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1.  Plasma Coenzyme Q10 levels and Prostate Cancer Risk: The Multiethnic Cohort Study 
Coenzyme Q10 (CoQ10) is considered to be a potential anti-cancer agent, but epidemiological evidence regarding CoQ10 and prostate cancer risk is lacking. We examined the association of circulating CoQ10 levels with prostate cancer risk using pre-diagnostic blood samples.
Each of the 307 cases was individually-matched to approximately 2 controls on age, ethnicity, geographic location, date/time of specimen collection, and hours of fasting, for a total of 596 controls. Logistic regression was used to compute odds ratios and 95% confidence intervals.
There was no overall statistically significant association of plasma CoQ10 levels with prostate cancer risk (Ptrend = 0.50). However, after matched sets in which controls had possible undiagnosed prostate cancer (PSA > 4.0) were excluded, the odds ratios for quintiles 2–5 were all <1.0.
The results suggest the possibility that moderate levels of circulating CoQ10 may be optimal for the reduction of prostate cancer risk; however, the findings were weak and not statistically significant. Since this is the first epidemiologic study of the association between CoQ10 and prostate cancer, further research on this topic is needed.
If a nutritional factor like CoQ10 were determined to reduce prostate cancer risk, it would have considerable public health significance because of the very high incidence of this cancer.
PMCID: PMC4439209  PMID: 21297042
Coenzyme Q10 prostate cancer
2.  Type I and II Endometrial Cancers: Have They Different Risk Factors? 
Journal of Clinical Oncology  2013;31(20):2607-2618.
Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors.
Patients and Methods
Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors.
Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m2 increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (Pheterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar.
The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed.
PMCID: PMC3699726  PMID: 23733771
3.  Common Breast Cancer Susceptibility Variants in LSP1 and RAD51L1 Are Associated with Mammographic Density Measures that Predict Breast Cancer Risk 
Vachon, Celine M. | Scott, Christopher G. | Fasching, Peter A. | Hall, Per | Tamimi, Rulla M. | Li, Jingmei | Stone, Jennifer | Apicella, Carmel | Odefrey, Fabrice | Gierach, Gretchen L. | Jud, Sebastian M. | Heusinger, Katharina | Beckmann, Matthias W. | Pollan, Marina | Fernández-Navarro, Pablo | González-Neira, Anna | Benítez, Javier | van Gils, Carla H. | Lokate, Mariëtte | Onland-Moret, N. Charlotte | Peeters, Petra H.M. | Brown, Judith | Leyland, Jean | Varghese, Jajini S. | Easton, Douglas F. | Thompson, Deborah J. | Luben, Robert N. | Warren, Ruth ML | Wareham, Nicholas J. | Loos, Ruth JF | Khaw, Kay-Tee | Ursin, Giske | Lee, Eunjung | Gayther, Simon A. | Ramus, Susan J. | Eeles, Rosalind A. | Leach, Martin O. | Kwan-Lim, Gek | Couch, Fergus J. | Giles, Graham G. | Baglietto, Laura | Krishnan, Kavitha | Southey, Melissa C. | Le Marchand, Loic | Kolonel, Laurence N. | Woolcott, Christy | Maskarinec, Gertraud | Haiman, Christopher A | Walker, Kate | Johnson, Nichola | McCormack, Valerie A. | Biong, Margarethe | Alnæs, Grethe I.G. | Gram, Inger Torhild | Kristensen, Vessela N. | Børresen-Dale, Anne-Lise | Lindström, Sara | Hankinson, Susan E. | Hunter, David J. | Andrulis, Irene L. | Knight, Julia A. | Boyd, Norman F. | Figueroa, Jonine D. | Lissowska, Jolanta | Wesolowska, Ewa | Peplonska, Beata | Bukowska, Agnieszka | Reszka, Edyta | Liu, JianJun | Eriksson, Louise | Czene, Kamila | Audley, Tina | Wu, Anna H. | Pankratz, V. Shane | Hopper, John L. | dos-Santos-Silva, Isabel
Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biological mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to inter-individual differences in mammographic density measures.
We established an international consortium (DENSNP) of 19 studies from 10 countries, comprising 16,895 Caucasian women, to conduct a pooled cross-sectional analysis of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures. Dense and non-dense areas, and percent density, were measured using interactive-thresholding techniques. Mixed linear models were used to assess the association between genetic variants and the square roots of mammographic density measures adjusted for study, age, case status, body mass index (BMI) and menopausal status.
Consistent with their breast cancer associations, the C-allele of rs3817198 in LSP1 was positively associated with both adjusted dense area (p=0.00005) and adjusted percent density (p=0.001) whereas the A-allele of rs10483813 in RAD51L1 was inversely associated with adjusted percent density (p=0.003), but not with adjusted dense area (p=0.07).
We identified two common breast cancer susceptibility variants associated with mammographic measures of radio-dense tissue in the breast gland.
We examined the association of 14 established breast cancer susceptibility loci with mammographic density phenotypes within a large genetic consortium and identified two breast cancer susceptibility variants, LSP1-rs3817198 and RAD51L1-rs10483813, associated with mammographic measures and in the same direction as the breast cancer association.
