Arecoline in buccal cells reflects Areca nut dose.

Areca nut (AN) is a carcinogen; its chewing cessation is, therefore, of worldwide interest. However, cessation biomarkers are lacking. We sought to establish arecoline in chewers' buccal cells (BCs) as a biomarker for AN dose. Self-reported AN doses, expressed as the average AN load ("AANL"), the product of AN amount, chewing time, and chewing frequency, were correlated by regression analysis with chewers' BC arecoline, measured by liquid chromatography mass spectrometry. We then determined whether associations differed between Class 1 chewers (who consume AN alone or with slaked lime, leaf, and/or spices) and Class 2 chewers (who consume any combination of the aforementioned ingredients plus tobacco). Among the 103 chewers, 28 Class 1 and 39 Class 2 chewers had detectable arecoline levels, which were used for analyses. A linear regression of cube-root transformed AANL on equally transformed BC arecoline levels provided the best model fit; resulting slopes and corresponding correlation coefficients were 0.86 and 0.40 (p < 0.01) for all; 1.09 and 0.51 (p < 0.01) for Class 1 chewers; 0.35 and 0.17 (p = 0.29) for Class 2 chewers; and 0.94 and 0.45 (p < 0.01), and 0.79 and 0.37 (p = 0.08), respectively, for those who included or excluded lime. Relationships between AANL and BC arecoline levels were similar between chewers who included or excluded lime (p = 0.76), but less between chewing classes (p = 0.14). This provides confidence that BC arecoline can generally act as a reliable biomarker for AN dose, useful for estimating efficacy in AN cessation studies and population-based chewing assessments.

Associations between Plasma Tocopherols and Lung Cancer Risk: Results from the Southern Community Cohort Study.

BACKGROUND: Despite the various anticancer activities of tocopherols, little is known about tocopherols associated with lung cancer risk among low-income African Americans (AA) and European Americans (EA) who are disproportionately affected by the disease. METHODS: We conducted a nested case-control study that included 209 incident lung cancer cases and 406 matched controls within the Southern Community Cohort Study. Using biospecimens collected at cohort enrollment, plasma levels of α-, ß/γ-, δ-, and total-tocopherols were measured by high-performance liquid chromatography with photodiode array detection. Conditional logistic regression was used to estimate ORs and 95% confidence intervals (CI) for lung cancer risk after adjusting for potential confounders. Stratified analyses were also conducted. RESULTS: Plasma levels of total-tocopherols were inversely associated with lung cancer risk overall [OR (95% CI) for the highest vs. lowest tertile = 0.51 (0.30-0.90)]. The inverse association remained significant among EAs [0.20 (0.06-0.65)], men [0.43 (0.21-0.90)], current smokers [0.49 (0.26-0.93)], and cases diagnosed within 2 years of blood draw [0.36 (0.15-0.86)], though we did not find a significant risk reduction among AAs [0.75 (0.39-1.45)]. Notably, we found significant interactions between α-tocopherol and race after controlling the FDR to correct for multiple comparisons (Pinteraction = 0.02). CONCLUSIONS: Our results indicate that plasma total-tocopherols are inversely associated with lung cancer risk, but the association may differ across specific isomeric forms of tocopherols, race, or other individuals' characteristics. Further large-scale studies are warranted to confirm our findings. IMPACT: Recommendations on tocopherols for lung cancer prevention should take isomers, race, and smoking behaviors into consideration.

Association of Endocrine Disrupting Chemicals With the Metabolic Syndrome Among Women in the Multiethnic Cohort Study.

Metabolic syndrome (MetS) is associated with a high risk of cardiovascular disease, a leading cause of death among women. MetS is a diagnosis of at least 3 of the following: high blood pressure, high fasting glucose, high triglycerides, high waist circumference, and low high-density lipoprotein cholesterol. Epidemiological studies suggest that endocrine disrupting chemical (EDC) exposure is positively associated with individual components of MetS, but evidence of an association between EDCs and MetS remains inconsistent. In a cross-sectional analysis within the Multiethnic Cohort Study, we evaluated the association between 4 classes of urinary EDCs (bisphenol A [BPA], triclosan, parabens, and phthalates) and MetS among 1728 women. Multivariable logistic regression was used to estimate odds ratios and 95% CI for the association between tertiles of each EDC and MetS adjusting for age, body mass index (BMI), racial and ethnic group, and breast cancer status. Stratified analyses by race and ethnicity and BMI were conducted. MetS was identified in 519 (30.0%) women. We did not detect statistically significant associations of MetS with BPA, triclosan, or phthalate metabolite excretion. MetS was inversely associated with total parabens (Ptrend = .002). Although there were suggestive inverse associations between EDCs and MetS among Latino and African American women, and women with BMI < 30 kg/m2, there was no statistically significant heterogeneity in associations by race and ethnicity or BMI. These findings suggest an inverse association between parabens and MetS in larger multiethnic studies. Prospective analyses to investigate suggested differences in associations by race, ethnicity, and BMI are warranted.

