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
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.
It is important to understand the adverse health sequelae that may result from the rising incidence of diabetes. Diabetics may have an increased risk for urothelial cancer but the evidence from prospective studies and ethnically diverse populations is sparse.
We examined this association in the Multiethnic Cohort (MEC) that was conducted in Hawaii and Los Angeles with nearly 186,000 participants in five ethnic groups. Over a median 10.7 years of follow-up, 918 incident cases of urothelial cancer (89% bladder and 11% other urinary tract sites) were identified through tumor registry linkages.
A self-reported diagnosis of diabetes was associated with an increased risk of urothelial cancer (relative risk = 1.25; 95% confidence interval: 1.04–1.50). The association was not explained by body mass index, physical activity, or smoking. There was some suggestion that the risk was higher in women, Whites and African Americans, and past smokers. The risk associated with diabetes for in situ and localized cancer was similar to that for regional and distant cancer.
This study demonstrates that the increased urothelial cancer risk with diabetes in this multiethnic population is very similar to that observed in mostly White or Asian populations. Whether or not the elevated risk is moderated by the degree of control of the hyperglycemia associated with diabetes will need to be determined in future studies.
Diabetes; Urothelial cancer; Bladder cancer; Prospective cohort; Epidemiology
Incidence rates in the U.S. show clear racial/ethnic disparities for colorectal cancer. We examined the extent to which ethnic differences in risk factors could explain the age-adjusted variation in the risk of colorectal cancer, overall and by stage at diagnosis, among 165,711 African Americans, Japanese Americans, Latinos, Native Hawaiians, and whites participating in the Multiethnic Cohort Study. Over a median follow-up period of 10.7 years, 2,564 incident cases of colorectal cancer were identified through SEER tumor registry linkages in Hawaii and California. Multivariable-adjusted Cox proportional hazard models were used to estimate relative risks (RR) and 95% confidence intervals (CI) for each ethnic group compared to whites. After accounting for known/suspected risk factors, Japanese Americans (men, RR = 1.27, 95% CI = 1.09-1.48; women, RR = 1.49, 95% CI = 1.24-1.78) and African American women (RR = 1.48, 95% CI = 1.23-1.79) remained at increased risk of colorectal cancer relative to whites; African American and Japanese American women were also at increased risk of advanced disease compared to whites. In site-specific analyses, after multivariable adjustment, African Americans (both sexes) and Japanese American women remained at increased risk for colon cancer, and Japanese Americans (both sexes) and Native Hawaiian men for rectal cancer compared to whites. The results of this study suggest that differences in the distribution of known/suspected risk factors account for only a modest proportion of the ethnic variation in colorectal cancer risk and that other factors, possibly including genetic susceptibility, are important contributors to the observed disparities in incidence.
colorectal cancer; cancer disparities; multiethnic cohort; ethnic groups; risk factors
To compare the prevalence of modifiable risk factors for cancer and other chronic diseases between adult cancer survivors and persons with no history of cancer.
Population-based sample residing in California and Hawaii.
A total of 177,003 men and women aged 45–75 years who participated in the Multiethnic Cohort Study (MEC). Logistic regression was used to examine adherence to recommendations regarding modifiable risk factors among cancer survivors (n = 16,346) when compared to cohort members with no history of cancer (n = 160,657).
Cancer survivors were less likely than cohort members with no history of cancer to meet recommendations specified in the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) 2007 report (OR = 0.97; CI 0.96, 0.99). No difference between groups was seen for adherence to dietary recommendations alone (OR = 0.99; CI 0.98, 1.01). Site specific analyses showed that results for colorectal cancer were similar to those for all cancers combined, but survivors of breast (OR = 1.04; CI 1.02, 1.07) and prostate (OR = 1.04; CI 1.01, 1.07) cancer were more likely to meet dietary recommendations. Latino survivors were less likely to adhere to WCRF/AICR recommendations than Latino controls; however, differences across ethnic groups were not significant (pinteraction = 0.64).
The modest differences found between adult cancer survivors and persons with no history of cancer suggest that a diagnosis of cancer in itself may not be associated with improvements in health behaviors related to cancer and other chronic diseases.
cancer survivors; health behaviors; diet and cancer
It is unclear whether mammographic breast density, a strong risk factor for breast cancer, predicts subtypes of breast cancer defined by estrogen receptor (ER) and/or progesterone receptor (PR) expression.
