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Introduction: As several behaviors captured by the Lifestyle Risk Factor Index (LSRI) are protective against Type 2 diabetes (T2D) and may affect body fat distribution, we examined its relation with both outcomes. Methods: In a subset of the Multiethnic Cohort, participants from five ethnic groups (60–77 years) were assigned LSRI scores (one point each for consuming <1 (women)/<2 (men) alcoholic drinks/day, ≥1.5 physical activity hours/week, not smoking, and adhering to ≥3/7 dietary recommendations). All participants completed an extensive Quantitative Food Frequency Questionnaire to allow estimation of adherence to intake recommendations for fruits, vegetables, refined and whole grains, fish, processed and non-processed meat. Glycemic/T2D status was classified according to self-reports and fasting glucose. We estimated prevalence odds ratios (POR) of LSRI with glycemic/T2D status and DXA- and MRI-based body fat distribution using logistic regression. Results: Of 1713 participants, 43% had normoglycemia, 30% Pre-T2D, 9% Undiagnosed T2D, and 18% T2D. Overall, 39% scored 0–2, 49% 3, and 12% 4 LSRI points. T2D prevalence was 55% (POR 0.45; 95% confidence intervals 0.27, 0.76) lower for 4 vs. 0–2 LSRI points with weaker associations for abnormal glycemic status. Despite the low adherence to dietary recommendations (22%), this was the only component related to lower T2D prevalence. The inverse LSRI-T2D association was only observed among Latinos and Japanese Americans in ethnic-specific models. Visceral fat measures were higher in T2D patients and attenuated the LSRI-T2D association. Conclusion: These findings support the role of a healthy lifestyle, especially diet, in T2D prevention with differences across ethnicity.

Age‐related loss in skeletal muscle mass, quality, and strength, known as sarcopenia, is a well‐known phenomenon of aging and is determined clinically using methods such as dual‐energy X‐ray absorptiometry (DXA). However, these clinical methods to measure sarcopenia are not practical for population‐based studies, and a five‐question screening tool known as SARC‐F has been validated to screen for sarcopenia. We investigated the relationship between appendicular skeletal lean mass/height2(ALM/HT2) (kg/m2) assessed by DXA and SARC‐F in a subset of 1538 (778 men and 760 women) participants in the Multiethnic Cohort (MEC) Study after adjustment for race/ethnicity, age, and body mass index (BMI) at the time of DXA measurement. We then investigated the association between SARC‐F and mortality among 71 283 (41 757 women and 29 526 men) participants in the MEC, who responded to the five SARC‐F questions on a mailed questionnaire as part of the MEC follow‐up in 2012–2016. In women, SARC‐F score was significantly inversely associated with ALM/HT2after adjusting for race/ethnicity, and age and BMI at DXA (r= −0.167, P< 0.001); the result was similar in men although it did not reach statistical significance (r= −0.056, P= 0.12). Among the 71 000+ MEC participants, SARC‐F score ≥ 4, as an indicator of sarcopenia, was higher in women (20.9%) than in men (11.2%) (P< 0.0001) and increased steadily with increasing age (6.3% in <70 vs. 41.3% in 90+ years old) (P< 0.0001). SARC‐F score ≥ 4 was highest among Latinos (30.8% in women and 16.1% in men) and lowest in Native Hawaiian women (15.6%) and Japanese American men (8.9%). During an average of 6.8 years of follow‐up, compared with men with SARC‐F score of 0–1 (indicator of no sarcopenia), men with SARC‐F 2–3 (indicator of pre‐sarcopenia) and SARC‐F ≥ 4 had significantly increased risk of all‐cause mortality [hazard ratio (HR) = 1.00, 1.77, 3.73, P< 0.001], cardiovascular disease (CVD) mortality (HR = 1.00, 1.85, 3.98, P< 0.001), and cancer mortality (HR = 1.00, 1.46, 1.96, P< 0.001) after covariate adjustment. Comparable risk association patterns with SARC‐F scores were observed in women (all‐cause mortality: HR = 1.00, 1.47, 3.10, P< 0.001; CVD mortality: HR = 1.00, 1.59, 3.54, P< 0.001; cancer mortality: HR = 1.00, 1.30, 1.77, P< 0.001). These significant risk patterns between SARC‐F and all‐cause mortality were found across all sex–race/ethnic groups considered (12 in total). An indicator of sarcopenia, determined using SARC‐F, showed internal validity against DXA and displayed racial/ethnic and sex differences in distribution. SARC‐F was associated with all‐cause mortality as well as cause‐specific mortality.

