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
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.
Although multivitamin/mineral supplements are commonly used in the United States, the efficacy of these supplements in preventing chronic disease or premature death is unclear. To assess the relation of multivitamin use with mortality and cancer, the authors prospectively examined these associations among 182,099 participants enrolled in the Multiethnic Cohort Study between 1993 and 1996 in Hawaii and California. During an average 11 years of follow-up, 28,851 deaths were identified. In Cox proportional hazards models controlling for tobacco use and other potential confounders, no associations were found between multivitamin use and mortality from all causes (for users vs. nonusers: hazard ratio = 1.07, 95% confidence interval: 0.96, 1.19 for men; hazard ratio = 0.96, 95% confidence interval: 0.85, 1.09 for women), cardiovascular diseases, or cancer. The findings did not vary across subgroups by ethnicity, age, body mass index, preexisting illness, single vitamin/mineral supplement use, hormone replacement therapy use, and smoking status. There also was no evidence indicating that multivitamin use was associated with risk of cancer, overall or at major sites, such as lung, colorectum, prostate, and breast. In conclusion, there was no clear decrease or increase in mortality from all causes, cardiovascular disease, or cancer and in morbidity from overall or major cancers among multivitamin supplement users.
cohort studies; mortality; neoplasms; vitamins
Cigarette smoking has been proposed as a risk factor for amyotrophic lateral sclerosis (ALS), but epidemiological studies supporting this hypothesis have been small and mostly retrospective. We therefore prospectively examined the relation between smoking and ALS in five well-established large cohorts.
Five prospective cohorts with study-specific follow-up ranging from 7 to 28 years.
Participants of the Nurses’ Health Study (NHS), the Health Professionals Follow-up Study (HPFS), the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort, and the NIH-American Association of Retired Persons Diet and Health Study.
Main Outcome Measure
ALS deaths identified through the National Death Index. In NHS and HPFS confirmed non-fatal incident ALS was also included.
832 participants with ALS were documented among 562,804 men and 556,276 women. Smokers had a higher risk of ALS than never smokers: age- and sex-adjusted relative risks=1.44 (95%CI: 1.23–1.68;p<0.0001) for former smokers, and 1.42 (95%CI: 1.07–1.88;p=0.016) for current smokers. Although the risk of ALS was positively associated with pack-years smoked (p<0.0001), duration (9% increase for each 10-years of smoking; p=0.006) and cigarettes smoked per day (10% increase for 10 cigarettes per day; p<0.001), these associations did not persist when never smokers were excluded. However, among ever-smokers, risk of ALS increased as age at smoking initiation decreased (p=0.028).
Results of this large longitudinal study support the hypothesis that cigarette smoking increases the risk of ALS. The potential importance of age at smoking initiation and the lack of a dose-response deserve further investigation.
The authors investigated whether vitamin E intake was associated with amyotrophic lateral sclerosis (ALS) in the Nurses’ Health Study (1976–2004), the Health Professionals Follow-up Study (1986–2004), the Cancer Prevention Study II Nutrition Cohort (1992–2004), the Multiethnic Cohort Study (1993–2005), and the National Institutes of Health-AARP Diet and Health Study (1995–2005). ALS deaths were identified through the National Death Index. In the Nurses' Health Study and the Health Professionals Follow-up Study, confirmed nonfatal ALS cases were also included. Cohort-specific results were estimated using Cox proportional hazards models and pooled using random-effects models. Among 1,055,546 participants, 805 developed ALS. Overall, using vitamin E supplements was not associated with ALS. However, within cohorts with information on duration of vitamin E supplement use (231 cases), ALS rates declined with increasing years of use (P-trend = 0.01). Compared with nonusers, the multivariable-adjusted relative risk was 1.05 (95% confidence interval (CI): 0.60, 1.84) among users for ≤1 year (12 cases), 0.77 (95% CI: 0.33, 1.77) among users for 2–4 years (7 cases), and 0.64 (95% CI: 0.39, 1.04) among users for ≥5 years (18 cases). For dietary vitamin E intake, the multivariable-adjusted relative risk comparing the highest quartile with the lowest was 0.79 (95% CI: 0.61, 1.03); an inverse dose-response was evident in women (P-trend = 0.002) but not in men (P-trend = 0.71). In this large, pooled prospective study, long-term vitamin E supplement use was associated with lower ALS rates. A possible protective effect of vitamin E deserves further consideration.
