Experimental studies have provided evidence that zinc has a protective effect against development and progression of prostate cancer. However, epidemiological studies have reported inconsistent findings. We evaluated the association between prediagnostic serum zinc and prostate cancer risk in a cohort of multiethnic population.
This case-control study is nested within the Multiethnic Cohort of African Americans, Native Hawaiians, Japanese Americans, Latinos, and whites in Hawaii and California. The analysis included 392 prostate cancer cases and 783 controls matched on age, race/ethnicity, date/time of blood draw and fasting status. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI).
The mean serum zinc concentrations did not significantly differ between cases (94.9 μg/dl) and controls (93.9 μg/dl). No association was found between serum zinc levels and prostate cancer either overall or by tumor stage/grade. In ethnic-specific analyses, positive associations were found in Japanese Americans (OR for the highest vs. the lowest tertile = 2.59, 95% CI: 1.09–6.17) and Latinos (OR = 2.74, 95% CI: 1.05–7.10), whereas no association was observed in African Americans and whites.
We found no evidence to support an inverse relationship between serum zinc and prostate cancer risk, and, to the contrary, found a suggestion in the ethnic-specific results of a possible increase in risk; however, blood concentrations of zinc may not adequately reflect the levels in prostate tissue. Further study with a larger sample size, and if possible, with assessment of zinc tissue levels, is warranted to confirm these findings.
zinc; prostate cancer; nested case-control study; multiethnic population
A common genetic variant (rs10993994) in the 5’ region of the gene encoding β-microseminoprotein (MSP) is associated with circulating levels of MSP and prostate cancer risk. Whether MSP levels are predictive of prostate cancer risk has not been evaluated.
We investigated the prospective relationship between circulating plasma levels of MSP and prostate cancer risk in a nested case–control study of 1503 case subjects and 1503 control subjects among black, Latino, Japanese, Native Hawaiian, and white men from the Multiethnic Cohort study. We also examined the ability of MSP to serve as a biomarker for discriminating prostate cancer case subjects from control subjects. All statistical tests are two-sided.
In all racial and ethnic groups, men with lower MSP levels were at greater risk of developing prostate cancer (odds ratio = 1.02 per one unit decrease in MSP, P < .001 in the prostate-specific antigen [PSA]–adjusted analysis). Compared with men in the highest decile of MSP, the multivariable PSA-adjusted odds ratio was 3.64 (95% confidence interval = 2.41 to 5.49) for men in the lowest decile. The positive association with lower MSP levels was observed consistently across racial and ethnic populations, by disease stage and Gleason score, for men with both high and low levels of PSA and across all genotype classes of rs10993994. However, we did not detect strong evidence of MSP levels in improving prostate cancer prediction beyond that of PSA.
Regardless of race and ethnicity or rs10993994 genotype, men with low blood levels of MSP have increased risk of prostate cancer.
Prior research has suggested the possible role of oxidative stress in the pathogenesis of amyotrophic lateral sclerosis (ALS). Prospective data examining dietary antioxidants such carotenoids and vitamin C are limited.
Risk of ALS associated with carotenoid and vitamin C intake was investigated in 5 prospective cohorts: the National Institutes of Health – AARP Diet and Health Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort, the Health Professionals Follow-up Study, and the Nurses Health Study. ALS deaths were documented using the National Death Index and confirmed nonfatal ALS cases were included from HPFS and NHS. A total of 1153 ALS deaths occurred among 1,100,910 participants (562,942 men; 537,968 women). Participants were categorized into cohort-specific quintiles of intake for dietary variables. We applied Cox proportional hazards regression to calculate cohort-specific risk ratios (RR), and pooled results using random-effects methods.
A greater total major carotenoids intake was associated with a reduced risk of ALS (pooled, multivariable-adjusted RR for the highest to the lowest quintile: 0.75; 95% CI: 0.61 to 0.91; P trend = 0.004). Individually, higher dietary intakes of β-carotene and lutein were inversely associated with ALS risk. The pooled multivariable RRs comparing the highest to the lowest quintile for β- carotene and lutein were 0.85 (95% CI: 0.64–1.13; P trend=0.03) and 0.79 (95% CI: 0.64 to 0.96; P trend=0.01), respectively. Lycopene, β-cryptoxanthin, and vitamin C were not associated with reduced risk of ALS.
Consumption of foods high in carotenoids may help prevent or delay onset of ALS.