Background/objective: As dietary intake and endocrine metabolism are vastly different by sex, we evaluated differences in the association of diet quality with body composition between men and women. Subjects/methods: Close to 2000 participants from the Multiethnic Cohort completed calibrated quantitative food frequency questionnaires at cohort entry (1993–96) and clinic visit (2013–16), from which the Healthy Eating Index (HEI-2010) was computed. Adiposity measures were obtained through DXA and MRI at clinic visit. Multivariable-adjusted mean adiposity measures were estimated by tertiles of HEI-2010 scores using general linear regression. The associations of diet quality with high visceral fat (VAT) and nonalcoholic fatty liver disease (NAFLD) were examined by logistic regression. To assess sex differences, cross-product terms with the HEI-2010 were added to the models. Results: Mean HEI-2010 scores were higher for women than men at cohort entry (67.4 vs. 64.0) and clinic visit (73.6 vs. 71.0). Past and current diet quality was inversely associated with adiposity measures in men and women. Although interaction terms were not significant, the magnitude of the slopes and differences in adjusted means across tertiles suggested a stronger association for women than men. When comparing individuals who maintained a high vs. poor quality diet over 20 years, women but not men showed significantly lower risks for high VAT, whereas high HEI-2010 scores predicted a lower risk of NAFLD in both sexes. Conclusions: The inverse association of diet quality with adiposity was similar in both sexes, but diet quality appeared to have a stronger influence on VAT in women than men.

AbstractObjective:To understand how diet quality affects chronic disease etiology, the associations of 4 a prioridiet quality indices with blood levels of lipid-soluble micronutrients and biomarkers of inflammation, lipid, and glucose metabolism were examined in 5 ethnic groups.Methods:In a cross-sectional design, the Adiposity Phenotype Study, a subset of the Multiethnic Cohort in Hawaii and Los Angeles, recruited participants of white, African American, Native Hawaiian, Japanese American, and Latino ancestry. A total of 896 men and 910 women completed a validated quantitative food frequency questionnaire and anthropometric measurements and donated a fasting blood sample. Using general linear models, covariate-adjusted mean levels of lipid-soluble micronutrients (total carotenes, lycopene, total tocopherols, total lutein, cryptoxanthins), biomarkers of inflammation (C-reactive protein [CRP], tumor necrosis factor-), adipokines (adiponectin, leptin), lipids (total cholesterol, high-density lipoprotein cholesterol [HDL-C], triglycerides), and glucose metabolism (glucose, insulin, homeostatic model assessment of insulin resistance [HOMA-IR]) were computed across tertiles of 4 a prioridietary indices Healthy Eating Index (HEI)-2010, Alternative HEI (AHEI)-2010, alternate Mediterranean Diet (aMED), Dietary Approaches to Stop Hypertension (DASH); trends were evaluated in models with diet quality scores as continuous variables.Results:With better diet quality, levels of carotenes, lutein, cryptoxanthin, adiponectin, and HDL-C were significantly higher (ptrend< 0.01), whereas levels of CRP, leptin, total cholesterol, triglycerides, glucose, insulin, and HOMA-IR were inversely associated (ptrend< 0.05) with diet quality. With the exception of cryptoxanthins and triglycerides, the associations were consistent across ethnic groups.Conclusions:These findings confirm the association between diet quality and nutrition-related biomarkers and support the idea that a high-quality diet positively influences biologic pathways involved in chronic disease etiology across different ethnic groups.

Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry1–3. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific4–10. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations11,12. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States—where minority populations have a disproportionately higher burden of chronic conditions13—the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities. Genetic analyses of ancestrally diverse populations show evidence of heterogeneity across ancestries and provide insights into clinical implications, highlighting the importance of including ancestrally diverse populations to maximize genetic discovery and reduce health disparities.