PMCID: PMC3569092  PMID: 22454379
breast density; breast cancer; genetics; biomarkers; mammography
4.  Obesity and breast cancer survival in ethnically diverse postmenopausal women: The Multiethnic Cohort Study 
Breast cancer survival has been found to be lower in obese women, but few studies have evaluated ethnic variations in this association. This study examined all-cause and breast cancer-specific survival by body mass index (BMI) in the Multiethnic Cohort (MEC) study for African American, Native Hawaiian, Japanese American, Latino, and Caucasian women. Female MEC participants free of breast cancer, aged ≥ 50 years at cohort entry, and diagnosed with primary invasive breast cancer during follow-up were included in the analyses (n = 3,842). Cox proportional hazards regression was used to estimate the effect of pre-diagnostic adult BMI (<22.5, 22.5–24.9, 25.0–29.9, ≥30 kg/m2) on the risk of mortality. Mean age at diagnosis was 68.8 years (range 50–89 years). During a mean follow-up of 6.2 ± 3.8 years after diagnosis, there were 804 deaths that included 376 breast cancer-specific deaths. After adjustment for breast cancer characteristics, including hormone receptor status, stage at diagnosis, and treatment, obese women had a higher risk of all-cause [hazard ratio (HR) = 1.54; 95% confidence interval (CI): 1.23, 1.91] and breast cancer-specific (HR = 1.45; 95% CI: 1.05, 2.00) mortality compared to women with high-normal BMI; however, being overweight did not affect survival. There was no evidence of ethnic differences in the BMI effect on all-cause (Pinteraction = 0.87) or breast cancer-specific (Pinteraction = 0.63) mortality. Our findings are consistent with the literature that maintaining moderate weight throughout adult life may be beneficial for breast cancer survival in women and this appears to hold for all ethnic groups.
PMCID: PMC3164157  PMID: 21499688
Breast carcinoma; ethnicity; obesity; survival; prognosis
5.  Estimating the heritability of colorectal cancer 
Human Molecular Genetics  2014;23(14):3898-3905.
A sizable fraction of colorectal cancer (CRC) is expected to be explained by heritable factors, with heritability estimates ranging from 12 to 35% twin and family studies. Genome-wide association studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) associated with CRC risk. Although it has been shown that these CRC susceptibility SNPs only explain a small proportion of the genetic risk, it is not clear how much of the heritability these SNPs explain and how much is left to be detected by other, yet to be identified, common SNPs. Therefore, we estimated the heritability of CRC under different scenarios using Genome-Wide Complex Trait Analysis in the Genetics and Epidemiology of Colorectal Cancer Consortium including 8025 cases and 10 814 controls. We estimated that the heritability explained by known common CRC SNPs identified in GWAS was 0.65% (95% CI:0.3–1%; P = 1.11 × 10−16), whereas the heritability explained by all common SNPs was at least 7.42% (95% CI: 4.71–10.12%; P = 8.13 × 10−8), suggesting that many common variants associated with CRC risk remain to be detected. Comparing the heritability explained by the common variants with that from twin and family studies, a fraction of the heritability may be explained by other genetic variants, such as rare variants. In addition, our analysis showed that the gene × smoking interaction explained a significant proportion of the CRC variance (P = 1.26 × 10−2). In summary, our results suggest that known CRC SNPs only explain a small proportion of the heritability and more common SNPs have yet to be identified.
PMCID: PMC4065150  PMID: 24562164
6.  Dietary Fat and Breast Cancer in Postmenopausal Women According to Ethnicity and Hormone Receptor Status: The Multiethnic Cohort Study 
Dietary fat has been widely studied as a risk factor for breast cancer, with little consistency in results. The Multiethnic Cohort Study (MEC) provides an opportunity to assess this relationship for possible hetero-geneity across different racial/ethnic groups, as well as by stratification on several other variables associated with risk. Therefore, we investigated the associations between dietary fat, overall and by type, and breast cancer risk among 85,089 postmenopausal women who entered the MEC by completing a comprehensive dietary questionnaire in 1993 to 1996. During a mean follow-up of 12 years, 3,885 incident invasive breast cancer cases were identified. The multivariate HR [95% confidence interval (CI)] for the highest versus lowest quintile of intake was 0.94 (95% CI, 0.85–1.05) for total fat and 0.93 (95% CI, 0.83–1.04) for saturated fat. Other specific types of dietary fat, including individual fatty acids, were not related to risk of postmenopausal breast cancer. We found no heterogeneity in these null findings across the five ethnic groups. Furthermore, we found no evidence that the association between dietary fat and postmenopausal breast cancer risk differed by estrogen/progesterone receptor status, tumor stage, body mass index, hormone replacement therapy use, follow-up period, family history of breast cancer, and smoking status at baseline. In conclusion, this comprehensive prospective analysis in the MEC does not support a role of adult intake of dietary fat in the etiology of postmenopausal breast cancer.
PMCID: PMC4495954  PMID: 22166249
7.  Genetic Variants, Prediagnostic Circulating Levels of Insulin-like Growth Factors, Insulin, and Glucose and the Risk of Colorectal Cancer: The Multiethnic Cohort Study 
Increased exposure of colonic and rectal epithelial cells to the promitotic and antiapoptotic effects of insulin and insulin-like growth factors (IGF) is hypothesized to increase colorectal cancer risk.