A relationship between female reproductive and menstrual factors, including exogenous hormone use, and renal cell cancer (RCC) has been hypothesized, but supporting epidemiologic evidence is limited and inconsistent. Here, the association of reproductive and menstrual factors with RCC risk was examined among 106,036 Hawaii-Los Angeles Multiethnic Cohort female participants who entered the cohort between 1993 and 1996. During an average 10.6 years of follow-up, 229 RCC cases were identified among these women. Data on known and potential risk factors were obtained from the baseline questionnaire. Relative risks and 95% confidence intervals for RCC associated with each factor were estimated using Cox proportional hazard models stratified by race/ ethnicity, study center, and menopausal status and adjusted for age and several confounding factors. We found no evidence of association between RCC and parity, age at first birth, age at menarche, age and type of menopause (hysterectomy or bilateral oophorectomy), use and duration of oral contraceptive, and type and duration of postmenopausal hormone use. Our results do not support the hypothesis that hormone-related factors play an etiologic role in RCC among women.
This study tested the hypothesis that prediagnostic soy intake was inversely associated with all-cause and breast cancer-specific mortality. The analyses included 3,842 female in the Multiethnic Cohort (MEC) study of African Americans, Native Hawaiians, Japanese Americans, Latinos, and Caucasians, who completed a quantitative food frequency questionnaire, aged ≥50 years at cohort entry, and diagnosed with primary invasive breast cancer following cohort entry (1993-2007). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated from Cox proportional hazards regression with adjustment for known clinical and lifestyle factors. During a mean follow-up after diagnosis of invasive breast cancer of 6.2±3.8 years, there were 804 deaths including 376 breast cancer-specific deaths. The HR (95%CI) for all-cause and breast cancer-specific morality comparing the highest versus lowest tertiles were 1.03 (0.81-1.33) and 1.03 (0.71-1.50) for soy products and 0.99 (0.82-1.20) and 0.95 (0.71-1.28) for total isoflavones, respectively (Ptrend > 0.60 for all). There was limited evidence of differences by hormone receptor status, tumor stage, or ethnic group. Prediagnostic soy intake was unrelated to mortality in postmenopausal women. Our findings are consistent with the literature that soy consumption does not adversely affect breast cancer survival in women.
Breast neoplasms; ethnic groups; soy foods; isoflavones; survival; postmenopause
Observational studies have found an inverse association between type 2 diabetes (T2D) and prostate cancer (PCa), and genome-wide association studies have found common variants near 3 loci associated with both diseases. The authors examined whether a genetic background that favors T2D is associated with risk of advanced PCa. Data from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium, a genome-wide association study of 2,782 advanced PCa cases and 4,458 controls, were used to evaluate whether individual single nucleotide polymorphisms or aggregations of these 36 T2D susceptibility loci are associated with PCa. Ten T2D markers near 9 loci (NOTCH2, ADCY5, JAZF1, CDKN2A/B, TCF7L2, KCNQ1, MTNR1B, FTO, and HNF1B) were nominally associated with PCa (P < 0.05); the association for single nucleotide polymorphism rs757210 at the HNF1B locus was significant when multiple comparisons were accounted for (adjusted P = 0.001). Genetic risk scores weighted by the T2D log odds ratio and multilocus kernel tests also indicated a significant relation between T2D variants and PCa risk. A mediation analysis of 9,065 PCa cases and 9,526 controls failed to produce evidence that diabetes mediates the association of the HNF1B locus with PCa risk. These data suggest a shared genetic component between T2D and PCa and add to the evidence for an interrelation between these diseases.
carcinoma; diabetes mellitus, type 2; genetic predisposition to disease; genetics; genome-wide association study; humans; polymorphism, single nucleotide; prostatic neoplasms
The survival of malignant breast cells depends upon remodeling of the extracellular matrix, including complex interactions with matrix metalloproteinases (MMPs). It has been hypothesized that circulating MMPs may serve as early indicators of breast cancer development in hospital-based case-control studies. A nested case-control study of the association of pre-diagnostic plasma levels of MMPs with the subsequent risk of postmenopausal breast cancer was conducted within the Multiethnic Cohort. During the follow-up period, 713 women with incident invasive breast cancer were identified and individually (1:1) matched to controls. Four types of MMPs (1, 2, 3, and 7) were analyzed by microsphere immunofluorescence assay. Mean plasma levels of MMPs did not differ significantly between cases and controls; nor were there differences in breast cancer risk by MMP level. No difference in the risk of breast cancer by plasma level of the MMPs was found within strata of age, or ethnicity, although MMP-1 levels were positively associated with breast cancer risk in obese women and women using hormone replacement medications (P Values for interaction < 0.05). Few significant differences in risk by levels of the MMPs were found by any of the clinical variables. Circulating MMPs were not associated with postmenopausal breast cancer risk.