ABSTRACTExcess body fat, especially intra-abdominal fat, is a leading risk factor for metabolic diseases. Differentially methylated regions (DMRs) of two imprinted genes, insulin-like growth factor 2(IGF2) and H19, have been associated with obesity due to their important roles in regulating body composition, but have not been examined in relation to intra-abdominal fat depots. Total body fat from whole-body dual energy X-ray absorptiometry and visceral and liver fat contents from abdominal magnetic resonance imaging in 48 healthy women aged 60–65 years (of White or Japanese ancestry) were each regressed on circulating leukocyte DNA methylation levels of IGF2(at DMR0, DMR2a, and DMR2b) and H19(at CTCF3) as assessed by pyrosequencing, while adjusting for age and race/ethnicity. Total fat mass was inversely associated with methylation levels of IGF2DMR2b (P = 0.016). Total fat-adjusted visceral fat area (P = 0.062) and percent visceral fat measured at L4-L5 (P = 0.045) were associated with higher methylation levels of IGF2DMR2b. Both total fat-adjusted percent liver fat (P = 0.039) and the presence of fatty liver (P = 0.015) were positively associated with IGF2DMR2a methylation. Methylation levels of H19CTCF3 were not associated with overall or intra/abdominal adiposity. The findings indicate that methylation levels of IGF2DMR regions in leukocytes are associated with total body fat and with fat distribution in the viscera and liver independently of total adiposity.

The ASA24 is a web application which enables the collection of self-administered dietary recalls thus utilizing technology to overcome some of the limitations of traditional assessment methodologies. Older adults, particularly those from certain ethnic groups may have less access to and may be less receptive to technology. This research sought to determine the level of access to the internet as well as evaluate the feasibility of using a web-based alternative dietary data collection method in older, multiethnic adults. Participants completed three telephone administered diet recalls (n=347), and were asked to complete a one day recall via the ASA24. They were also asked to evaluate their experience with using the ASA24 system. Almost 60% of the participants reported no access to a computer or internet access, with African Americans and Latinos less likely than non-Hispanic Whites and Japanese-Americans to have access. Of those with access to the internet (n=100), 44% of the participants accessed the ASA24 system and 37% successfully launched the ASA24 program. However, most respondents preferred the traditional diet recall methodology over the ASA24. Further research is needed to investigate recruitment and use of electronic data collection methodologies in older adults.

Understanding patterns of etiologic commonality and heterogeneity for non-Hodgkin lymphomas may illuminate lymphomagenesis. We present the first systematic comparison of risks by lymphoma subtype for a broad range of putative risk factors in a population-based case-control study, including diffuse large B-cell (DLBCL; N = 416), follicular (N = 318), and marginal zone lymphomas (N = 106), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; N = 133). We required at least 2 of 3 analyses to support differences in risk: (1) polytomous logistic regression, (2) homogeneity tests, or (3) dichotomous logistic regression, analyzing all 7 possible pairwise comparisons among the subtypes, corresponding to various groupings by clinical behavior, genetic features, and differentiation. Late birth order and high body mass index (≥ 35) kg/m2) increased risk for DLBCL alone. Autoimmune conditions increased risk for marginal zone lymphoma alone. The tumor necrosis factor G-308A polymorphism (rs1800629) increased risks for both DLBCL and marginal zone lymphoma. Exposure to certain dietary heterocyclic amines from meat consumption increased risk for CLL/SLL alone. We observed no significant risk factors for follicular lymphoma alone. These data clearly support both etiologic commonality and heterogeneity for lymphoma subtypes, suggesting that immune dysfunction is of greater etiologic importance for DLBCL and marginal zone lymphoma than for CLL/SLL and follicular lymphoma.

Understanding patterns of etiologic commonality and heterogeneity for non-Hodgkin lymphomas may illuminate lymphomagenesis. We present the first systematic comparison of risks by lymphoma subtype for a broad range of putative risk factors in a population-based case-control study, including diffuse large B-cell (DLBCL; N = 416), follicular (N = 318), and marginal zone lymphomas (N = 106), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; N = 133). We required at least 2 of 3 analyses to support differences in risk: (1) polytomous logistic regression, (2) homogeneity tests, or (3) dichotomous logistic regression, analyzing all 7 possible pairwise comparisons among the subtypes, corresponding to various groupings by clinical behavior, genetic features, and differentiation. Late birth order and high body mass index (≥ 35) kg/m2) increased risk for DLBCL alone. Autoimmune conditions increased risk for marginal zone lymphoma alone. The tumor necrosis factor G-308A polymorphism (rs1800629) increased risks for both DLBCL and marginal zone lymphoma. Exposure to certain dietary heterocyclic amines from meat consumption increased risk for CLL/SLL alone. We observed no significant risk factors for follicular lymphoma alone. These data clearly support both etiologic commonality and heterogeneity for lymphoma subtypes, suggesting that immune dysfunction is of greater etiologic importance for DLBCL and marginal zone lymphoma than for CLL/SLL and follicular lymphoma.