The Betel Nut Intervention Trial (BENIT)-A Randomized Clinical Trial for Areca Nut and Betel Quid Cessation: Primary Outcomes.

BACKGROUND: Areca nut and betel quid (ANBQ) chewing is a widespread carcinogenic habit. The BENIT (ClinicalTrials-NCT02942745) is the first known randomized trial designed for ANBQ chewers. METHODS: We compared the intensive behavioral treatment intervention condition (IC) with the control condition (CC) in the BENIT and included a 5-stage early stopping rule. We report the primary analysis at stage 3. English-literate adults in Guam and Saipan who self-identified as ANBQ chewers with tobacco were enrolled between August 2016 and August 2020. IC participants (n = 88) received five in-person sessions over 22 days and a brochure containing quitting advice. CC participants (n = 88) received only the brochure. Participants were assessed at baseline and on day 22 of follow-up. Self-reported chewing status at day 22 was determined by a composite of two survey items with disparate wording and response options for cross-verification. RESULTS: Cessation rates were 38.6% (IC) and 9.1% (CC). Proportional hazards regression revealed a p = 0.0058, which met the Stage 3 criteria for significance, and an estimated reduction in ANBQ chewing for IC compared to the CC of 71% (95% CI: 41%-88%). CONCLUSIONS: Robust self-reported intervention effects at day 22 suggest that intensive cessation programs such as BENIT should be further developed and implemented on a larger scale.

Circulating 27-hydroxycholesterol, lipids, and steroid hormones in breast cancer risk: a nested case-control study of the Multiethnic Cohort Study.

BACKGROUND: Laboratory studies have indicated that a cholesterol metabolite and selective estrogen receptor modulator, 27-hydroxycholesterol (27HC), may be important in breast cancer etiology and explain associations between obesity and postmenopausal breast cancer risk. Epidemiologic evidence for 27HC in breast cancer risk is limited, particularly in multiethnic populations. METHODS: In a nested case-control study of 1470 breast cancer cases and 1470 matched controls within the Multiethnic Cohort Study, we examined associations of pre-diagnostic circulating 27HC with breast cancer risk among African American, Japanese American, Native Hawaiian, Latino, and non-Latino White postmenopausal females. We used multivariable logistic regression adjusted for age, education, parity, body mass index, and smoking status. Stratified analyses were conducted across racial and ethnic groups, hormone receptor (HR) status, and use of lipid-lowering drugs. We assessed interactions of 27HC with steroid hormones. RESULTS: 27HC levels were inversely related to breast cancer risk (odds ratio [OR] 0.80; 95% confidence interval [CI] 0.58, 1.12), but the association was not statistically significant in the full model. Directions of associations differed by racial and ethnic group. Results suggested an inverse association with HR-negative breast cancer (OR 0.46; 95% CI 0.20, 1.06). 27HC interacted with testosterone, but not estrone, on risk of breast cancer; 27HC was only inversely associated with risk among those with the highest levels of testosterone (OR 0.46; 95% CI 0.24, 0.86). CONCLUSION: This is the first US study to examine circulating 27HC and breast cancer risk and reports a weak inverse association that varies across racial and ethnic groups and testosterone level.

Particulate matter, traffic-related air pollutants, and circulating C-reactive protein levels: The Multiethnic Cohort Study.

