantly higher serum concentrations of all carotenoids, total tocopherols, and α-tocopherol, whereas γ-tocopherol was inversely associated with diet quality. Adjusted means for the lowest vs. highest tertile of HEI 2010 were 1.2 vs. 1.5 mg/L for total carotenoids, 11.4 vs. 12.3 mg/L for total tocopherols, and 1.9 vs. 1.6 mg/L for γ-tocopherol (ptrend < 0.0001). The associations for the other dietary indices were similar; no indication for sex and ethnic differences was detected. Vegetable and fruit components were major predictors of most circulating micronutrients, but most other components were also associated. CONCLUSIONS: Higher diet-quality scores measured by four a priori diet quality indices were significantly associated higher serum concentrations of carotenoids and α-tocopherol, whereas γ-tocopherol was inversely associated with diet quality.

Dietary Red and Processed Meat Intake and Markers of Adiposity and Inflammation: The Multiethnic Cohort Study.

OBJECTIVE: The potential influence of dietary factors on inflammation is important for cancer prevention. Utilizing data from control participants (312 men, 911 women) in 2 nested case-control studies of cancer within the Multiethnic Cohort, we examined the associations of red and processed meat intake with serum levels of leptin, adiponectin, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 and the mediator effect of body mass index (BMI) on the above associations (if present). METHODS: Multivariable linear models were applied to assess the association between red and processed meat intake at cohort entry and serum biomarker levels measured 9.1 years later after adjusting for covariates and to determine the mediator effect of BMI. RESULTS: Overall red and processed meat intake was positively associated with serum leptin levels in men (ß = 0.180, p = 0.0004) and women (ß = 0.167, p < 0.0001). In women, higher red and processed meat consumption was significantly associated with higher CRP (ß = 0.069, p = 0.03) and lower adiponectin levels (ß = -0.082, p = 0.005). In mediation analyses with red and processed meat intake and BMI as predictors, the associations of red and processed meat with biomarkers decreased substantially (as indicated by percentage change in effect: leptin in men, 13.4%; leptin in women, 13.7%; adiponectin in women, -4.7%; CRP in women, 7.4%) and were no longer significant (p > 0.05), whereas BMI remained significantly associated with serum leptin (men: ß = 3.209, p < 0.0001; women: ß = 2.891, p < 0.0001), adiponectin (women: ß = -1.085, p < 0.0001), and CRP (women: ß = 1.581, p < 0.0001). CONCLUSION: The current data suggest that the amount of excess body weight or the degree of adiposity may mediate the relations between dietary red and processed meat intake and serum biomarkers associated with obesity and inflammation.

Depression, Anxiety, and Pharmacotherapy Around the Time of Pregnancy in Hawaii.

BACKGROUND: Depression and anxiety are common conditions among pregnant and postpartum women, but population-based information is lacking on treatments and help-seeking behaviors. PURPOSE: This study described the prevalence of depression, anxiety, pharmaceutical treatment, and help-seeking behaviors among a multiethnic population of women with recent live births in Hawaii. METHOD: Hawaii Pregnancy Risk Assessment Monitoring System data from 4735 respondents were weighted to be representative of all pregnancies resulting in live births in Hawaii in 2009-2011 and were used to estimate the prevalence of several indicators related to anxiety and depression before, during, and after pregnancy among women with recent live births. RESULTS: Of Hawaii women with live births in 2009-2011, 7.3 % reported visiting a healthcare worker to be checked or treated for depression or anxiety in the year before their most recent pregnancy, 4.9 % reported having depression in the 3 months before pregnancy, 5.9 % reported having anxiety in the same period, 9.1 % screened positive for postpartum depression, and 6.9 % reported asking a doctor, nurse, or other healthcare worker for help for anxiety postpartum. The prevalence of antianxiety and antidepressant prescription drug use was 2.3 % in the month before pregnancy and 1.4 % during pregnancy. Hawaii had lower prevalence of pre-pregnancy depression, anxiety, and depression/anxiety health visits than other US states. Pre-pregnancy depression and anxiety and postpartum anxiety help-seeking behaviors differed significantly by race/ethnicity. CONCLUSION: Depression and anxiety are common among pregnant and postpartum women in Hawaii. More research could better inform heath care professionals and patients of the treatment options available and their potential risks and benefits.

Adherence to cancer prevention recommendations and antioxidant and inflammatory status in premenopausal women.