alpha-tocopherol; amyotrophic lateral sclerosis; antioxidants; cohort studies; diet; vitamin E
Genome-wide association studies (GWAS) have identified common variants associated with breast cancer risk among women of European and Asian ancestries. To assess the generalizability across ethnic/racial populations of a risk score derived from genotyping 12 highly replicated breast cancer GWAS hits, we performed a case-control study (2224 cases and 2827 controls) nested in the Multiethnic Cohort (MEC) study, which was initiated in 1993–1996 and consists of subjects mainly from European-American, African-American, Native Hawaiian, Japanese and Latino populations. When viewed as a summary risk score, the total number of risk alleles carried by women was significantly associated with breast cancer risk overall (OR per allele, 1.09; 95% CI, 1.06–1.12; P=2.0 × 10−10) and in all populations except African-Americans, in which no significant association was observed (OR, 1.03; 95% CI, 0.98–1.08). In aggregate, the number of risk alleles is strongly associated with breast cancer risk in all populations studied except African-Americans. These results emphasize the need for large-scale association studies of multiple racial/ethnic groups for discovery and characterization of risk alleles relevant to all populations in the United States.
breast cancer; risk markers; summary score; generalizability; diverse populations
Genome-wide association studies (GWAS) in populations of European ancestry have identified several loci that confer an increased risk of colorectal cancer (CRC).
We studied the generalizability of the associations with 11 risk variants for CRC on 8q23 (rs16892766), 8q24 (rs6983267), 9p24 (rs719725), 10p14 (rs10795668), 11q23 (rs3802842), 14q22 (rs4444235), 15q13 (rs4779584), 16q22 (rs9929218), 18q21 (rs4939827), 19q13 (rs10411210) and 20p12 (rs961253) in a multiethnic sample of 2,472 CRC cases, 839 adenoma cases and 4,466 controls comprised of European American, African American, Native Hawaiian, Japanese American and Latino men and women. Because findings for CRC and adenoma were similar, we combined both groups in the analyses.
We confirmed the associations with an increased risk of CRC/adenoma for the 8q24, 11q23 and 15q13 loci in European Americans, and observed significant associations between the 8q24 and 20p12 loci with CRC/adenoma risk in African Americans. Moreover, we found statistically significant cumulative effects of risk alleles on CRC/adenoma risk in all populations (odds ratio (OR) per allele = 1.07–1.09, p≤0.039) except in Japanese Americans (OR=1.01, p=0.52). We found heterogeneity in the associations by tumor subsite, age of CRC/adenoma onset, sex, body mass index (BMI) and smoking status for some of the variants.
These results provide evidence that the known variants are in aggregate significantly associated with CRC/adenoma risk in multiple populations except Japanese Americans, and the influences may differ across groups defined by clinicopathological characteristics for some variants.
These results underline the importance of studying the epidemiologic architecture of these genetic effects in large and diverse populations.
Colorectal Cancer; Genetic Susceptibility; Cancer in minority; Underserved populations; Multiethnic Cohort
Beta-microseminoprotein (MSP) is one of the three most abundantly secreted proteins of the prostate, and has been suggested as a biomarker for prostate cancer risk. A common variant, rs10993994, in the 5’ region of the gene which encodes MSP (MSMB), has recently been identified as a risk factor for prostate cancer.
We examined the association between rs10993994 genotype and MSP levels in a sample of 500 prostate cancer-free men from four racial/ethnic populations in the Multiethnic Cohort (European Americans, African Americans, Latinos, and Japanese Americans). Generalized linear models were used to estimate the association between rs10993994 genotype and MSP levels.
We observed robust associations between rs10994994 genotype and MSP levels in each racial/ethnic population (all P<10−8) with carriers of the C allele having lower geometric mean MSP levels (ng/mL) (CC/CT/TT genotypes: European Americans, 28.8/20.9/10.0; African Americans, 29.0/21.9/10.9; Latinos, 29.2/17.1/8.3; and Japanese Americans 25.8/16.4/6.7). We estimated the variant accounts for 30–50% of the variation in MSP levels in each population. We also observed significant differences in MSP levels between populations (P=3.5×10−6), with MSP levels observed to be highest in African Americans and lowest in Japanese Americans.
Rs10993994 genotype is strongly associated with plasma MSP levels in multiple racial/ethnic populations.
This supports the hypothesis that rs10993994 may be the biologically functional allele.