Breast cancer; matrix metalloproteinases; body mass index; hormone replacement therapy; neoplasm staging; nested case-control study
Adiposity is often approximated by body mass index (BMI) in population studies based on self-reported weight and height (kg/m2). However, self-reports tend to underestimate weight and overestimate height, leading to an underestimation of BMI and the prevalence of overweight and obesity. We examined a subgroup of the Multiethnic Cohort Study participants to determine how well self-reported and measured anthropometry correlate with each other, overall and by race/ethnicity, total and abdominal adiposity level, and amount of adulthood weight gain. A cross-sectional sample of 30 Caucasian and 30 Japanese American female cohort participants, between ages 60–65, was selected in such a way the two groups had a similar BMI distribution across the range (18.5–40 kg/m2). Subjects first reported their weight, height, and waist and hip circumferences at home and within several days underwent objective measurements by trained staff and also a whole-body scan of dual energy X-ray absorptiometry (DXA) at a study clinic. The women under-reported their weight by 0.93 kg, waist circumference by 3.95 cm and hip circumference by 0.10 cm and over-reported their height by 0.85 cm. This led to an under-estimation of BMI by 0.67 kg/m2 and waist/hip ratio by 0.04. The effect of misreporting (self-report minus measurement) on BMI and waist/hip ratio was significantly greater in higher BMI groups (p-heterogeneity = 0.007 for BMI, 0.0005 for waist/hip ratio), among women with central obesity (waist circumference > 88 cm; p-heterogeneity = 0.006, 0.01) and among women who had gained higher amounts of weight since age 21 (p-heterogeneity = 0.03, 0.01) compared to their counterparts. A similar trend of greater self-report bias was found among women with higher levels of DXA-based total and abdominal adiposity. We did not observe any heterogeneity in these findings by ethnicity. Our results confirm that a small degree of under-reporting exists in self-reported BMI and waist/hip ratio values, and it tends to increase in women with a larger current body size or history of greater weight gain. Studies are underway to investigate this question in greater depth in men and women from five race/ethnic groups.
anthropometry; central obesity; obesity; race/ethnicity; self-report
Evidence from experimental and epidemiological studies suggests that vitamin B6 may reduce the risk of breast cancer.
We examined the association of prediagnostic plasma concentrations of pyridoxal-5’-phosphate (PLP), an active form of vitamin B6, with postmenopausal breast cancer risk in a case-control study nested in the Multiethnic Cohort in Hawaii and Southern California, including 706 cases and 706 controls matched on date of birth, ethnicity, study site, date of blood draw, time of blood draw, hours of fasting prior to blood draw, and use of menopausal hormones. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression models.
Women with plasma PLP concentrations in the highest quartile had a 30% reduced risk of invasive breast cancer (CI: 0.50–0.98) compared to the women in the lowest PLP quartile (P for trend=0.02). The association appeared to be limited to cases with hormone receptor-positive tumors (P for heterogeneity=0.04); and remained unchanged in the analysis restricted to women with blood samples collected more than one year prior to cancer diagnosis (OR=0.69; CI: 0.48–0.99; P for trend=0.03).
These data suggest that higher circulating levels of vitamin B6 are associated with a reduced risk of invasive postmenopausal breast cancer.
These results, in combination with information from two other prospective studies, suggest a role for vitamin B6 in the prevention of postmenopausal breast cancer. Additional studies are needed to further investigate potential heterogeneity of the vitamin B6 association with breast cancer risk by tumor hormone receptor status.
invasive breast carcinoma; pyridoxal 5'-phosphate; nested case-control study
Greater consumption of red and processed meat has been associated with an increased risk of colorectal cancer in several recent meta-analyses. Heterocyclic amines (HCAs) have been hypothesized to underlie this association. In this prospective analysis conducted within the Multiethnic Cohort Study, we examined whether greater consumption of total, red, or processed meat was associated with the risk of colorectal cancer among 165,717 participants who completed a detailed food frequency questionnaire at baseline. In addition, we examined whether greater estimated intake of HCAs was associated with the risk of colorectal cancer among 131,763 participants who completed a follow-up questionnaire that included a meat-cooking module. A total of 3,404 and 1,757 invasive colorectal cancers were identified from baseline to the end of follow-up, and from the date of administration of the meat-cooking module to the end of follow-up, respectively. Proportional hazards models were used to estimate basic and multivariable-adjusted relative risks (RRs) and 95% confidence intervals (CIs) for colorectal cancer associated with dietary exposures. In multivariable models, no association with the risk of colorectal cancer was detected for density-adjusted total meat (RRQ5 vs Q1=0.93 [0.83–1.05]), red meat (RR =1.02 [0.91–1.16]), or processed meat intake (RR =1.06 [0.94–1.19]), or for total (RR =0.90 [0.76–1.05]) or specific HCA intake whether comparing quintiles of dietary exposure or using continuous variables. Although our results do not support a role for meat or for HCAs from meat in the etiology of colorectal cancer, we cannot rule out the possibility of a modest effect.
colorectal cancer; meat; multiethnic population; heterocyclic amines; food frequency questionnaire
Composition of dietary fatty acid intake, which influences cytokine production, may contribute to the development of non-Hodgkin’s lymphoma (NHL). Serum lipid levels may serve as biomarkers of inflammation associated with NHL risk.