For cancer prevention, the World Cancer Research Fund and American Institute for Cancer Research (WCRF/AICR) emphasise recommendations to improve individual behaviour, including avoidance of tobacco products, maintaining a lean body mass, participating in physical activity, consuming a plant-based diet, and minimising the consumption of energy-dense foods, such as sodas, red and processed meats and alcohol. In the present study of 275 healthy premenopausal women, we explored the association of adherence scores with levels of three biomarkers of antioxidant and inflammation status: serum C-reactive protein (CRP), serum γ-tocopherol and urinary F2-isoprostane. The statistical analysis applied linear regression across categories of adherence to WCRF/AICR recommendations. Overall, seventy-two women were classified as low ( ≤ 4), 150 as moderate (5-6), and fifty-three as high adherers ( ≥ 7). The unadjusted means for CRP were 2.7, 2.0 and 1.7 mg/l for low, moderate and high adherers (P trend= 0.03); this association was strengthened after adjustment for confounders (P trend= 0.006). The respective values for serum γ-tocopherol were 1.97, 1.63 and 1.45 µg/ml (P trend= 0.02 before and P trend= 0.03 after adjustment). Only for urinary F2-isoprostane, the lower values in high adherers (16.0, 14.5, and 13.3 ng/ml) did not reach statistical significance (P trend= 0.18). In an analysis by BMI, overweight and obese women had higher biomarker levels than normal weight women; the trend was significant for CRP (P trend< 0.001) and γ-tocopherol (P trend= 0.003) but not for F2-isoprostane (P trend= 0.14). These findings suggest that both adherence to the WCRF/AICR guidelines and normal BMI status are associated with lower levels of biomarkers that indicate oxidative stress and inflammation.

Pilot study for the establishment of biomarkers for radiation damage after computed tomography in children.

Computed tomography (CT) is an imaging modality that exposes patients to ionizing radiation (IR). We review and report findings from our pilot study evaluating whether blood markers are altered in 17 children undergoing medically indicated CT scans. Blood was drawn before ('pre-CT') and 1 hour after ('post-CT' CT scans. Plasma carotenoids, tocopherols, Q10, ascorbic acid (AA) and uric acid (UA) were analyzed by RP-HPLC with diode-array and electrochemical detection. Dehydroascorbic acid (DHAA) was calculated by subtraction from total AA. Total antioxidant capacity (TAC) was measured using the ORAC assay. Cytokines were quantified using a multiplex immunoassay. γ-H2AX foci were visualized using immunofluorescence. Mean pre- and post-CT changes were compared using t-tests; P-levels < .05 indicated significance. All major plasma lipid soluble antioxidant levels were lower post- vs pre-CT (P < .05) possibly from the scavenging of free radicals formed by CT-induced IR. Average AA levels increased (134%) while DHAA levels were decreased (29%) post-CT, probably due to intracellular recycling of AA from DHAA. TAC levels in lipophilic and hydrophilic extracts were unchanged, suggesting that other antioxidants may have assisted in free radical quenching, which would corroborate their lower concentrations post-CT. Cytokine levels were unchanged and dose-dependent increases in γ-H2AX foci, a measure of double strand DNA breaks, were observed (P = .046, n = 3 children). Our results suggest that CT-derived IR can influence the antioxidant system and may elicit detrimental responses on the cellular level of young children. When possible and if appropriate non-IR based techniques such as ultrasound or magnetic resonance imaging should be used.

Serum coenzyme Q10, α-tocopherol, γ-tocopherol, and C-reactive protein levels and body mass index in adolescent and premenopausal females.