We previously reported a lower risk of non-Hodgkin lymphoma (NHL) associated with high consumption of vitamin B6 and methionine, dietary determinants of one-carbon metabolism. Evidence has linked genetic variants involved in one-carbon metabolism to NHL. We investigated 30 polymorphisms in 18 genes for their main effect on NHL among 1141 incident cases and 949 population-based controls and examined gene-nutrient interactions in a subgroup of 386 cases and 319 controls who provided detailed food-frequency information. Odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted for age, sex, and race. We observed a decreased risk of NHL overall with BHMT Ex8+453A>T and increased risk with CBS Ex13+41C>T, FPGS Ex15-263T>C, and SHMT1 Ex12+138C>T and Ex12+236C>T. Furthermore, significant gene-nutrient interactions limited the protective association comparing high versus low vitamin B6 to FPGS Ex15-263T>C CC (OR = 0.22; 95% CI = 0.10-0.52), MTHFS IVS2-1411T>G TT/TG (OR = 0.54; 95% CI = 0.36-0.81), and MTR Ex26-20A>G AA (OR = 0.55; 95% CI = 0.35-0.86) genotypes, and the protective association of methionine to FTHFD Ex10-40G>T GG (OR = 0.63; 95% CI = 0.44-0.91), MTHFR Ex8-62A>C CC (OR = 0.13; 95% CI = 0.04-0.39), and MTRR Ex5+136T>C TT (OR = 0.67; 95% CI = 0.47-0.97) genotypes. Warranting replication, our finding of gene-nutrient interactions in one-carbon metabolism supports their etiologic involvement in lymphomagenesis.

We previously reported a lower risk of non-Hodgkin lymphoma (NHL) associated with high consumption of vitamin B6 and methionine, dietary determinants of one-carbon metabolism. Evidence has linked genetic variants involved in one-carbon metabolism to NHL. We investigated 30 polymorphisms in 18 genes for their main effect on NHL among 1141 incident cases and 949 population-based controls and examined gene-nutrient interactions in a subgroup of 386 cases and 319 controls who provided detailed food-frequency information. Odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted for age, sex, and race. We observed a decreased risk of NHL overall with BHMTEx8+453A>T and increased risk with CBSEx13+41C>T, FPGSEx15-263T>C, and SHMT1Ex12+138C>T and Ex12+236C>T. Furthermore, significant gene-nutrient interactions limited the protective association comparing high versus low vitamin B6 to FPGSEx15-263T>C CC (OR = 0.22; 95% CI = 0.10-0.52), MTHFSIVS2-1411T>G TT/TG (OR = 0.54; 95% CI = 0.36-0.81), and MTREx26-20A>G AA (OR = 0.55; 95% CI = 0.35-0.86) genotypes, and the protective association of methionine to FTHFDEx10-40G>T GG (OR = 0.63; 95% CI = 0.44-0.91), MTHFREx8-62A>C CC (OR = 0.13; 95% CI = 0.04-0.39), and MTRREx5+136T>C TT (OR = 0.67; 95% CI = 0.47-0.97) genotypes. Warranting replication, our finding of gene-nutrient interactions in one-carbon metabolism supports their etiologic involvement in lymphomagenesis.

Because of conflicting findings about the relationship between ultraviolet (UV) radiation and the risk of non-Hodgkin lymphoma (NHL), we evaluated the risk of several indicators related to UV, including two not previously studied: dietary vitamin D, and ambient UV levels by residential location.As part of a case–control study conducted in four Surveillance, Epidemiology, and End Results (SEER) registries, we collected UV information from a self-administered questionnaire and computer-assisted personal interview with 551 NHL cases and 462 controls. We estimated the relative risk (RR) and 95% confidence intervals (CI) from unconditional logistic regression models.Eye color, a marker of host susceptibility to UV, showed a decreasing risk gradient for lightest eyes (0.47) compared to darkest. Relative risks were in the range of 0.73–0.78 for participants reporting more hours in the mid-day summer sun. Use of sunlamps or tanning booths was associated with decreased risk (RR = 0.88), as was estimated overall ambient UV (RR = 0.76 per 50 RB-units) overall. Vitamin D intake from diet and supplements was not related to risk. Results were thus consistent for the various indicators, although some estimated risks were not statistically significant. Effects were generally similar for diffuse large B-cell (DLBCL) and follicular lymphomas.These data suggest a slight protective effect of sunlight against NHL, and they agree with geographic patterns of NHL incidence observed in the US.