We conducted a case-control analysis (275 cases and 549 controls) nested within the Multiethnic Cohort Study (whites, Japanese Americans, Latinos, African Americans, and Native Hawaiians) to examine the association of pre-diagnostic, erythrocyte membrane phospholipid fatty acid composition and serum cholesterol and triglyceride (TG) concentrations with the risk of NHL. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) by tertiles of biomarker concentrations.
Higher total saturated fatty acids (SFA) were associated with an increase in NHL risk (ORT3 vs. T1=1.57 [95% CI: 1.03-2.39]; ptrend=0.01), whereas no associations were detected for total n-3 or n-6 polyunsaturated fatty acids. Inverse associations were observed for total cholesterol (TC; OR T3 vs. T1=0.51 [95% CI: 0.35, 0.74]; ptrend <0.0001) and high-density lipoprotein cholesterol (HDL-C; OR T3 vs. T1=0.47 [95% CI: 0.31, 0.71]; ptrend =0.0001) but not for low-density lipoprotein cholesterol or TG. Adjustment for the use of lipid-lowering medication did not modify the results substantially.
This prospective biomarker investigation offers supportive evidence for an adverse effect of higher erythrocyte membrane SFA levels on NHL risk, but preclinical effects cannot be excluded. Inverse relations between pre-diagnostic, circulating TC and HDL-C and NHL risk may be due to reverse causation or a result of protective actions of these lipids and lipoproteins.
non-Hodgkin lymphoma; fatty acids; serum lipids; multiethnic population; nested case-control study
Obesity is a leading contributor to colorectal cancer risk. We investigated whether the risk variants identified in genome-wide association studies of body mass index (BMI) and waist size are associated with colorectal cancer risk, independently of the effect of obesity phenotype due to a shared etiology. Twenty four SNPs in 15 loci (BDNF, FAIM2, FTO, GNPDA2, KCTD15, LYPLAL1, MC4R, MSRA, MTCH2, NEGR1, NRXN3, SEC16B, SH2B1, TFAP2B, and TMEM18) were genotyped in a case-control study of 2,033 colorectal cancer cases and 9,640 controls nested within the Multiethnic Cohort Study, as part of the Population Architecture using Genomics and Epidemiology (PAGE) consortium. Risk alleles for two obesity SNPs were associated with colorectal cancer risk – KCTD15 rs29941 [odds ratio (OR) for C allele = 0.90, 95% confidence interval (CI) 0.83–0.98; p = 0.01] and MC4R rs17782313 (OR for C allele = 1.12, 95% CI 1.02–1.22; p = 0.02). These associations were independent of the effect of BMI. However, none of the results remained significant after adjustment for multiple comparisons. No heterogeneity was observed across race/ethnic groups. Our findings suggest that the obesity risk variants are not likely to affect the risk of colorectal cancer substantially.
genotype-phenotype interactions; obesity; pleiotropy; prospective nested case-control studies; race/ethnicity
Stroke is the fourth leading cause of death in the U.S. and stroke mortality rates differ substantially by ethnic group. The impact of adherence to the USDA dietary guidelines on risk for fatal stroke among different ethnic groups has not previously been examined.
A prospective cohort design was used to examine associations between adherence with dietary recommendations for fruit and vegetable intake and risk for stroke mortality among 174,888 men and women representing five ethnic groups; African American, Native Hawaiian, Japanese American, Latino, and Caucasian. Dietary intake was assessed using a mailed quantitative food frequency questionnaire. Associations were examined using Cox proportional hazards models.
There was no evidence that ethnicity modified associations between fruit and vegetable intake and stroke mortality. When data for different ethnicities were combined, a reduced risk for fatal stroke was observed among women who were adherent with the USDA dietary recommendations for vegetable intake, although this result did not reach statistical significance (RR = 0.84, 95% CI = 0.68-1.04). No associations were observed among men.
The results of this study do not provide evidence that dietary intake of fruits and vegetables differentially impacts risk for stroke mortality among different ethnic groups.
Fruits; Vegetables; Stroke mortality; Ethnicity
Chronic inflammation may play an etiologic role in ovarian and endometrial cancer, and it is hypothesized that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the risk of developing these malignancies. No prospective study with a large multiethnic population has explored this hypothesis.
We investigated whether NSAID use was associated with risks of ovarian and endometrial cancer in the Multiethnic Cohort Study. Medication use of at least twice a week for ≥ 1 month was assessed at baseline. Multivariable relative risks (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models.