OBJECTIVE: Lipid-soluble antioxidants are associated with a lower incidence for many chronic diseases of aging, possibly by preventing damage from chronic inflammation. In the current study, we compared serum levels of coenzyme Q10 (CoQ10), α-tocopherol, γ-tocopherol, and C-reactive protein (CRP) between adolescent girls and premenopausal women to assess changes from childhood to midlife. METHODS: Baseline serum CoQ10, α-tocopherol, γ-tocopherol, and CRP levels were measured in 207 girls (13-19 years) and 183 premenopausal women (34-47 years) using standard methods and the 2 age groups were compared by t test. The influence of age, body mass index (BMI), and race/ethnicity and interaction effects on serum values were assessed using analysis of covariance. Pearson correlation coefficients were used to assess associations between pairs of lipid micronutrients. RESULTS: Overall, adolescent girls had significantly lower mean serum CoQ10, α-tocopherol, γ-tocopherol, and CRP levels relative to premenopausal women (CoQ10: 376 vs 544 ng/mL, p < 0.0001; α-tocopherol: 6.9 vs 13.5 µg/mL, p < 0.0001; γ-tocopherol: 1.3 vs 1.7 µg/mL, p < 0.0001; CRP: 1.29 vs 2.13 mg/L, p < 0.0001). The differences in CoQ10 and tocopherols remained significant after adjustment for BMI and race/ethnicity. CoQ10 was significantly and positively correlated to α- and γ-tocopherol, and BMI was positively associated with CRP and γ-tocopherol in both groups. CONCLUSIONS: Lower serum CoQ10, α-tocopherol, γ-tocopherol, and CRP levels in adolescent girls compared to women suggests that adolescents may have a reduced need for antioxidants possibly due to their lower BMI and inflammatory status as indicated by CRP.

In vivo changes in plasma coenzyme Q10, carotenoid, tocopherol, and retinol levels in children after computer tomography.

BACKGROUND: Low dose X-irradiation (IR) from computer tomography (CT) can generate free radicals, which can damage biologically relevant molecules and ultimately lead to cancer. These effects are especially concerning for children owing to their higher radiosensitivity and longer life expectancy than adults. The lipid phase micronutrients (LPM) coenzyme Q10, carotenoids, E vitamers, and vitamin A are potent radical scavengers that can act as intracellular antioxidants. METHODS: We investigated changes in circulating levels of these LPM in 17 children (0.25-6 y) undergoing medically indicated CT scans involving relatively low IR doses. Blood was drawn before and 1h after CT scans and analyzed using HPLC with electrochemical and UV/VIS detection. RESULTS: We found significant decreases (p<0.05) in post-CT plasma levels in several LPM which suggests that these LPM can serve as biodosimeters and may protect against damage from IR during clinical procedures such as CT. The strongest predictors for pre- to post-CT changes for many LPM were their baseline levels. CONCLUSION: Future larger studies are warranted to confirm our findings and to test whether high circulating antioxidant levels protect against IR damage in vivo with an ultimate goal of establishing prophylactic modalities for CT-induced IR damage.

Plasma 25-hydroxyvitamin D3 is associated with decreased risk of postmenopausal breast cancer in whites: a nested case-control study in the multiethnic cohort study.

BACKGROUND: Higher sunlight exposure is correlated with lower incidence of breast cancer in ecological studies, but findings from prospective studies regarding the association of circulating levels of vitamin D with the risk of breast cancer have been null. The objective of this study was to examine the relation between plasma levels of vitamin D and the risk of postmenopausal breast cancer. METHODS: We conducted a nested case-control study within the Multiethnic Cohort Study of five race/ethnic groups (white, African-American, Native Hawaiian, Japanese, and Latino) from Hawaii and Los Angeles between 2001 and 2006. Pre-diagnostic plasma levels of 25-hydroxyvitamin D2 [25(OH)D2], 25-hydroxyvitamin D3 [25(OH)D3] and 25(OH)D (sum of 25(OH)D2 and 25(OH)D3) were examined among 707 postmenopausal breast cancer cases and matched controls. RESULTS: Using conditional logistic regression models, 20 ng/mL increases of plasma 25(OH)D3 (odds ratio (OR) 0.28; 95% confidence interval (CI) 0.14-0.56) and 25(OH)D (OR 0.43; 95% CI 0.23-0.80) were inversely associated with breast cancer risk among white women, but not among women in other race/ethnic groups. Using two-segmented, piecewise-linear logistic regression models, the change-points of the ORs, either for 25(OH)D3 or for 25(OH)D, were detected as 20 ng/mL among whites. CONCLUSIONS: Circulating 25(OH)D3 and 25(OH)D were associated with a reduced risk of postmenopausal breast cancer among whites, but not in other ethnic groups, who reside in low latitude regions.

Prediagnostic serum tocopherol levels and the risk of non-hodgkin lymphoma: the multiethnic cohort.