Inhaled particles and gases can harm health by promoting chronic inflammation in the body. Few studies have investigated the relationship between outdoor air pollution and inflammation by race and ethnicity, socioeconomic status, and lifestyle risk factors. We examined associations of particulate matter (PM) and other markers of traffic-related air pollution with circulating levels of C-reactive protein (CRP), a biomarker of systemic inflammation. CRP was measured from blood samples obtained in 1994-2016 from 7,860 California residents participating in the Multiethnic Cohort (MEC) Study. Exposure to PM (aerodynamic diameter ≤2.5 µm [PM2.5], ≤10 µm [PM10], and between 2.5 and 10 µm [PM10-2.5]), nitrogen oxides (NOx, including nitrogen dioxide [NO2]), carbon monoxide (CO), ground-level ozone (O3), and benzene averaged over one or twelve months before blood draw were estimated based on participants' addresses. Percent change in geometric mean CRP levels and 95% confidence intervals (CI) per standard concentration increase of each pollutant were estimated using multivariable generalized linear regression. Among 4,305 females (55%) and 3,555 males (45%) (mean age 68.1 [SD 7.5] years at blood draw), CRP levels increased with 12-month exposure to PM10 (11.0%, 95% CI: 4.2%, 18.2% per 10 µg/m3), PM10-2.5 (12.4%, 95% CI: 1.4%, 24.5% per 10 µg/m3), NOx (10.4%, 95% CI: 2.2%, 19.2% per 50 ppb), and benzene (2.9%, 95% CI: 1.1%, 4.6% per 1 ppb). In subgroup analyses, these associations were observed in Latino participants, those who lived in low socioeconomic neighborhoods, overweight or obese participants, and never or former smokers. No consistent patterns were found for 1-month pollutant exposures. This investigation identified associations of primarily traffic-related air pollutants, including PM, NOx, and benzene, with CRP in a multiethnic population. The diversity of the MEC across demographic, socioeconomic, and lifestyle factors allowed us to explore the generalizability of the effects of air pollution on inflammation across subgroups.

Genome-wide association study of abdominal MRI-measured visceral fat: The multiethnic cohort adiposity phenotype study.

Few studies have explored the genetic underpinnings of intra-abdominal visceral fat deposition, which varies substantially by sex and race/ethnicity. Among 1,787 participants in the Multiethnic Cohort (MEC)-Adiposity Phenotype Study (MEC-APS), we conducted a genome-wide association study (GWAS) of the percent visceral adiposity tissue (VAT) area out of the overall abdominal area, averaged across L1-L5 (%VAT), measured by abdominal magnetic resonance imaging (MRI). A genome-wide significant signal was found on chromosome 2q14.3 in the sex-combined GWAS (lead variant rs79837492: Beta per effect allele = -4.76; P = 2.62 × 10-8) and in the male-only GWAS (lead variant rs2968545: (Beta = -6.50; P = 1.09 × 10-9), and one suggestive variant was found at 13q12.11 in the female-only GWAS (rs79926925: Beta = 6.95; P = 8.15 × 10-8). The negatively associated variants were most common in European Americans (T allele of rs79837492; 5%) and African Americans (C allele of rs2968545; 5%) and not observed in Japanese Americans, whereas the positively associated variant was most common in Japanese Americans (C allele of rs79926925, 5%), which was all consistent with the racial/ethnic %VAT differences. In a validation step among UK Biobank participants (N = 23,699 of mainly British and Irish ancestry) with MRI-based VAT volume, both rs79837492 (Beta = -0.026, P = 0.019) and rs2968545 (Beta = -0.028, P = 0.010) were significantly associated in men only (n = 11,524). In the MEC-APS, the association between rs79926925 and plasma sex hormone binding globulin levels reached statistical significance in females, but not in males, with adjustment for total adiposity (Beta = -0.24; P = 0.028), on the log scale. Rs79837492 and rs2968545 are located in intron 5 of CNTNAP5, and rs79926925, in an intergenic region between GJB6 and CRYL1. These novel findings differing by sex and racial/ethnic group warrant replication in additional diverse studies with direct visceral fat measurements.

Salivary Areca and tobacco alkaloids for bioverification in the Betel Nut Intervention Trial.