During an 13.3 years of follow up, 275 ovarian and 620 endometrial incident cases were identified among ~64,000 women included in this analysis (16.5% African Americans, 30.8% Japanese, 7.7% Native Hawaiians, 18.9%, Latinas and 26.0% whites). The RR (95% CI) for ovarian cancer associated with aspirin, non-aspirin NSAIDs, and acetaminophen were 0.87 (0.68, 1.14), 0.97 (0.74, 1.26), and 0.86 (0.67, 1.12), respectively. The RR (95% CI) for endometrial cancer associated with aspirin, non-aspirin NSAIDs, and acetaminophen were 0.93 (0.79, 1.10), 0.88 (0.74, 1.05), 0.96 (0.81, 1.13), respectively. No heterogeneity across ethnic groups (P’s ≥0.29) or dose-response relation with increased duration of use (P’s for trend ≥0.16) was observed. The results did not differ by tumor histology.
We found no compelling evidence to support an association between use of NSAIDs and risk of ovarian and endometrial cancers in a multiethnic population.
It is unlikely that NSAID involves in the etiology of endometrial and ovarian cancer.
NSAID; aspirin; ovarian cancer; uterine cancer; multiethnic
The purpose of this study was to test the associations between cognitive and psychological eating behavior traits and detailed measures of adiposity and body fat distribution using imaging-based methods in a cross-sectional study. Eating behavior traits (compensatory and routine restraint, external eating, and emotional eating) were assessed using the validated Weight-Related Eating Questionnaire, and measures of adiposity using anthropometry, dual energy X-ray absorptiometry (DXA), and magnetic resonance imaging (MRI). Each adiposity outcome of interest (total fat, ratio of trunk fat to periphery fat, visceral and subcutaneous fat as % of abdominal area, and % liver fat) was regressed on the four eating behaviors while adjusting for age and race/ethnicity. This study included a total of 60 postmenopausal Japanese American (n=30) and white (n=30) women (age: 60-65y, BMI: 18.8-39.6 kg/m2). Weight-related eating behavior traits did not differ by ethnicity. Higher external eating scores were associated with measures of total adiposity, including higher BMI (β = 0.36, p = 0.02) and DXA total fat mass (β = 0.41, p = 0.001), and with MRI abdominal subcutaneous fat (β = 0.55, p = 0.001). Higher routine restraint scores were associated with visceral adiposity (β = 0.42, p = 0.04). Our findings suggest that different weight-related eating behavior traits might increase not only total adiposity but also abdominal and visceral fat deposition associated with higher metabolic risks. Future research, preferably in a prospective study of men and women and including biomarkers related to psychological stress, will be needed to explore potential underlying biological mechanisms.
Eating Behaviors; Body Fat Distribution; Central Obesity; Liver Fat; Subcutaneous Adipose Tissue; Visceral Fat
Physical inactivity is an established risk factor for diabetes; however, little is known about this association across ethnic groups with different diabetes risk. Therefore, we evaluated the association between physical activity and diabetes and potential effect modification by ethnicity in the Hawaii component of the Multiethnic Cohort.
Participants, aged 45–75 years, were enrolled by completing a questionnaire on demographics, diet, and self-reported weekly hours of strenuous sports, vigorous work, and moderate activity. Among the 74,913 participants (39% Caucasian, 14% Native Hawaiian, 47% Japanese American), 8561 incident diabetes cases were identified by self-report, a medication questionnaire, and through health plan linkages. Cox regression was applied to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) while adjusting for known confounders.
Engaging in strenuous sports was inversely related to diabetes risk with HRs (4+ h/week vs. never) of 0.67 (95%CI: 0.57–0.79) in women and 0.80 (95%CI: 0.72–0.88) in men. In stratified analyses, the inverse association was consistent across ethnic groups. The inverse association of vigorous work with diabetes was limited to men, while beneficial effects of moderate activity were observed only in Caucasians.
These findings support a role of high-intensity physical activity and ethnic-specific guidelines in diabetes prevention.
ethnicity; prospective study; effect modification
Motivation: The question of how to best use information from known associated variants when conducting disease association studies has yet to be answered. Some studies compute a marginal P-value for each Several Nucleotide Polymorphisms independently, ignoring previously discovered variants. Other studies include known variants as covariates in logistic regression, but a weakness of this standard conditioning strategy is that it does not account for disease prevalence and non-random ascertainment, which can induce a correlation structure between candidate variants and known associated variants even if the variants lie on different chromosomes. Here, we propose a new conditioning approach, which is based in part on the classical technique of liability threshold modeling. Roughly, this method estimates model parameters for each known variant while accounting for the published disease prevalence from the epidemiological literature.
Results: We show via simulation and application to empirical datasets that our approach outperforms both the no conditioning strategy and the standard conditioning strategy, with a properly controlled false-positive rate. Furthermore, in multiple data sets involving diseases of low prevalence, standard conditioning produces a severe drop in test statistics whereas our approach generally performs as well or better than no conditioning. Our approach may substantially improve disease gene discovery for diseases with many known risk variants.