BACKGROUND: Compromised immunity and chronic inflammation are thought to contribute to the development of non-Hodgkin lymphoma (NHL). Because tocopherols protect cells through antioxidant mechanisms, they may play a role in NHL etiology. METHODS: This nested case-control study within the Multiethnic Cohort examined the association of prediagnostic serum tocopherols levels measured in 271 NHL cases and 538 matched controls by high-pressure liquid chromatography/photodiode array detection with NHL risk. Conditional logistic regression was used to calculate ORs and 95% confidence intervals (CI). RESULTS: We observed U-shaped associations with NHL for total and α-tocopherols [Ptrend < 0.01 for polynomial terms (3 df)]. The ORs (95% CI) for total tocopherols, which consisted primarily of α-tocopherol, were 0.41 (0.25-0.68), 0.52 (0.32-0.85), 0.39 (0.23-0.65), and 0.78 (0.47-1.29) for the second to fifth quintiles as compared with the first. The risk estimates were similar for α-tocopherol but nonsignificant for ß- and γ-tocopherol combined and for γ-tocopherol. Adjustment for serum lipids strengthened the nonlinear associations for total and α-tocopherols. Serum total tocopherol levels were higher for vitamin E supplement users at cohort entry than nonusers (21.32 ± 9.04 vs. 17.72 ± 7.43 µg/mL; P < 0.0001), but supplement use was not associated with NHL risk. No heterogeneity in risk estimates was detected by sex, ethnicity, vitamin E supplement use, or NHL subtype. CONCLUSIONS: Circulating tocopherols, at levels likely reflecting adequate dietary intakes, may be protective against NHL, whereas higher intakes from supplementation may not be beneficial. IMPACT: The association between serum tocopherol levels and NHL risk provides possible new insights into the etiology of NHL.

Effects of calcium and vitamin D supplementation on blood pressure and serum lipids and carotenoids: a randomized, double-blind, placebo-controlled, clinical trial.

PURPOSE: To estimate the effects of calcium or vitamin D supplementation or a combination of both on blood pressure and serum lipid and carotenoid levels. METHODS: Ninety-two colorectal adenoma patients were randomized in a pilot, double-blind, placebo-controlled clinical trial of supplemental vitamin D3 800 IU and elemental calcium 2.0 g (as calcium carbonate) alone or in combination in divided doses twice daily with meals over 6 months. RESULTS: Relative to placebo, mean serum triglycerides decreased 30% (P = .10) and 32% (P = .10) in the calcium and calcium plus vitamin D3 treatment groups, respectively. When the two calcium intervention groups were pooled and compared with the pooled noncalcium groups, the estimated supplemental calcium treatment effects were statistically significant for triglycerides (P = .04). Similar but nonstatistically significant decreases (5%-7%) were observed for serum total cholesterol levels. Mean systolic blood pressure increased 6% (P = .08) in the calcium group; otherwise, there were no appreciable changes in systolic or diastolic blood pressures in any active treatment group. Mean serum total carotenoid levels decreased 14% (P = .07) in the calcium and 9% (P = .10) in the calcium plus vitamin D3 groups. CONCLUSIONS: Our results suggest that supplemental calcium alone or combined with vitamin D3 but not vitamin D3 alone may reduce serum lipids and lipophilic micronutrients.

C-reactive protein, lipid-soluble micronutrients, and survival in colorectal cancer patients.

BACKGROUND: Identification of biomarkers associated with survival in patients with cancer is important for elucidating the underlying mechanisms of cancer progression and identifying possible interventions to reduce cancer morbidity and mortality. METHODS: Using stored patient plasma samples from a multiethnic population-based case-control study of invasive colorectal cancer, we measured posttreatment blood levels of C-reactive protein (CRP) and lipid-soluble micronutrients. Patients (n = 368) were followed after phlebotomy (mean of 8 years), during which time 47% died (25% colorectal cancer specific). HRs were estimated by Cox proportional hazards regression with adjustment for stage, age at diagnosis, ethnicity, sex, smoking status, and month of blood draw. RESULTS: A positive association with overall risk of death was observed for CRP [HR for highest vs. lowest quintile: 1.80; 95% confidence interval (CI), 1.07-3.04; Ptrend = 0.01], whereas inverse associations were generally observed for retinol and carotenoids (HRs for overall risk of death for the highest quintile ranging from 0.5-0.8); these associations were significant for retinol (Ptrend = 0.0002), α-carotene (Ptrend = 0.02), and total carotenoids (Ptrend = 0.02) and were generally consistent across subgroups (sex, ethnicity, cancer anatomical subtype, and stage). HRs for retinol and carotenoids were attenuated somewhat after adjustment for CRP. Similar trends for CRP were observed for colorectal cancer-specific deaths (HR for highest vs. lowest tertile: 2.06; 95% CI, 1.18-3.61; Ptrend = 0.01) as for deaths from all other causes (Pheterogeneity = 0.78). CONCLUSIONS: These observations are consistent with a direct relationship between circulating CRP and overall survival among patients with colorectal cancer. IMPACT: These results, if reproduced, suggest that reduction of inflammation should be explored as a potential complementary treatment strategy.