In a case–control study nested within the Multiethnic Cohort, we attempted to replicate associations for five genetic variants associated with IGF system biomarkers, insulin, or glucose and to examine their association with the risk of colorectal cancer. In a subset of participants, the association between circulating biomarkers and colorectal cancer risk was examined. Unconditional logistic regression was used to calculate ORs and 95% confidence intervals (CI) for genetic variants (1,954 cases/2,587 controls) and serum biomarkers (258 cases/1,701 controls).
Associations with circulating biomarkers were replicated in the Multiethnic Cohort for IGF1 rs35767 and for IGFBP3 rs2854744, rs2854746, and rs3110697 (P < 0.05). Homozygous carriers of the glucokinase regulator (GCKR) rs780094 variant T-allele were at a decreased risk of colorectal cancer (OR, 0.77; 95% CI, 0.64–0.92). In risk factor–adjusted models, participants with the highest prediagnostic IGF-II levels were at an increased risk [OR (T1 vs. T3), 1.58; 95% CI, 1.09–2.28; Ptrend = 0.011] and participants with the highest prediagnostic IGF-binding protein (IGFBP)-3 levels were at a decreased risk of colorectal cancer (OR, 0.53; 95% CI, 0.34–0.83; Ptrend = 0.003).
These data provide further support for a role of prediagnostic IGF and insulin levels in the etiology of colorectal cancer.
Future studies attempting to replicate the association between the GCKR rs780094 variant and the risk of colorectal cancer are warranted.
PMCID: PMC4494075  PMID: 22354904
8.  Body mass index and mortality in an ethnically diverse population: the Multiethnic Cohort Study 
European journal of epidemiology  2012;27(7):489-497.
Body mass index (BMI) has been strongly related to overall mortality, but the consistency of this association across diverse ethnic groups and the effects of early adult BMI versus BMI in later adulthood have not been adequately studied. A prospective analysis was performed using data from 183,211 adults aged 45–75 who enrolled the population-based Multiethnic Cohort Study by completing a questionnaire that included self-reported weight and height information in 1993–1996. Participants were African Americans, Native Hawaiians, Japanese Americans, Latinos, and whites living in Hawaii and California. During an average 12.5 years of follow-up, 35,664 deaths were identified. To control for confounding caused by conditions that lead to weight loss and mortality, we excluded participants with a history of cancer or heart disease, who ever smoked, and who died within the first 3 years of follow-up. An increased risk of mortality was observed in participants with a BMI ≥ 27.5 in both men and women compared with the reference category of BMI 23.0–24.9; a BMI ≥ 35.0 carried a greater risk of mortality in men than in women. Although the findings were generally similar across ethnic groups, the association of higher BMI with mortality in Latino men appeared to be weaker than in the other groups. A BMI of 25.0–34.9 at age 21 showed a stronger positive association, with no further increase in risk for a BMI ≥ 35.0, than did BMI in later adulthood. These results indicate that the association of BMI with mortality is generally consistent across sex and ethnic groups, with some variation in the strength of the effect. Most notably, the effect of overweight in young adulthood appears to be much stronger than that of overweight in later adulthood on mortality in later life. This emphasizes the importance of weight management in childhood and adolescence.
PMCID: PMC4494097  PMID: 22644110
Body mass index; Cohort studies; Mortality; Multiethnic population; Obesity
9.  Dietary sources of five nutrients in ethnic groups represented in the Multiethnic Cohort 
The British journal of nutrition  2012;109(8):1479-1489.
Data are limited on how dietary sources of energy and nutrient intakes differ among ethnic groups in the USA. The objective of the present study was to characterise dietary sources of energy, total fat, saturated fat, protein, dietary fibre and added sugar for five ethnic groups. A validated quantitative FFQ was used to collect dietary data from 186916 men and women aged 45–75 years who were living in Hawaii and Los Angeles between 1993 and 1996. Participants represented five ethnic groups: African-American; Japanese-American; Native Hawaiian; Latino; Caucasian. The top ten dietary sources of energy contributed 36·2–49·6 % to total energy consumption, with rice and bread contributing the most (11·4–27·8 %) across all ethnic–sex groups. Major dietary sources of total fat were chicken/turkey dishes and butter among most groups. Ice cream, ice milk or frozen yogurt contributed 4·6–6·2 % to saturated fat intake across all ethnic–sex groups, except Latino-Mexico women. Chicken/turkey and bread were among the top dietary sources of protein (13·9–19·4 %). The top two sources of dietary fibre were bread and cereals (18·1–22 %) among all groups, except Latino-Mexico men. Regular sodas contributed the most to added sugar consumption. The present study provides, for the first time, data on the major dietary sources of energy, fat, saturated fat, protein, fibre and added sugar for these five ethnic groups in the USA. Such data are valuable for identifying target foods for nutritional intervention programmes and directing public health strategies aimed at reducing dietary risk factors for chronic disease.
PMCID: PMC4489548  PMID: 22947145
Dietary sources; Nutrients; Ethnicity; Multiethnic Cohort
10.  Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults 
PLoS ONE  2015;10(6):e0131106.
Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi-analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious.