Availability: LTSOFT software is available online http://www.hsph.harvard.edu/faculty/alkes-price/software/
Supplementary information: Supplementary data are available at Bioinformatics online.
Common genetic risk variants for type 2 diabetes (T2D) have primarily been identified in populations of European and Asian ancestry. We tested whether the direction of association with 20 T2D risk variants generalizes across six major racial/ethnic groups in the U.S. as part of the Population Architecture using Genomics and Epidemiology Consortium (16,235 diabetes case and 46,122 control subjects of European American, African American, Hispanic, East Asian, American Indian, and Native Hawaiian ancestry). The percentage of positive (odds ratio [OR] >1 for putative risk allele) associations ranged from 69% in American Indians to 100% in European Americans. Of the nine variants where we observed significant heterogeneity of effect by racial/ethnic group (Pheterogeneity < 0.05), eight were positively associated with risk (OR >1) in at least five groups. The marked directional consistency of association observed for most genetic variants across populations implies a shared functional common variant in each region. Fine-mapping of all loci will be required to reveal markers of risk that are important within and across populations.
Research indicates that a diet rich in whole grains may reduce the risk of prevalent chronic diseases, including cardiovascular disease, diabetes, and some cancers, and that risk for these diseases varies by ethnicity. The objective of the current study was to identify major dietary sources of grains and describe their contribution to B vitamins in five ethnic groups.
A cross-sectional mail survey was used to collect data from participants in the Multiethnic Cohort Study in Hawaii and Los Angeles County, United States, from 1993 to 1996. Dietary intake data collected using a quantitative food frequency questionnaire was available for 186,916 participants representing five ethnic groups (African American, Latino, Japanese American, Native Hawaiian and Caucasian) aged 45–75 years. The top sources of grain foods were determined, and their contribution to thiamin, riboflavin, niacin, vitamin B6, and folic acid intakes were analyzed.
The top source of whole grains was whole wheat/rye bread for all ethnic-sex groups, followed by popcorn and cooked cereals, except for Native Hawaiian men and Japanese Americans, for whom brown/wild rice was the second top source; major contributors of refined grains were white rice and white bread, except for Latinos. Refined grain foods contributed more to grain consumption (27.1-55.6%) than whole grain foods (7.4-30.8%) among all ethnic-sex groups, except African American women. Grain foods made an important contribution to the intakes of thiamin (30.2-45.9%), riboflavin (23.1-29.2%), niacin (27.1-35.8%), vitamin B6 (22.9-27.5%), and folic acid (23.3-27.7%).
This is the first study to document consumption of different grain sources and their contribution to B vitamins in five ethnic groups in the U.S. Findings can be used to assess unhealthful food choices, to guide dietary recommendations, and to help reduce risk of chronic diseases in these populations.
Whole grains; Refined grains; B vitamins; Ethnicity
Among US Latinas and Mexican women, those with higher European ancestry have increased risk of breast cancer. We combined an admixture mapping and genome-wide association mapping approach to search for genomic regions that may explain this observation. Latina women with breast cancer (n= 1497) and Latina controls (n= 1272) were genotyped using Affymetrix and Illumina arrays. We inferred locus-specific genetic ancestry and compared the ancestry between cases and controls. We also performed single nucleotide polymorphism (SNP) association analyses in regions of interest. Correction for multiple-hypothesis testing was conducted using permutations (Pcorrected). We identified one region where genetic ancestry was significantly associated with breast cancer risk: 6q25 [odds ratio (OR) per Indigenous American chromosome 0.75, 95% confidence interval (CI): 0.65–0.85, P= 1.1 × 10−5, Pcorrected= 0.02]. A second region on 11p15 showed a trend towards association (OR per Indigenous American chromosome 0.77, 95% CI: 0.68–0.87, P= 4.3 × 10−5, Pcorrected= 0.08). In both regions, breast cancer risk decreased with higher Indigenous American ancestry in concordance with observations made on global ancestry. The peak of the 6q25 signal includes the estrogen receptor 1 (ESR1) gene and 5′ region, a locus previously implicated in breast cancer. Genome-wide association analysis found that a multi-SNP model explained the admixture signal in both regions. Our results confirm that the association between genetic ancestry and breast cancer risk in US Latinas is partly due to genetic differences between populations of European and Indigenous Americans origin. Fine-mapping within the 6q25 and possibly the 11p15 loci will lead to the discovery of the biologically functional variant/s behind this association.