Prediagnostic leptin, adiponectin, C-reactive protein, and the risk of postmenopausal breast cancer.

Obesity has been associated with an increased risk of postmenopausal breast cancer. Adipokines and systemic inflammation have been hypothesized to underlie this association. In a case-control study nested within the Multiethnic Cohort, conditional logistic regression was used to calculate the ORs and 95% confidence intervals (CI) for postmenopausal breast cancer associated with prediagnostic levels of serum leptin, adiponectin, the leptin:adiponectin ratio, and C-reactive protein (CRP). The 706 cases and 706 controls were matched on ethnicity, location (Hawaii or Los Angeles), birth year, date and time of blood draw, hours fasting before blood draw, and hormone replacement therapy use at blood draw. Higher circulating levels of leptin [ORQ4 vs. Q1, 1.94 (1.37-2.75); Ptrend ≤ 0.001), the leptin:adiponectin ratio [OR, 1.91 (1.36-2.68); Ptrend = 0.005], and CRP [OR, 1.41 (1.01-1.96); Ptrend = 0.014] were associated with an increased risk of postmenopausal breast cancer. The positive associations for these markers remained after adjustment for body mass index (BMI). No associations were detected for adiponectin. These data suggest that adipokines and systemic inflammation may be associated with the risk of postmenopausal breast cancer independently of BMI. Further prospective studies examining the role of adipokines and inflammatory processes in the etiology of postmenopausal breast cancer are warranted. Cancer Prev Res; 6(3); 188-95. ©2013 AACR.

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-1ß, 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.

Predicting total, abdominal, visceral and hepatic adiposity with circulating biomarkers in Caucasian and Japanese American women.

BACKGROUND: Characterization of abdominal and intra-abdominal fat requires imaging, and thus is not feasible in large epidemiologic studies. OBJECTIVE: We investigated whether biomarkers may complement anthropometry (body mass index [BMI], waist circumference [WC], and waist-hip ratio [WHR]) in predicting the size of the body fat compartments by analyzing blood biomarkers, including adipocytokines, insulin resistance markers, sex steroid hormones, lipids, liver enzymes and gastro-neuropeptides. METHODS: Fasting levels of 58 blood markers were analyzed in 60 healthy, Caucasian or Japanese American postmenopausal women who underwent anthropometric measurements, dual energy X-ray absorptiometry (DXA), and abdominal magnetic resonance imaging. Total, abdominal, visceral and hepatic adiposity were predicted based on anthropometry and the biomarkers using Random Forest models. RESULTS: Total body fat was well predicted by anthropometry alone (R(2) = 0.85), by the 5 best predictors from the biomarker model alone (leptin, leptin-adiponectin ratio [LAR], free estradiol, plasminogen activator inhibitor-1 [PAI1], alanine transaminase [ALT]; R(2) = 0.69), or by combining these 5 biomarkers with anthropometry (R(2) = 0.91). Abdominal adiposity (DXA trunk-to-periphery fat ratio) was better predicted by combining the two types of predictors (R(2) = 0.58) than by anthropometry alone (R(2) = 0.53) or the 5 best biomarkers alone (25(OH)-vitamin D(3), insulin-like growth factor binding protein-1 [IGFBP1], uric acid, soluble leptin receptor [sLEPR], Coenzyme Q10; R(2) = 0.35). Similarly, visceral fat was slightly better predicted by combining the predictors (R(2) = 0.68) than by anthropometry alone (R(2) = 0.65) or the 5 best biomarker predictors alone (leptin, C-reactive protein [CRP], LAR, lycopene, vitamin D(3); R(2) = 0.58). Percent liver fat was predicted better by the 5 best biomarker predictors (insulin, sex hormone binding globulin [SHBG], LAR, alpha-tocopherol, PAI1; R(2) = 0.42) or by combining the predictors (R(2) = 0.44) than by anthropometry alone (R(2) = 0.29). CONCLUSION: The predictive ability of anthropometry for body fat distribution may be enhanced by measuring a small number of biomarkers. Studies to replicate these data in men and other ethnic groups are warranted.