BACKGROUND: The Betel Nut Intervention Trial (BENIT) is the first known randomized controlled intervention trial designed to help minority Pacific Islanders in Guam and Saipan quit chewing the carcinogenic Areca catechu nut (AN). We report the BENIT's saliva bioverification results against the self-reported chewing status ("quitter" or "chewer") at day 22 follow-up. MATERIAL AND METHODS: AN-specific (arecoline, arecaidine, guvacoline, and guvacine) and tobacco-specific (nicotine, cotinine, and hydroxycotinine) alkaloids were analyzed in saliva from 176 BENIT participants by an established and sensitive liquid chromatography mass spectrometry-based assay. RESULTS: The combined four AN alkaloid levels decreased from baseline in quitters (n = 50) and chewers (n = 108) by 32% and 9%, respectively. In quitters, decreases were significant for arecoline (p = 0.044)-the most prominent AN alkaloid, along with arecaidine (p = 0.042) and nicotine (p = 0.011). In chewers, decreases were significant only for hydroxycotinine (p = 0.004). Similar results were obtained when quitters and chewers were stratified by treatment arm. DISCUSSION: Salivary AN alkaloid levels generally agreed with self-reported chewing status, which suggests the former can be used to verify the latter. CONCLUSION: Our results can help to objectively evaluate compliance and program effectiveness in AN cessation programs.

Phytoestrogens and lung cancer risk: a nested case-control study in never-smoking Chinese women.

BACKGROUND: Since several lines of evidence suggest that estrogens may be involved in lung carcinogenesis, it has been hypothesized that intake of phytoestrogens, similar in molecular structure to mammalian estrogens, may be associated with lung cancer development. OBJECTIVE: The aim was to prospectively evaluate the association between phytoestrogen exposure and lung cancer risk in never-smoking women. METHODS: We conducted a nested case-control study within a population-based prospective cohort study of women. A total of 478 incident lung cancer cases and their individually matched controls were identified among never-smoking women after a mean follow-up of 15.6 years. Habitual intake of and internal exposure to phytoestrogens were assessed by repeated dietary surveys and urinary biomarkers, respectively. ORs and 95% CIs for lung cancer were estimated in conditional logistic regression models. RESULTS: After adjustment for potential confounders, a moderate intake of dietary isoflavones was inversely associated with lung cancer risk in never-smoking women, with the OR for the second quartile vs. the lowest quartile of intake being 0.52 (95% CI: 0.35, 0.76). Further increasing intake did not convey additional benefits, with ORs (95% CI) for the third and fourth quartiles of 0.53 (0.36, 0.78) and 0.47 (0.31, 0.72), respectively (P-overall < 0.001 and P-nonlinearity = 0.006). A similar association was seen when exposure to isoflavones was assessed by urinary biomarkers. ORs (95% CI) for the second, third, and fourth quartiles compared with the lowest quartile of urinary isoflavone excretion were 0.57 (0.39, 0.83), 0.64 (0.44, 0.92), and 0.60 (0.41, 0.86), respectively. The inverse association reached a plateau beyond the second quartile, with P-overall = 0.04 and P-nonlinearity = 0.15. Urinary excretion of gut-microbiota-derived metabolites of lignans was not related to lung cancer risk. CONCLUSIONS: This study suggests that moderately increasing intake of isoflavone-rich foods is associated with lower risk of lung cancer in never-smoking women.

The Gut Microbiome Is Associated with Circulating Dietary Biomarkers of Fruit and Vegetable Intake in a Multiethnic Cohort.

BACKGROUND: Results from observational studies suggest high diet quality favorably influences the human gut microbiome. Fruit and vegetable consumption is often a key contributor to high diet quality. OBJECTIVE: To evaluate measures of gut bacterial diversity and abundance in relation to serum biomarkers of fruit and vegetable intake. DESIGN: Secondary analysis of cross-sectional data. PARTICIPANTS AND SETTING: Men and women from Los Angeles, CA, and Hawai'i who participated in the Multiethnic Cohort-Adiposity Phenotype Study from 2013 to 2016 (N = 1,709). MAIN OUTCOME MEASURES: Gut microbiome diversity and composition in relation to dietary biomarkers. STATISTICAL ANALYSIS: Carotenoid (beta carotene, alpha carotene, cryptoxanthins, lutein, lycopene, and zeaxanthin), tocopherol (α, ß + γ, and δ), and retinol concentrations were assessed in serum. The α and ß diversity and composition of the gut microbiome were classified based on 16S rRNA gene sequencing of bacterial DNA from self-collected fecal samples. Global differences in microbial community profiles in relation dietary biomarkers were evaluated using multivariable permutational analysis of variance. Associations of α diversity (Shannon index), ß diversity (weighted and unweighted UniFrac) with center log-ratio-transformed phyla and genera abundances were evaluated using linear regression, adjusted for covariates. RESULTS: Increasing total carotenoid, beta carotene, alpha carotene, cryptoxanthin, and lycopene concentrations were associated with higher gut bacterial diversity (Shannon Index) (P < 0.001). Total tocopherol, α-tocopherol, and δ-tocopherol concentrations contributed significantly to more than 1% of the microbiome variation in gut bacterial community: total tocopherol: 1.74%; α-tocopherol: 1.70%; and δ-tocopherol: 1.16% (P < 0.001). Higher total carotenoid was associated with greater abundance of some genera relevant for microbial macronutrient metabolism (P < 0.001). CONCLUSIONS: Objective biomarkers of fruit and vegetable intake, particularly carotenoids, were favorably associated with gut bacterial composition and diversity in this multiethnic population. These observations provide supportive evidence that fruit and vegetable intake is related to gut bacterial composition; more work is needed to elucidate how this influences host health.