Rare variation in protein coding sequence is poorly captured by GWAS arrays and has been hypothesized to contribute to disease heritability. Using the Illumina HumanExome SNP array, we successfully genotyped 191,032 common and rare non-synonymous, splice site, or nonsense variants in a multiethnic sample of 2,984 breast cancer cases, 4,376 prostate cancer cases, and 7,545 controls. In breast cancer, the strongest associations included either SNPs in or gene burden scores for genes LDLRAD1, SLC19A1, FGFBP3, CASP5, MMAB, SLC16A6, and INS-IGF2. In prostate cancer, one of the most associated SNPs was in the gene GPRC6A (rs2274911, Pro91Ser, OR = 0.88, P = 1.3×10−5) near to a known risk locus for prostate cancer; other suggestive associations were noted in genes such as F13A1, ANXA4, MANSC1, and GP6. For both breast and prostate cancer, several of the most significant associations involving SNPs or gene burden scores (sum of minor alleles) were noted in genes previously reported to be associated with a cancer-related phenotype. However, only one of the associations (rs145889899 in LDLRAD1, p = 2.5×10−7 only seen in African Americans) for overall breast or prostate cancer risk was statistically significant after correcting for multiple comparisons. In addition to breast and prostate cancer, other cancer-related traits were examined (body mass index, PSA level, and alcohol drinking) with a number of known and potentially novel associations described. In general, these findings do not support there being many protein coding variants of moderate to high risk for breast and prostate cancer with odds ratios over a range that is probably required for protein coding variation to play a truly outstanding role in risk heritability. Very large sample sizes will be required to better define the role of rare and less penetrant coding variation in prostate and breast cancer disease genetics.
For breast and prostate cancer, GWAS have revealed many risk variants (>70 for each cancer as of this report). All together the common variants in these regions explain only a minority of familial risk of these cancers. Using the Illumina HumanExome SNP array, we explored the hypothesis of rare coding variation contributing to breast and prostate cancer risk in a sample of African American, Latino, Japanese, Native Hawaiian, and European American breast and prostate cancer cases and controls from the Multiethnic Cohort study. While only one association exceeded significance thresholds after correcting for multiple comparisons, a number of suggestive associations involving genes previously reported to be associated with a cancer-related phenotype were noted. Our results do not generally support a major role of protein-coding variants with odds ratios over a range that is probably required for protein coding variation to play a truly outstanding role in risk heritability. If very rare and/or less penetrant coding variants underlie disease heritability of these cancers, then very large sample sizes (i.e. consortia) will be required for their discovery.
It is unknown whether the established risk factors for malignant melanoma in whites influence malignant melanoma risk in non-whites. We examined the risk factors for melanoma among 39,325 whites and 101,229 non-whites/multiracials (Japanese American [47.5%], Latino American [34.8%], Native Hawaiian [2.1%] and multiracial [15.6%], excluding African Americans) in the Multiethnic Cohort study. With an average follow-up of 12.7 years, 581 invasive malignant melanoma (IMM) and 412 melanoma in situ (MIS) cases were identified, of which 107 (IMM) and 74 (MIS) were among non-whites/multiracials. The relative risks (RRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards models using days from cohort entry as the underlying time variable. Among non-white/multiracial males, location of IMM tumors differed from those of white males (p<0.001); and non-white/multiracial females were more likely to be diagnosed with later stage of disease (p<0.001). After adjusting for potential confounders, age at cohort entry, male sex, higher education, and sunburn susceptibility phenotypes were associated with an increased risk of invasive malignant melanoma in non-whites/multiracials (p<0.05). The risk estimates for age at cohort entry and lighter hair and eye color were greater in non-whites/multiracials than in whites (p-heterogeneity=0.062, 0.016, and 0.005, respectively). For MIS risk, RRs between whites and non-whites/multiracials also differed for study location and education (p-heterogeneity ≤ 0.015). In conclusion, similar to whites, age at cohort entry, male sex, and susceptibility to sunburn phenotypes may be predictive of malignant melanoma risk in non-white populations excluding African-Americans.
melanoma risk factors; non-whites
To improve our understanding of excess body weight and risk for diabetes type 2, we examined the influence of weight change in the Hawaii component of the Multiethnic Cohort with 78,006 Caucasians, Japanese Americans, and Native Hawaiians.
Participants aged 58.5±9.2 years completed a questionnaire at cohort entry (Qx1) that included weight at age 21 and a follow-up questionnaire 5 years later (Qx2). After 14 years of follow-up, 8,892 incident diabetes cases were identified through self-report or linkages to the major health plans in Hawaii. We applied Cox regression, stratified by age and adjusted for confounders, to estimate hazard ratios (HR).