PMCID: PMC4488332  PMID: 26125186
11.  Body size and breast cancer risk: the Multiethnic Cohort 
The influence of body size on postmenopausal breast cancer risk was investigated among five racial/ethnic groups in the Multiethnic Cohort. Participants were 45–75 years old at recruitment (1993–1996), living in Hawaii and California. Of the 82,971 White, African American, Native Hawaiian, Japanese and Latina women included in this analysis, 3,030 were diagnosed with invasive breast cancer. Body mass index (BMI), height, weight and adulthood weight gain were associated with a significantly higher risk and, with the exception of height, were found to vary across ethnic groups. Native Hawaiians and Japanese with a BMI ≥30.0 compared to 20.0–24.9 kg/m2 had the highest risk (hazard ratio = 1.82, 95% confidence interval: 1.31, 2.54, p-trend = 0.001, and hazard ratio = 1.59, 95% confidence interval: 1.24, 2.05, p-trend < 0.0001, respectively). Current hormone replacement therapy use modified the impact of a high BMI, as non- and former users had a significantly higher risk compared to current users. BMI also had a more pronounced risk for advanced tumors compared to localized tumors. When both BMI and adult weight gain were analyzed simultaneously, adult weight gain, rather than BMI, was a significant risk factor overall. These findings emphasize the significance of maintaining a healthy weight throughout adulthood for the prevention of postmenopausal breast cancer.
PMCID: PMC4484854  PMID: 22120517
breast cancer; body size; body mass index
12.  A food pattern that is predictive of flavonol intake and risk of pancreatic cancer2 
In the Multiethnic Cohort (MEC) study, we showed inverse associations between flavonols and pancreatic cancer risk.
We aimed to define a food pattern associated with intakes of quercetin, kaempferol, and myricetin; to examine the association of that pattern with pancreatic cancer risk; and to investigate the associations in an independent study.
Reduced rank regression was applied to dietary data for 183 513 participants in the MEC. A food group pattern was extracted and simplified and applied to dietary data of 424 978 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Dietary intake in both studies was assessed by using specially developed questionnaires. Multivariate Cox proportional hazards models were used to estimate relative risks for pancreatic cancer in the MEC (610 cases) and the EPIC (517 cases) studies.
The food group pattern consisted mainly of tea, fruit, cabbage, and wine. In the MEC, inverse associations with pancreatic cancer in smokers were observed for the food group pattern [relative risk: 0.59 (95% CI: 0.31, 1.12) when extreme quintiles were compared; P for trend = 0.03]. In the EPIC study, the simplified pattern was not associated with pancreatic cancer risk (P for trend = 0.78).
A food pattern associated with the intake of quercetin, kaempferol, and myricetin was associated with lower pancreatic cancer risk in smokers in a US-based population. However, failure to replicate the associations in an independent study weakens the conclusions and raises questions about the utility of food patterns for flavonols across populations.
PMCID: PMC4484860  PMID: 19064528
13.  The association of glycemic load and carbohydrate intake with colorectal cancer risk in the Multiethnic Cohort Study1–3 
High-glycemic-load diets may increase colorectal cancer risk through hyperinsulinemic effects.
We analyzed data for 191 004 participants in the Multiethnic Cohort Study to determine the risk of colorectal cancer associated with glycemic load (GL), carbohydrate, and sucrose and to ascertain whether this risk was modified by sex and ethnicity.
During 8 y of follow-up, 2379 incident cases of colorectal adenocarcinoma occurred. We used baseline quantitative food-frequency questionnaire data to assess usual dietary intake over the preceding year. Using Cox regression, we calculated adjusted relative risks (RRs) and 95% CIs for colorectal cancer associated with quintiles of GL, carbohydrate, and sucrose.
For both men and women in this cohort, white rice was the major contributor to GL. In multivariate models, RRs for colorectal cancer decreased significantly with increasing GL in women (RR for the highest quintile versus the lowest: 0.75; 95% CI: 0.57, 0.97; P for trend = 0.02) but not in men (RR: 1.15; 95% CI: 0.89, 1.48; P for trend = 0.19). Results for carbohydrate and sucrose were similar. The inverse association with GL was found in women of all ethnic groups (P for interaction = 0.58). In men, an interaction was found between ethnicity and GL (P < 0.01): white men had a positive association with increasing GL (RR: 1.69; 95% CI: 0.98, 2.92; P for trend < 0.01), but men of other ethnic groups did not.
GL and carbohydrate intake appear to protect against colorectal cancer in women in the Multiethnic Cohort, perhaps because a major source of GL is white rice.
PMCID: PMC4482108  PMID: 18842796
14.  A Multiethnic Cohort in Hawaii and Los Angeles: Baseline Characteristics 
American journal of epidemiology  2000;151(4):346-357.
The authors describe the design and implementation of a large multiethnic cohort established to study diet and cancer in the United States. They detail the source of the subjects, sample size, questionnaire development, pilot work, and approaches to future analyses. The cohort consists of 215,251 adult men and women (age 45–75 years at baseline) living in Hawaii and in California (primarily Los Angeles County) with the following ethnic distribution: African-American (16.3%), Latino (22.0%), Japanese-American (26.4%), Native Hawaiian (6.5%), White (22.9%), and other ancestry (5.8%). From 1993 to 1996, participants entered the cohort by completing a 26-page, self-administered mail questionnaire that elicited a quantitative food frequency history, along with demographic and other information. Response rates ranged from 20% in Latinos to 49% in Japanese-Americans. As expected, both within and among ethnic groups, the questionnaire data show substantial variations in dietary intakes (nutrients as well as foods) and in the distributions of non-dietary risk factors (including smoking, alcohol consumption, obesity, and physical activity). When compared with corresponding ethnic-specific cancer incidence rates, the findings provide tentative support for several current dietary hypotheses. As sufficient numbers of cancer cases are identified through surveillance of the cohort, dietary and other hypotheses will be tested in prospective analyses.