Body Fat Distribution, Glucose Metabolism, and Diabetes Status Among Older Adults: The Multiethnic Cohort Adiposity Phenotype Study.

BACKGROUND: As the proportion of visceral (VAT) to subcutaneous adipose tissue (SAT) may contribute to type 2 diabetes (T2D) development, we examined this relation in a cross-sectional design within the Multiethnic Cohort that includes Japanese Americans known to have high VAT. The aim was to understand how ectopic fat accumulation differs by glycemic status across ethnic groups with disparate rates of obesity, T2D, and propensity to accumulate VAT. METHODS: In 2013-2016, 1,746 participants aged 69.2 (standard deviation, 2.7) years from five ethnic groups completed questionnaires, blood collections, and whole-body dual X-ray absorptiometry and abdominal magnetic resonance imaging scans. Participants with self-reported T2D and/or medication were classified as T2D, those with fasting glucose >125 and 100-125 mg/dL as undiagnosed cases (UT2D) and prediabetes (PT2D), respectively. Using linear regression, we estimated adjusted means of adiposity measures by T2D status. RESULTS: Overall, 315 (18%) participants were classified as T2D, 158 (9%) as UT2D, 518 (30%) as PT2D, and 755 (43%) as normoglycemic (NG), with significant ethnic differences (P < 0.0001). In fully adjusted models, VAT, VAT/SAT, and percent liver fat increased significantly from NG, PT2D, UT2D, to T2D (P < 0.001). Across ethnic groups, the VAT/SAT ratio was lowest for NG participants and highest for T2D cases. Positive trends were observed in all groups except African Americans, with highest VAT/SAT in Japanese Americans. CONCLUSION: These findings indicate that VAT plays an important role in T2D etiology, in particular among Japanese Americans with high levels of ectopic adipose tissue, which drives the development of T2D to a greater degree than in other ethnic groups.

Metabolomics profiles of premenopausal women are different based on O-desmethylangolensin metabotype.

Urinary O-desmethylangolensin (ODMA) concentrations provide a functional gut microbiome marker of dietary isoflavone daidzein metabolism to ODMA. Individuals who do not have gut microbial environments that produce ODMA have less favourable cardiometabolic and cancer risk profiles. Urinary metabolomics profiles were evaluated in relation to ODMA metabotypes within and between individuals over time. Secondary analysis of data was conducted from the BEAN2 trial, which was a cross-over study of premenopausal women consuming 6 months on a high and a low soya diet, each separated by a 1-month washout period. In all of the 672 samples in the study, sixty-six of the eighty-four women had the same ODMA metabotype at seven or all eight time points. Two or four urine samples per woman were selected based on temporal metabotypes in order to compare within and across individuals. Metabolomics assays for primary metabolism and biogenic amines were conducted in sixty urine samples from twenty women. Partial least-squares discriminant analysis was used to compare metabolomics profiles. For the same ODMA metabotype across different time points, no profile differences were detected. For changes in metabotype within individuals and across individuals with different metabotypes, distinct metabolomes emerged. Influential metabolites (variables importance in projection score > 2) included several phenolic compounds, carnitine and derivatives, fatty acid and amino acid metabolites and some medications. Based on the distinct metabolomes of producers v. non-producers, the ODMA metabotype may be a marker of gut microbiome functionality broadly involved in nutrient and bioactive metabolism and should be evaluated for relevance to precision nutrition initiatives.