In a nested case-control study, we compared the breast density of 667 controls and 607 breast cancer cases among women of Caucasian, Japanese, and Native Hawaiian ancestry in the Hawaii component of the Multiethnic Cohort study. A reader blinded to disease status performed computer assisted density assessment on prediagnostic mammograms. Receptor status was obtained from the statewide Hawaii Tumor Registry. Tumors were classified into ER+PR+ (n=341), ER−PR− (n=50), ER+PR−/ER−PR+ (n=64), and unstaged/unknown (n=152). Mean density values were computed for women with more than one mammogram. Polytomous logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) while adjusting for confounders.
Mean density was significantly greater for ER+PR+ but not for ER−PR− tumors compared to controls after adjusting for age: 37.3%, 28.9%, versus 29.4%, respectively. The overall ORs per 10% increase in density were similar for ER+PR+ and ER+PR−/ER−PR+ tumors: 1.26 (95% CI 1.17–1.36) and 1.23 (95% CI 1.07–1.42), respectively. However, percent density was not found to be a predictor for ER−PR− tumors (OR 1.00, 95% CI 0.84–1.18). The results did not differ by ethnicity, nor by menopausal status, parity, or HRT use.
Our findings indicate that within a multiethnic population, women with higher breast density have an increased risk for ER+PR+ but not ER−PR− tumors.
estrogen receptor; mammographic density; progesterone receptor; tumor characteristics
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.
Breast carcinoma; ethnicity; obesity; survival; prognosis
Epidemiologic studies have found evidence of an inverse association between diabetes status and prostate cancer risk. We explored the hypothesis that common genetic variation may explain, in part, the inverse association between diabetes and prostate cancer.
We tested 17 diabetes risk variants for association with prostate cancer risk in a prostate cancer case-control study of 2,746 cases and 3,317 controls from five racial-ethnic groups in the Multiethnic Cohort.
After adjustment for multiple testing none of the alleles were statistically significantly associated with prostate cancer risk. Aggregate scores that sum the risk alleles were also not significantly associated with risk.
We did not find evidence of association of this set of diabetes risk alleles with prostate cancer.
Resequencing and fine-mapping of the GWAS-identified loci for diabetes and prostate cancer is necessary to understand any genetic contribution for the inverse association between these common diseases.
Genitourinary cancer; prostate; type 2 diabetes; multiethnic; epidemiology
We examined the relationship of insulin-like growth factor-I (IGF-I) and its primary growth factor, IGF binding protein-3 (IGFBP-3) with malignant melanoma using interview data and sera from cases (n=286) and controls (n=289) in a population-based case-control study conducted in 1986–1992 on Oahu, Hawaii. Serum IGF-I and IGFBP-3 concentrations were measured by ELISA. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression and adjusted for age, sex, education, number of blistering sunburns, ability to tan, hair color, energy intake, BMI, height, smoking status, and drinking status. An inverse relationship was found between IGF-I concentration and melanoma (OR for upper vs. lower tertile: 0.44, 95% CI: 0.25–0.79), but clear associations were not observed between malignant melanoma and upper tertiles of IGFBP-3 and the IGF-1:IGFBP-3 molar ratio. The inverse association with IGF-I was strongest among subjects who did not report a history of non-melanoma skin cancer (NMSC) (OR for ≥ vs. < median: 0.39, 95% CI: 0.24–0.65), and a positive association was found among those with such a history (OR: 3.6, 95% CI: 1.0–13; pinteraction=0.0035). Our findings observed here between serum IGF-I and malignant melanoma warrants replication in studies with a larger sample size and a prospective design.
Malignant melanoma; insulin-like growth factor-I (IGF-I); insulin-like growth factor binding protein-3 (IGFBP-3)
Recently, several genome-wide association studies have identified various genetic susceptibility loci for breast cancer. Relatively little is known about the possible interactions between these loci and the established risk factors for breast cancer.