PMCID: PMC4482109  PMID: 10695593
alcohol drinking; cohort studies; diet; ethnic groups; obesity; physical fitness; prospective studies; smoking
15.  Calibration of the Dietary Questionnaire for a Multiethnic Cohort in Hawaii and Los Angeles 
American journal of epidemiology  2000;151(4):358-370.
The performance of the dietary questionnaire used in a multiethnic cohort study in Hawaii and Los Angeles was assessed in a calibration substudy that compared diet reported from the questionnaire with three 24-hour dietary recalls. For the calibration substudy, subjects from each of eight subgroups defined by sex and ethnic group (African-American, Japanese-American, Latino, and White) were chosen randomly from among the cohort members, and each participant’s previous day’s diet was assessed by telephone recall on three occasions over approximately 2 months. After completing the three 24-hour recalls, each calibration subject was sent a second questionnaire; 1,606 persons completed three recalls and a second questionnaire (127 to 267 per ethnic-sex group). This report describes correlation coefficients and calibration slopes for the relation between the 24-hour recalls and second questionnaire values for a selected set of macro- and micronutrients, as absolute intakes, nutrient densities, and calorie-adjusted nutrients. In all subgroups, estimates of the correlation between the questionnaire and 24-hour recalls were greater after energy adjustment (average correlations ranged from 0.57–0.74 for nutrient densities and from 0.55–0.74 for calorie-adjusted nutrients) than when absolute nutrient values were used (average range 0.26–0.57). For absolute nutrient intakes, the correlations were greatest for Whites, somewhat lower for Japanese-Americans and Latinos, and lowest for African-Americans. After energy adjustment, the difference between subgroups were diminished, and the correlations were generally highly satisfactory.
PMCID: PMC4482461  PMID: 10695594
calibration; diet surveys; epidemiologic methods; ethnic groups; nutrition surveys; questionnaires
16.  Association of vegetable, fruit, and grain intakes with colorectal cancer: the Multiethnic Cohort Study123 
It is uncertain whether or not vegetables, fruit, or grains protect against colorectal cancer.
In a large prospective study, we investigated the association of vegetable, fruit, and grain intakes with colorectal cancer risk.
Between 1993 and 1996, 85 903 men and 105 108 women completed a quantitative food-frequency questionnaire that included ≈180 foods and beverages in the Multiethnic Cohort Study. A diagnosis of colorectal cancer was made in 1138 men and 972 women after an average follow-up of 7.3 y. Cox proportional hazards models were used to calculate multivariate-adjusted relative risks and 95% CIs for colorectal cancer.
In men, multivariate adjustment for energy intake, dietary, and nondietary variables resulted in relative risks in the highest quintile group of 0.74 (95% CI: 0.59, 0.93; P for trend = 0.02) for vegetables and fruit combined, 0.80 (95% CI: 0.64, 0.99; P for trend = 0.09) for fruit alone, and 0.85 (95% CI: 0.69, 1.05; P for trend = 0.05) for vegetables alone. When colon and rectal cases were separated among men, the inverse associations were stronger for colon than for rectal cancer. In women, none of the associations with vegetables, fruit, or vegetables and fruit combined were significant. Grain intake was not associated with colorectal cancer for either men or women.
The intake of vegetables and fruit was inversely related to colorectal cancer risk among men but not among women. The association appears stronger for colon than for rectal cancer.
PMCID: PMC4482464  PMID: 18779290
17.  The Prevalence of Obesity in Ethnic Admixture Adults 
Obesity (Silver Spring, Md.)  2008;16(5):1138-1143.
To determine whether the prevalence of obesity in ethnic admixture adults varies systematically from the average of the prevalence estimates for the ethnic groups with whom they share a common ethnicity.
Methods and Procedures
The sample included 215,000 adults who reported one or more ethnicities, height, weight, and other characteristics through a mailed survey.
The highest age-adjusted prevalence of overweight (BMI ≥ 25) was in Hawaiian/Latino men (88%; n = 41) and black/Latina women (74.5%; n = 79), and highest obesity (BMI ≥ 30) rates were in Hawaiian/Latino men (53.7%; n = 41) and Hawaiian women (39.2%, n = 1,247). The prevalence estimates for most admixed groups were similar to or higher than the average of the prevalences for the ethnic groups with whom they shared common ethnicities. For instance, the prevalence of overweight/obesity in five ethnic admixtures—Asian/white, Hawaiian/white, Hawaiian/Asian, Latina/white, and Hawaiian/Asian/white ethnic admixtures—was significantly higher (P < 0.0001) than the average of the prevalence estimates for their component ethnic groups.
The identification of individuals who have a high-risk ethnic admixture is important not only to the personal health and well-being of such individuals, but could also be important to future efforts in order to control the epidemic of obesity in the United States.
PMCID: PMC4479279  PMID: 18356848
18.  Dietary Fiber and Amyotrophic Lateral Sclerosis: Results From 5 Large Cohort Studies 
American Journal of Epidemiology  2014;179(12):1442-1449.