Associations of Subtype and Isomeric Plasma Carotenoids with Prostate Cancer Risk in Low-Income African and European Americans.

BACKGROUND: Various carotenoids in circulation, including isomers, may have different influences on cancer risk. METHODS: We conducted a nested case-control study including 343 incident prostate cancer cases and 640 controls individually matched on age, race, study site, and time of blood collection. Carotenoids investigated were carotene, cryptoxanthin, lycopene, dihydrolycopene, lutein, anhydrolutein, and zeaxanthin, including α versus ß configurations and cis versus trans isomers. General linear model and conditional logistic regression were applied to evaluate associations for prostate cancer risk, with adjustment for potential confounders. We conducted additional analyses with further stratification by race, multivitamin use, and smoking status. RESULTS: Case-control differences were found in carotenoid subtype levels, although not all reached the multiple comparison adjusted threshold for significance. Plasma lycopene [ORT1 vs. T3 = 0.51; 95% confidence interval (CI), 0.29-0.87; P trend = 0.014], dihydrolycopene (ORT1 vs. T3 = 0.37; 95% CI, 0.18-0.74; P trend = 0.006), and cis-anhydrolutein (ORT1 vs. T3 = 0.57; 95% CI, 0.33-0.96; P trend = 0.037) were inversely, while ß-trans-carotene (ORT1 vs. T3 = 2.13; 95% CI, 1.32-3.43; P trend = 0.002) and trans-lutein (ORT1 vs. T3, 1.86; 95% CI, 1.20-2.88; P trend = 0.006) were positively associated with prostate cancer risk. Stratified analyses showed inverse associations of lycopene, dihydrolycopene, and cis-anhydrolutein with prostate cancer risk in subjects without multivitamin use; lycopene and dihydrolycopene in African-Americans and current smokers; and dihydrolycopene in nonsmokers. Positive associations of ß-trans-carotene and trans-lutein were observed in African-Americans, nonsmokers, and multivitamin users. CONCLUSIONS: The associations of carotenoids with risk of prostate cancer differed by carotenoid subtypes. IMPACT: Public health recommendations on carotenoid intakes for prostate cancer prevention should take subtypes and isomers into consideration.

Genome-wide association study of pancreatic fat: The Multiethnic Cohort Adiposity Phenotype Study.

Several studies have found associations between higher pancreatic fat content and adverse health outcomes, such as diabetes and the metabolic syndrome, but investigations into the genetic contributions to pancreatic fat are limited. This genome-wide association study, comprised of 804 participants with MRI-assessed pancreatic fat measurements, was conducted in the ethnically diverse Multiethnic Cohort-Adiposity Phenotype Study (MEC-APS). Two genetic variants reaching genome-wide significance, rs73449607 on chromosome 13q21.2 (Beta = -0.67, P = 4.50x10-8) and rs7996760 on chromosome 6q14 (Beta = -0.90, P = 4.91x10-8) were associated with percent pancreatic fat on the log scale. Rs73449607 was most common in the African American population (13%) and rs79967607 was most common in the European American population (6%). Rs73449607 was also associated with lower risk of type 2 diabetes (OR = 0.95, 95% CI = 0.89-1.00, P = 0.047) in the Population Architecture Genomics and Epidemiology (PAGE) Study and the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM), which included substantial numbers of non-European ancestry participants (53,102 cases and 193,679 controls). Rs73449607 is located in an intergenic region between GSX1 and PLUTO, and rs79967607 is in intron 1 of EPM2A. PLUTO, a lncRNA, regulates transcription of an adjacent gene, PDX1, that controls beta-cell function in the mature pancreas, and EPM2A encodes the protein laforin, which plays a critical role in regulating glycogen production. If validated, these variants may suggest a genetic component for pancreatic fat and a common etiologic link between pancreatic fat and type 2 diabetes.

Biomarker-based visceral adiposity score and incident type 2 diabetes in the multiethnic cohort.