ABSTRACTNonalcoholic fatty liver disease (NAFLD) is a risk factor for liver cancer and prevalence varies by ethnicity. Along with genetic and lifestyle factors, the gut microbiome (GM) may contribute to NAFLD and its progression to advanced liver disease. Our cross-sectional analysis assessed the association of the GM with hepatic adiposity among African American, Japanese American, White, Latino, and Native Hawaiian participants in the Multiethnic Cohort. We used MRI to measure liver fat and determine nonalcoholic fatty liver disease (NAFLD) status (n = 511 cases) in 1,544 participants, aged 60–77 years, with 12–53% overall adiposity (BMI of 17.8–46.2 kg/m2). The GM was measured by 16S rRNA gene sequencing and, on a subset, by metagenomic sequencing. Alpha diversity was lower overall with NAFLD and in certain ethnicities (African Americans, Whites, and Latinos). In models regressing genus on NAFLD status, 62 of 149 genera (40%) exhibited a significant interaction between NAFLD and ethnicity stratified analysis found 69 genera significantly associated with NAFLD in at least one ethnic group. No single genus was significantly associated with NAFLD across all ethnicities. In contrast, the same bacterial metabolic pathways were over-represented in participants with NAFLD regardless of ethnicity. Imputed secondary bile acid and carbohydrate pathways were associated with NAFLD, the latter of which was corroborated by metagenomics, although different genera in different ethnicities were associated with these pathways. Overall, we found that NAFLD was associated with altered bacterial composition and metabolism, and that bacterial endotoxin, assessed by plasma lipopolysaccharide binding protein (LBP), may mediate liver fat-associated systemic inflammation in a manner that seems to vary by ethnicity.

Mitochondrial DNA (mtDNA) copy number is increased in patients with chronic lymphocytic leukemia (CLL), in Burkitt lymphoma and Epstein-Barr virus–transformed lymphoblastoid cell lines, and in T cells activated via the T-cell receptor. We hypothesized that having a higher mtDNA copy number in peripheral white blood cell DNA from healthy subjects would be associated with future risk of non-Hodgkin lymphoma (NHL). We analyzed mtDNA copy number in 104 incident male NHL cases and 104 matched controls within the prospective Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention cohort. There was a dose-response relationship between tertiles of mtDNA copy number and risk of NHL (odds ratio [OR], 95% confidence interval [CI]: 1.0; 1.4 [0.7-2.8]; and 2.4 [1.0-5.5], respectively; Ptrend = .046). The effect was most pronounced for the CLL/small lymphocytic lymphoma (SLL) subtype (OR: 1.0; 3.2 [0.7-15.7]; 14.1 [1.9-103.2]; Ptrend = .009). These results suggest that mtDNA copy number could be associated with the risk of NHL, particularly CLL/SLL.

Mitochondrial DNA (mtDNA) copy number is increased in patients with chronic lymphocytic leukemia (CLL), in Burkitt lymphoma and Epstein-Barr virus–transformed lymphoblastoid cell lines, and in T cells activated via the T-cell receptor. We hypothesized that having a higher mtDNA copy number in peripheral white blood cell DNA from healthy subjects would be associated with future risk of non-Hodgkin lymphoma (NHL). We analyzed mtDNA copy number in 104 incident male NHL cases and 104 matched controls within the prospective Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention cohort. There was a dose-response relationship between tertiles of mtDNA copy number and risk of NHL (odds ratio [OR], 95% confidence interval [CI]: 1.0; 1.4 [0.7-2.8]; and 2.4 [1.0-5.5], respectively; Ptrend= .046). The effect was most pronounced for the CLL/small lymphocytic lymphoma (SLL) subtype (OR: 1.0; 3.2 [0.7-15.7]; 14.1 [1.9-103.2]; Ptrend= .009). These results suggest that mtDNA copy number could be associated with the risk of NHL, particularly CLL/SLL.