Amyotrophic lateral sclerosis (ALS) is a fast-progressing neurodegenerative disease with a median survival time from diagnosis of 1.5–3 years. The cause of ALS is unknown, but inflammation may play a role. Fiber has been shown to lower inflammatory markers, and a high fiber intake was associated with a lower risk of ALS in a case-control study; however, prospective studies are lacking. We explored the relation between dietary intake of fiber and the risk of ALS in 5 large prospective cohort studies comprising over 1,050,000 US citizens who contributed 1,133 ALS cases during a mean of 15 years of follow-up (1980–2008). Cox proportional hazards models were used within each cohort, and cohort-specific estimates were subsequently pooled using a random-effects model. We found that intakes of total fiber, cereal fiber, vegetable fiber, and fruit fiber were not associated with ALS risk when comparing the highest quintile of intake with the lowest (for total fiber, pooled multivariable relative risk (RR) = 0.99, 95% confidence interval (CI): 0.80, 1.24; for cereal fiber, RR = 1.13, 95% CI: 0.94, 1.37; for vegetable fiber, RR = 0.97, 95% CI: 0.77, 1.23; and for fruit fiber, RR = 1.05, 95% CI: 0.86, 1.29). These findings do not support the hypothesis that fiber intake is a major determinant of ALS risk.
PMCID: PMC4051879  PMID: 24816788
amyotrophic lateral sclerosis; fiber; longitudinal cohort studies; motor neuron disease
20.  Coffee Intake and Risk of Type 2 Diabetes: The Multiethnic Cohort 
Public health nutrition  2013;17(6):1328-1336.
We evaluated the influence of coffee consumption on diabetes incidence among the Hawaii component of the Multiethnic Cohort (MEC).
Prospective cohort.
Population-based sample residing in Hawaii.
After exclusions, 75,140 men and women of Caucasian, Japanese American, and Native Hawaiian ancestry aged 45–75 were part of this analysis. All participants provided information on diet and lifestyle through a food frequency questionnaire. After 14 years of follow-up 8,582 incident diabetes cases were identified using self-reports, medication questionnaires, and health plan linkages. Hazard ratios (HR) and 95% confidence intervals (95%CI) were calculated using Cox regression while adjusting for known covariates.
The risk for diabetes associated with total coffee consumption differed by sex (Pinteraction<0.0001). Women consuming ≥3 cups/day of any type of coffee had a significantly lower risk (HR: 0.66; 95%CI: 0.58, 0.77; Ptrend<0.0001) than those reporting <1 cup, whereas the relation in men was borderline (HR: 0.89; 95%CI: 0.80, 0.99; Ptrend=0.09). The same difference by sex was seen for regular coffee with HRs of 0.65 (95%CI: 0.54, 0.78; Ptrend<0.0001) and 0.86 (95%CI: 0.75, 0.98; Ptrend=0.09) in men and women, respectively. No significant association with diabetes was apparent for decaffeinated coffee in women (HR: 0.85; 95%CI: 0.72, 1.01; Ptrend=0.73) or men (HR: 1.07; 95%CI: 0.93, 1.23; Ptrend=0.71). Despite small differences by ethnicity, the interaction terms between coffee intake and ethnicity were not significant.
In this multiethnic population, regular, but not decaffeinated, coffee intake was much more protective against diabetes in women of all ethnic groups than in men.
PMCID: PMC4230482  PMID: 23442347
Type 2 diabetes; coffee; ethnicity; risk factors; cohort study
21.  A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer 
Al Olama, Ali Amin | Kote-Jarai, Zsofia | Berndt, Sonja I. | Conti, David V. | Schumacher, Fredrick | Han, Ying | Benlloch, Sara | Hazelett, Dennis J. | Wang, Zhaoming | Saunders, Ed | Leongamornlert, Daniel | Lindstrom, Sara | Jugurnauth-Little, Sara | Dadaev, Tokhir | Tymrakiewicz, Malgorzata | Stram, Daniel O. | Rand, Kristin | Wan, Peggy | Stram, Alex | Sheng, Xin | Pooler, Loreall C. | Park, Karen | Xia, Lucy | Tyrer, Jonathan | Kolonel, Laurence N. | Le Marchand, Loic | Hoover, Robert N. | Machiela, Mitchell J. | Yeager, Merideth | Burdette, Laurie | Chung, Charles C. | Hutchinson, Amy | Yu, Kai | Goh, Chee | Ahmed, Mahbubl | Govindasami, Koveela | Guy, Michelle | Tammela, Teuvo L.J. | Auvinen, Anssi | Wahlfors, Tiina | Schleutker, Johanna | Visakorpi, Tapio | Leinonen, Katri A. | Xu, Jianfeng | Aly, Markus | Donovan, Jenny | Travis, Ruth C. | Key, Tim J. | Siddiq, Afshan | Canzian, Federico | Khaw, Kay-Tee | Takahashi, Atsushi | Kubo, Michiaki | Pharoah, Paul | Pashayan, Nora | Weischer, Maren | Nordestgaard, Borge G. | Nielsen, Sune F. | Klarskov, Peter | Røder, Martin Andreas | Iversen, Peter | Thibodeau, Stephen N. | McDonnell, Shannon K | Schaid, Daniel J | Stanford, Janet L. | Kolb, Suzanne | Holt, Sarah | Knudsen, Beatrice | Coll, Antonio Hurtado | Gapstur, Susan M. | Diver, W. Ryan | Stevens, Victoria L. | Maier, Christiane | Luedeke, Manuel | Herkommer, Kathleen | Rinckleb, Antje E. | Strom, Sara S. | Pettaway, Curtis | Yeboah, Edward D. | Tettey, Yao | Biritwum, Richard B. | Adjei, Andrew A. | Tay, Evelyn | Truelove, Ann | Niwa, Shelley | Chokkalingam, Anand P. | Cannon-Albright, Lisa | Cybulski, Cezary | Wokołorczyk, Dominika | Kluźniak, Wojciech | Park, Jong | Sellers, Thomas | Lin, Hui-Yi | Isaacs, William B. | Partin, Alan W. | Brenner, Hermann | Dieffenbach, Aida Karina | Stegmaier, Christa | Chen, Constance | Giovannucci, Edward L. | Ma, Jing | Stampfer, Meir | Penney, Kathryn L. | Mucci, Lorelei | John, Esther M. | Ingles, Sue A. | Kittles, Rick A. | Murphy, Adam B. | Pandha, Hardev | Michael, Agnieszka | Kierzek, Andrzej M. | Blot, William | Signorello, Lisa B. | Zheng, Wei | Albanes, Demetrius | Virtamo, Jarmo | Weinstein, Stephanie | Nemesure, Barbara | Carpten, John | Leske, Cristina | Wu, Suh-Yuh | Hennis, Anselm | Kibel, Adam S. | Rybicki, Benjamin A. | Neslund-Dudas, Christine | Hsing, Ann W. | Chu, Lisa | Goodman, Phyllis J. | Klein, Eric A | Zheng, S. Lilly | Batra, Jyotsna | Clements, Judith | Spurdle, Amanda | Teixeira, Manuel R. | Paulo, Paula | Maia, Sofia | Slavov, Chavdar | Kaneva, Radka | Mitev, Vanio | Witte, John S. | Casey, Graham | Gillanders, Elizabeth M. | Seminara, Daniella | Riboli, Elio | Hamdy, Freddie C. | Coetzee, Gerhard A. | Li, Qiyuan | Freedman, Matthew L. | Hunter, David J. | Muir, Kenneth | Gronberg, Henrik | Neal, David E. | Southey, Melissa | Giles, Graham G. | Severi, Gianluca | Cook, Michael B. | Nakagawa, Hidewaki | Wiklund, Fredrik | Kraft, Peter | Chanock, Stephen J. | Henderson, Brian E. | Easton, Douglas F. | Eeles, Rosalind A. | Haiman, Christopher A.
Nature genetics  2014;46(10):1103-1109.
Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of >10 million SNPs in 43,303prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three novel susceptibility loci were revealed at P<5×10-8; 15 variants were identified among men of European ancestry, 7 from multiethnic analyses and one was associated with early-onset prostate cancer. These 23 variants, in combination with the known prostate cancer risk variants, explain 33% of the familial risk of the disease in European ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the utility of combining ancestrally diverse populations to discover risk loci for disease.
PMCID: PMC4383163  PMID: 25217961
22.  Multi-Ancestral Analysis of Inflammation-Related Genetic Variants and C-Reactive Protein in the Population Architecture using Genomics and Epidemiology (PAGE) Study 
C-reactive protein (CRP) is a biomarker of inflammation. Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with CRP concentrations and inflammation-related traits such as cardiovascular disease, type 2 diabetes, and obesity. We aimed to replicate previous CRP-SNP associations, assess whether these associations generalize to additional race/ethnicity groups, and evaluate inflammation-related SNPs for a potentially pleiotropic association with CRP.
Methods and Results
We selected and analyzed 16 CRP-associated and 250 inflammation-related GWAS SNPs among 40,473 African American, American Indian, Asian/Pacific Islander, European American, and Hispanic participants from 7 studies collaborating in the Population Architecture using Genomics and Epidemiology (PAGE) study. Fixed-effect meta-analyses combined study-specific race/ethnicity-stratified linear regression estimates to evaluate the association between each SNP and high-sensitivity CRP. Overall, 18 SNPs in 8 loci were significantly associated with CRP (Bonferroni-corrected p<3.1×10−3 for replication, p<2.0×10−4 for pleiotropy): Seven of these were specific to European Americans, while 9 additionally generalized to African Americans (1), Hispanics (5), or both (3); 1 SNP was seen only in African Americans and Hispanics. Two SNPs in the CELSR2/PSRC1/SORT1 locus showed a potentially novel association with CRP: rs599839 (p=2.0×10−6) and rs646776 (p=3.1×10−5).
We replicated 16 SNP-CRP associations, 10 of which generalized to African Americans and/or Hispanics. We also identified potentially novel pleiotropic associations with CRP for two SNPs previously associated with coronary artery disease and LDL cholesterol. These findings demonstrate the benefit of evaluating genotype-phenotype associations in multiple race/ethnicity groups, and of looking for pleiotropic relationships among SNPs previously associated with related phenotypes.
PMCID: PMC4104750  PMID: 24622110
genetic epidemiology; inflammation; C-reactive protein; race and ethnicity; single nucleotide polymorphism; pleiotropy
23.  Ethnic differences and predictors of colonoscopy, prostate-specific antigen, and mammography screening participation in the multiethnic cohort 
Cancer epidemiology  2014;38(2):162-167.