PURPOSE: Visceral adipose tissue (VAT) may be more important than subcutaneous fat in type 2 diabetes (T2D) etiology. We examined a VAT score developed in reference to MRI measurement of VAT in the Multiethnic Cohort (MEC) as a risk factor for incident T2D. METHODS: Two nested case-control studies of cancer allowed calculation of the VAT score based on anthropometric measures and 8 biomarkers among 2,556 participants without T2D. Incident cases were identified from Medicare linkages and self-reports after blood draws in 2001-2006. Cox regression with age as time metric was applied to estimate the association of the VAT score with T2D. RESULTS: During 10.1 ± 2.4 years, 355 incident T2D cases were identified. VAT scores were higher in T2D cases than among those without disease (5.06±0.43 vs. 4.95±0.41; P<0.0001) and significantly associated with T2D (HR = 2.70; 95%CI 1.60, 4.58 per unit) with similar values in men (HR = 2.99; 95%CI 1.03, 8.73) and women (HR = 2.61; 95%CI 1.39, 4.91). A significant association was observed in all five ethnic groups but only statistically significant among Japanese Americans (HR = 6.24; 95%CI 2.34, 16.68). CONCLUSION: These findings support that VAT as estimated by a biomarker-based score predicts T2D incidence beyond BMI in particular among older adults of Japanese ancestry.

The gut microbiome and type 2 diabetes status in the Multiethnic Cohort.

BACKGROUND: The gut microbiome may play a role in inflammation associated with type 2 diabetes (T2D) development. This cross-sectional study examined its relation with glycemic status within a subset of the Multiethnic Cohort (MEC) and estimated the association of circulating bacterial endotoxin (measured as plasma lipopolysaccharide-binding protein (LBP)) with T2D, which may be mediated by C-reactive protein (CRP). METHODS: In 2013-16, cohort members from five ethnic groups completed clinic visits, questionnaires, and stool and blood collections. Participants with self-reported T2D and/or taking medication were considered T2D cases. Those with fasting glucose >125 and 100-125 mg/dL were classified as undiagnosed (UT2D) and pre-diabetes (PT2D) cases, respectively. We characterized the gut microbiome through 16S rRNA gene sequencing and measured plasma LBP and CRP by standard assays. Linear regression was applied to estimate associations of the gut microbiome community structure and LBP with T2D status adjusting for relevant confounders. RESULTS: Among 1,702 participants (59.9-77.4 years), 735 (43%) were normoglycemic (NG), 506 (30%) PT2D, 154 (9%) UT2D, and 307 (18%) T2D. The Shannon diversity index decreased (ptrend = 0.05), while endotoxin, measured as LBP, increased (ptrend = 0.0003) from NG to T2D. Of 10 phyla, Actinobacteria (ptrend = 0.007), Firmicutes (ptrend = 0.003), and Synergistetes (ptrend = 0.02) were inversely associated and Lentisphaerae (ptrend = 0.01) was positively associated with T2D status. Clostridium sensu stricto 1, Lachnospira, and Peptostreptococcaceae were less, while Escherichia-Shigella and Lachnospiraceae were more abundant among T2D patients, but the associations with Actinobacteria, Clostridium sensu stricto 1, and Escherichia-Shigella may be due metformin use. PT2D/UT2D values were closer to NG than T2D. No indication was detected that CRP mediated the association of LBP with T2D. CONCLUSIONS: T2D but not PT2D/UT2D status was associated with lower abundance of SCFA-producing genera and a higher abundance of gram-negative endotoxin-producing bacteria suggesting that the gut microbiome may contribute to chronic systemic inflammation and T2D through bacterial translocation.

Metabolic syndrome screening using visceral adipose tissue (VAT) from opportunistic MRI locations in a multi-ethnic population.

OBJECTIVE: To determine if visceral adipose tissue (VAT) area measured through MRI can be used opportunistically to assess the presence of cardiometabolic risk factors and compare its performance to simpler adiposity measures. METHODS: A cross-sectional analysis was carried out on a subset of 1683 participants (856 women) from the Adiposity Phenotype Study (mean age=69.2y; range 59.9-77.4). The association of total VAT area (sum of four cross sections, L1-L2, L2-L3, L3-L4, L4-L5) and each location, as well as BMI and body fat % (per SD) with the metabolic syndrome (MetSx) or its components was evaluated through logistic regression analysis. RESULTS: Total VAT can be accurately predicted using all sites evaluated (R2 range=0.82-0.96). In men, VAT did not show a superior association to MetSx compared to BMI in men. However, in women, VAT was consistently superior to BMI and body fat % in its association to MetSx, independent of ethnicity [odds ratio for BMI, body fat %and total VAT area=2.25 (95% CI: 1.93-2.62); 1.66 (95% CI: 1.36-2.03); 6.20 (95% CI: 4.69-8.21) respectively in all women]. Ethnic-specific odds ratios to MetSx in women ranged from 5.38 to 8.63 for total VAT area and 2.12-4.08 for BMI. CONCLUSION: Total VAT area can be accurately predicted from individual VAT regions in men and women and offers superior association to BMI for MetSx in women but not in men for five ethnicities. Therefore, opportunistic screening for elevated VAT area in women may be warranted across multiple ethnic groups.