To assess interactions between single-nucleotide polymorphisms (SNPs) and established risk factors, we prospectively collected DNA samples and questionnaire data from 8576 breast cancer case subjects and 11 892 control subjects nested within the National Cancer Institute’s Breast and Prostate Cancer Cohort Consortium (BPC3). We genotyped 17 germline SNPs (FGFR2-rs2981582, FGFR2-rs3750817, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, CASP8-rs1045485, LSP1-rs3817198, COL1A1-rs2075555, COX11-rs6504950, RNF146-rs2180341, 6q25-rs2046210, SLC4A7-rs4973768, NOTCH2-rs11249433, 5p12-rs4415084, 5p12-rs10941679, RAD51L1-rs999737), and odds ratios were estimated by logistic regression to confirm previously reported associations with breast cancer risk. We performed likelihood ratio test to assess interactions between 17 SNPs and nine established risk factors (age at menarche, parity, age at menopause, use of hormone replacement therapy, family history, height, body mass index, smoking status, and alcohol consumption), and a correction for multiple testing of 153 tests (adjusted P value threshold = .05/153 = 3 × 10−4) was done. Case–case comparisons were performed for possible differential associations of polymorphisms by subgroups of tumor stage, estrogen and progesterone receptor status, and age at diagnosis. All statistical tests were two-sided.
We confirmed the association of 14 SNPs with breast cancer risk (Ptrend = 2.57 × 10−3 –3.96 × 10−19). Three SNPs (LSP1-rs3817198, COL1A1-rs2075555, and RNF146-rs2180341) did not show association with breast cancer risk. After accounting for multiple testing, no statistically significant interactions were detected between the 17 SNPs and the nine risk factors. We also confirmed that SNPs in FGFR2 and TNRC9 were associated with greater risk of estrogen receptor–positive than estrogen receptor–negative breast cancer (Pheterogeneity = .0016 for FGFR2-rs2981582 and Pheterogeneity = .0053 for TNRC9-rs3803662). SNP 5p12-rs10941679 was statistically significantly associated with greater risk of progesterone receptor–positive than progesterone receptor–negative breast cancer (Pheterogeneity = .0028).
This study does not support the hypothesis that known common breast cancer susceptibility loci strongly modify the associations between established risk factors and breast cancer.
To estimate the population attributable risk (PAR) associated with modifiable risk factors for diabetes among Caucasians, Native Hawaiians, and Japanese Americans in the Hawaii component of the Multiethnic Cohort.
This analysis is based on 74,970 cohort participants aged 45–75 years who completed a questionnaire on demographics, diet, and lifestyle factors in 1993–1996. After a mean follow-up time of 12.1 (0.01–14.4) years, 8559 diabetes cases were identified by self-report, a medication questionnaire, and through health plan linkages. Hazard ratios for diabetes and partial PARs for single and different combinations of modifiable risk factors were estimated.
Overweight, physical inactivity, high meat intake, no alcohol consumption, and smoking were positively associated with diabetes risk in all ethnic groups. The estimated PARs suggested that among men, 78%, and among women, 83%, of new diabetes cases could have been avoided if all individuals had been in the low risk category for all of the modifiable risk factors. The slightly lower PARs in Japanese Americans were not significantly different from those in Caucasians and Native Hawaiians.
Although PARs varied slightly over ethnicity, our findings do not support ethnic-specific prevention strategies; interventions targeted at multiple behaviors are needed in all ethnic groups.
ethnicity; prevention; prospective study; risk factors; type 2 diabetes mellitus
Nationwide surveys in the United States found that certain health-related factors, in particular cigarette smoking and obesity, were more prevalent in veterans than in non-veterans.
The objective of this paper was to compare health-related characteristics and dietary intakes between veterans and non-veterans in the Multiethnic Cohort.
Materials and Methods
The cohort participants (aged 45–75 years), residing in Hawaii and California at baseline, completed a mailed questionnaire on diet, medical history, and lifestyle in 1993–1996. The current analyses included 20,939 men (14,975 veterans and 5,964 non-veterans) who returned a survey questionnaire on military service in 2007.
Compared to non-veterans, veterans were more likely to be overweight and obese (BMI≥25, 61% vs. 55%), former smokers (54% vs. 47%), heavier consumers of red and processed meat, and lighter consumers of fruits and vegetables. Within the veteran group, enlisted men were more likely to be obese, to have a history of smoking, to consume more processed meat and to consume smaller amounts of dairy products and fruits than officers.
The findings imply that veterans as a group are at somewhat higher risk of developing lifestyle-related chronic diseases than are non-veterans. Comparisons of actual differences in disease incidence and mortality in the Multiethnic Cohort between veterans and non-veterans will require several more years of follow-up.