Given the relation between screening and improved cancer outcomes and the persistence of ethnic disparities in cancer mortality, we explored ethnic differences in colonoscopy, prostate-specific antigen (PSA), and mammography screening in the Multiethnic Cohort Study.
Logistic regression was applied to examine the influence of ethnicity as well as demographics, lifestyle factors, comorbidities, family history of cancer, and previous screening history on self-reported screening participation collected in 1999–2002.
The analysis included 140,398 participants who identified as white, African American, Native Hawaiian, Japanese American, US born-Latino, or Mexican born-Latino. The screening prevalences overall were mammography: 88% of women, PSA: 45% of men, and colonoscopy: 35% of men and women. All minority groups reported 10–40% lower screening utilization than whites, but Mexican-born Latinos and Native Hawaiian were lowest. Men were nearly twice as likely to have a colonoscopy (OR = 1.94, 95% CI = 1.89–1.99) as women. A personal screening history, presence of comorbidities, and family history of cancer predicted higher screening utilization across modalities, but to different degrees across ethnic groups.
This study confirms previously reported sex differences in colorectal cancer screening and ethnic disparities in screening participation. The findings suggest it may be useful to include personal screening history and family history of cancer into counseling patients about screening participation.
PMCID: PMC4325992  PMID: 24667037
Mammogram; PSA; Colonoscopy; Cancer screening; Ethnic differences
24.  Vitamin D Metabolic Pathway Genes and Pancreatic Cancer Risk 
PLoS ONE  2015;10(3):e0117574.
Evidence on the association between vitamin D status and pancreatic cancer risk is inconsistent. This inconsistency may be partially attributable to variation in vitamin D regulating genes. We selected 11 vitamin D-related genes (GC, DHCR7, CYP2R1, VDR, CYP27B1, CYP24A1, CYP27A1, RXRA, CRP2, CASR and CUBN) totaling 213 single nucleotide polymorphisms (SNPs), and examined associations with pancreatic adenocarcinoma. Our study included 3,583 pancreatic cancer cases and 7,053 controls from the genome-wide association studies of pancreatic cancer PanScans-I-III. We used the Adaptive Joint Test and the Adaptive Rank Truncated Product statistic for pathway and gene analyses, and unconditional logistic regression for SNP analyses, adjusting for age, sex, study and population stratification. We examined effect modification by circulating vitamin D concentration (≤50, >50 nmol/L) for the most significant SNPs using a subset of cohort cases (n = 713) and controls (n = 878). The vitamin D metabolic pathway was not associated with pancreatic cancer risk (p = 0.830). Of the individual genes, none were associated with pancreatic cancer risk at a significance level of p<0.05. SNPs near the VDR (rs2239186), LRP2 (rs4668123), CYP24A1 (rs2762932), GC (rs2282679), and CUBN (rs1810205) genes were the top SNPs associated with pancreatic cancer (p-values 0.008–0.037), but none were statistically significant after adjusting for multiple comparisons. Associations between these SNPs and pancreatic cancer were not modified by circulating concentrations of vitamin D. These findings do not support an association between vitamin D-related genes and pancreatic cancer risk. Future research should explore other pathways through which vitamin D status might be associated with pancreatic cancer risk.
PMCID: PMC4370655  PMID: 25799011
25.  Anthropometric and Hormonal Risk Factors for Male Breast Cancer: Male Breast Cancer Pooling Project Results 
The etiology of male breast cancer is poorly understood, partly because of its relative rarity. Although genetic factors are involved, less is known regarding the role of anthropometric and hormonally related risk factors.
In the Male Breast Cancer Pooling Project, a consortium of 11 case–control and 10 cohort investigations involving 2405 case patients (n = 1190 from case–control and n = 1215 from cohort studies) and 52013 control subjects, individual participant data were harmonized and pooled. Unconditional logistic regression generated study design–specific (case–control/cohort) odds ratios (ORs) and 95% confidence intervals (CIs), with exposure estimates combined using fixed effects meta-analysis. All statistical tests were two-sided.
Risk was statistically significantly associated with weight (highest/lowest tertile: OR = 1.36; 95% CI = 1.18 to 1.57), height (OR = 1.18; 95% CI = 1.01 to 1.38), and body mass index (BMI; OR = 1.30; 95% CI = 1.12 to 1.51), with evidence that recent rather than distant BMI was the strongest predictor. Klinefelter syndrome (OR = 24.7; 95% CI = 8.94 to 68.4) and gynecomastia (OR = 9.78; 95% CI = 7.52 to 12.7) were also statistically significantly associated with risk, relations that were independent of BMI. Diabetes also emerged as an independent risk factor (OR = 1.19; 95% CI = 1.04 to 1.37). There were also suggestive relations with cryptorchidism (OR = 2.18; 95% CI = 0.96 to 4.94) and orchitis (OR = 1.43; 95% CI = 1.02 to 1.99). Although age at onset of puberty and histories of infertility were unrelated to risk, never having had children was statistically significantly related (OR = 1.29; 95% CI = 1.01 to 1.66). Among individuals diagnosed at older ages, a history of fractures was statistically significantly related (OR = 1.41; 95% CI = 1.07 to 1.86).
Consistent findings across case–control and cohort investigations, complemented by pooled analyses, indicated important roles for anthropometric and hormonal risk factors in the etiology of male breast cancer. Further investigation should focus on potential roles of endogenous hormones.
PMCID: PMC3975166  PMID: 24552677

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