Risk of breast cancer and prediagnostic urinary excretion of bisphenol A, triclosan and parabens: The Multiethnic Cohort Study.

Exposure to bisphenol A (BPA), triclosan and parabens is widespread but their impact on breast cancer risk remains unclear. This nested case-control study investigated endocrine-disrupting chemicals (EDCs) and breast cancer risk within the Multiethnic Cohort (MEC). We measured prediagnostic urinary BPA, triclosan and parabens in 1032 postmenopausal women with breast cancer (48 African American, 77 Latino, 155 Native Hawaiian, 478 Japanese American and 274 White) and 1030 individually matched controls, using a sensitive and validated liquid chromatography mass spectrometry assay. Conditional logistic regression was used to examine risk with these EDCs with adjustment for creatinine and potential confounders. In all women, breast cancer risk was not associated with BPA (Ptrend  = 0.53) and was inversely associated with triclosan (ORT3 vs T1  = 0.83, 95% CI: 0.66-1.04, Ptrend  = 0.045) and total parabens (ORT3 vs T1  = 0.77, 95% CI: 0.62-0.97, Ptrend  = 0.03). While risk of hormone receptor positive (HR+) cancer was 20% to 23% lower among women in the upper two tertiles of paraben exposure (Ptrend  = 0.02), risk of HR negative (HR-) was reduced 27% but only among those in the upper tertile of exposure. Although risk associations did not differ significantly by ethnicity or by body mass index (BMI), the inverse association with triclosan was observed mainly among overweight/obese women (ORT3 vs T1  = 0.76, 95% CI: 0.56-1.02, Ptrend  = 0.02). In summary, breast cancer risk in a multiethnic population was unrelated to BPA and was weakly inversely associated with triclosan and paraben exposures. Studies with multiple urine samples collected before breast cancer diagnosis are needed to further investigate these EDCs and breast cancer risk.

Gut microbiota-derived metabolites and risk of coronary artery disease: a prospective study among US men and women.

BACKGROUND: Accumulating evidence has suggested that human gut microbiota metabolize certain dietary compounds and subsequently produce bioactive metabolites that may exert beneficial or harmful effects on coronary artery disease (CAD) risk. OBJECTIVES: This study examined the joint association of 2 gut microbiota metabolites, enterolactone and trimethylamine N-oxide (TMAO), that originate from intake of plant-based foods and animal products, respectively, in relation to CAD risk. METHODS: A prospective nested case-control study of CAD was conducted among participants who were free of diabetes, cardiovascular disease, and cancer in the Nurses' Health Study II and the Health Professionals Follow-up Study. Plasma concentrations of enterolactone and TMAO, as well as choline and L-carnitine, were assayed among 608 CAD case-control pairs. RESULTS: A high enterolactone and low TMAO profile was associated with better diet quality, especially higher intake of whole grains and fiber and lower intake of red meats, as well as lower concentrations of plasma triglycerides and C-reactive protein. Participants with a high enterolactone/low TMAO profile had a significantly lower risk of CAD: the multivariate-adjusted OR was 0.58 (95% CI: 0.38, 0.90), compared with participants with a low enterolactone/high TMAO profile. No significant interaction between enterolactone and TMAO on CAD risk was observed. Neither TMAO nor enterolactone alone were associated with CAD risk in pooled analyses. In women, a higher enterolactone concentration was significantly associated with a 54% lower CAD risk (P trend = 0.03), although the interaction by sex was not significant. CONCLUSIONS: Our results show that a profile characterized by high enterolactone and low TMAO concentrations in plasma is linked to a healthful dietary pattern and significantly associated with a lower risk of CAD. Overall, these data suggest that, compared with individual markers, multiple microbiota-derived metabolites may facilitate better differentiation of CAD risk and characterization of the relations between diet, microbiota, and CAD risk.