The mean weight gain from age 21 to Qx1 was 10.5 ± 11.0 kg and 0.8 ± 5.6 kg between Qx1 and Qx2. Diabetes risk showed a significant dose-response relation with weight gain since age 21 (p <0.0001). The respective HRs for a weight gain of 5-10 kg and of ≥25 kg were 1.8 (95% CI: 1.7-2.0) and 7.7 (95% CI: 7.1-8.4), while weight loss of more than 5 kg significantly reduced risk (HR = 0.7; 95% CI: 0.6-0.9). The association of weight loss and reduced diabetes risk were was strongest for Caucasians, intermediate for Japanese Americans, and weakest for Native Hawaiians. On the other hand, the absolute risk of developing diabetes was higher for Japanese Americans and Native Hawaiians than for Caucasians at all BMI levels. Weight change between Qx1 and Qx2 conferred a smaller risk.
These findings support current public health recommendations for weight control, in particular among ethnic groups at high risk for diabetes.
Type 2 diabetes; BMI; obesity; weight gain, ethnicity; prospective studies
Mammographic density, a strong predictor for breast cancer incidence, may also worsen prognosis in women with breast cancer. This prospective analysis explored the effect of prediagnostic mammographic density among 607 breast cancer cases diagnosed within the Hawaii component of the Multiethnic Cohort (MEC).
Female MEC participants, aged ≥ 50 years at cohort entry, diagnosed with primary invasive breast cancer, and enrolled in a mammographic density case-control study were part of this analysis. At cohort entry, anthropometric and demographic information was collected by questionnaire. Tumor characteristics and vital status were available through linkage with the Hawaii Tumor Registry. Multiple digitized prediagnostic mammograms were assessed for mammographic density using a computer-assisted method. Cox proportional hazards regression was applied to examine the effect of mammographic density on breast cancer survival while adjusting for relevant covariates.
Of the 607 cases, 125 were diagnosed as in situ, 380 as localized, and 100 as regional/distant stage. After a mean follow-up time of 12.9 years, 27 deaths from breast cancer and 100 deaths from other causes had occurred; 71 second breast cancer primaries were diagnosed. In an overall model, mammographic density was not associated with breast cancer-specific survival (HR = 0.95 per 10%; 95%CI: 0.79-1.15), but the interaction with radiotherapy was highly significant (p = 0.006). In stratified models, percent density was associated with a reduced risk of dying from breast cancer (HR = 0.77; 95%CI: 0.60-0.99; p = 0.04) in women who had received radiation, but with an elevated risk (HR = 1.46; 95% CI: 1.00-2.14; p = 0.05) in patients who had not received radiation. High breast density predicted a borderline increase in risk for a second primary (HR = 1.72; 95% CI: 0.88-2.55; p = 0.15).
Assessing mammographic density in women with breast cancer may identify women with a poorer prognosis and provide them with radiotherapy to improve outcomes.
Phytochemicals found in soy and other legumes have been speculated to reduce the risk of endometrial cancer; however, inconsistent findings have been reported in the few epidemiological studies conducted to date.
We conducted a prospective analysis of 46 027 nonhysterectomized postmenopausal women who were recruited into the Multiethnic Cohort (MEC) Study between August 1993 and August 1996 and provided detailed baseline information on diet and other endometrial cancer risk factors. A total of 489 women diagnosed with incident endometrial cancer were identified through the Surveillance, Epidemiology, and End Results tumor registry linkages during a median follow-up period of 13.6 years. Cox proportional hazards models were used to estimate multivariable-adjusted relative risks (RRs) and 95% confidence intervals (CIs) for endometrial cancer associated with dietary intake of legumes, soy, and tofu, and for total isoflavones and specific isoflavones (daidzein, genistein, or glycitein). Truncated (age 50–89 years) age-adjusted incidence rates were calculated by applying age-specific rates within isoflavone quintiles to the overall MEC population eligible for endometrial cancer. To estimate the percentage of endometrial cancers that may have been prevented by consuming the highest quintile of total isoflavones, the partial population attributable risk percent was calculated.
A reduced risk of endometrial cancer was associated with total isoflavone intake (highest vs lowest quintile, ≥7.82 vs <1.59 mg per 1000 kcal/d, RR = 0.66, 95% CI = 0.47 to 0.91), daidzein intake (highest vs lowest quintile, ≥3.54 vs <0.70 mg per 1000 kcal/d, RR = 0.64, 95% CI = 0.46 to 0.90), and genistein intake (highest vs lowest quintile, ≥3.40 vs <0.69 mg per 1000 kcal/d, RR = 0.66, 95% CI = 0.47 to 0.91). No statistically significant association with endometrial cancer risk was observed for increasing intake of legumes, soy, tofu, or glycitein. Truncated age-adjusted incidence rates of endometrial cancer for the highest vs lowest quintile of total isoflavone intake were 55 vs 107 per 100 000 women per year, respectively. The partial population attributable risk percent for total isoflavone intake lower than the highest quintile was 26.7% (95% CI = 5.3% to 45.8%).
This study suggests that greater consumption of isoflavone-containing foods is associated with a reduced risk of endometrial cancer in this population of nonhysterectomized postmenopausal women.