MSMB; beta-microseminoprotein; prostate; genetic; multiethnic
Insulin-like growth factor-I (IGF-I) has mitogenic properties and stimulates cell growth. In this analysis, we investigated the relation between common genetic variation in IGF1, IGFBP1, and IGFBP3 and mammographic density among 819 women of Hawaiian, European and Japanese ancestry from the Multiethnic Cohort Study. Mammographic density was assessed using a quantitative computer-assisted method. Previously identified tag single nucleotide polymorphisms (SNPs) for IGF1 (26 tag SNPs) and IGFBP1/IGFBP3 (22 tag SNPs) were genotyped among the 819 women. Mixed models were conducted to evaluate the associations between genetic variation and mammographic density. Two SNPs were borderline statistical significantly associated with mammographic density; rs35539615 on IGFBP1 (p=0.05) and rs2453839 on IGFBP3 (p=0.01). Rs35767on IGF1 (p=0.03) was also associated with mammographic density, although in opposite direction of what was expected from previous findings with IGF-I levels. The majority of SNPs were, however, not associated with mammographic density. Analyses stratified by ethnicity showed similar results as the overall analyses for IGF1 and IGFBP1. However, for four SNPs in the IGFBP3 gene, the minor allele was associated with lower mammographic density in Japanese Americans and higher mammographic density in Caucasians. Given the large number of SNPs tested and the few borderline significant results, we only found weak evidence that genetic variations in IGFBP1 or IGFBP3 may be related to mammographic density. Ethnicity may modify these relations.
Breast cancer; Mammographic density; Multiethnic cohort; SNP; IGF-I
Coenzyme Q10 (CoQ10) is a component of the mitochondrial electron transport chain and is considered an important cellular antioxidant. Decreased circulating CoQ10 levels have been reported in women with breast cancer, but evidence is limited. We examined the association of plasma CoQ10 levels with postmenopausal breast cancer risk using prospectively collected blood samples.
Pre-diagnostic plasma levels of total CoQ10 were measured among 160 incident postmenopausal breast cancer cases and 289 controls in the Multiethnic Cohort Study. Cases and controls were individually-matched on age, sex, ethnicity, study location (Hawaii or California), hormone replacement therapy use, date/time of specimen collection and hours of fasting. Logistic regression was used to compute odds ratios and 95% confidence intervals.
Plasma CoQ10 levels were positively associated with breast cancer risk, overall (P = 0.04). The association was stronger after women diagnosed within one year of blood draw were excluded to eliminate possible preclinical cases (odds ratio for the highest versus the lowest tertile, 2.26; 95% confidence interval, 1.22-4.19; P for trend, 0.01).
Higher CoQ10 levels in postmenopausal women may be associated with increased breast cancer risk.
A potential role for CoQ10 in the development and progression of breast cancer has been postulated, but epidemiological evidence is lacking. Findings from this prospective cohort study add to the limited literature, indicating the potential positive association of circulating CoQ10 with postmenopausal breast cancer risk.
Coenzyme Q10 postmenopausal breast cancer
Based on the hypothesis that soy consumption may improve glucose tolerance, we examined the association of soy intake with diabetes risk in the Hawaii component of the Multiethnic Cohort. Among 29,719 Caucasian, 35,141 Japanese American, and 10,484 Native Hawaiian men and women, 8,564 incident diabetes cases were identified during 14 years of follow-up. Cox regression was used to calculate hazard ratios while adjusting for known confounders with stratifications by sex, ethnicity, and weight status. We observed no protective effect of soy food consumption on diabetes risk in this population, which has a wide range of soy intakes though lower than in Asian populations. Indeed, higher soy food intake was associated with a weakly elevated diabetes risk across ethnic groups; the higher risk was limited to overweight and obese individuals. The current findings do not support a protective effect of modest levels of soy food consumption against diabetes.
Diabetes mellitus type 2; ethnicity; soy foods; obesity; prospective study
It is well-known that population substructure may lead to confounding in case-control association studies. Here, we examined genetic structure in a large racially and ethnically diverse sample consisting of 5 ethnic groups of the Multiethnic Cohort study (African Americans, Japanese Americans, Latinos, European Americans and Native Hawaiians) using 2,509 SNPs distributed across the genome. Principal component analysis on 6,213 study participants, 18 Native Americans and 11 HapMap III populations revealed 4 important principal components (PCs): the first two separated Asians, Europeans and Africans, and the third and fourth corresponded to Native American and Native Hawaiian (Polynesian) ancestry, respectively. Individual ethnic composition derived from self-reported parental information matched well to genetic ancestry for Japanese and European Americans. STRUCTURE-estimated individual ancestral proportions for African Americans and Latinos are consistent with previous reports. We quantified the East Asian (mean 27%), European (mean 27%) and Polynesian (mean 46%) ancestral proportions for the first time, to our knowledge, for Native Hawaiians. Simulations based on realistic settings of case-control studies nested in the Multiethnic Cohort found that the effect of population stratification was modest and readily corrected by adjusting for race/ethnicity or by adjusting for top PCs derived from all SNPs or from ancestry informative markers; the power of these approaches was similar when averaged across causal variants simulated based on allele frequencies of the 2,509 genotyped markers. The bias may be large in case-only analysis of gene by gene interactions but it can be corrected by top PCs derived from all SNPs.
AIMs; African American; Native Hawaiian; Latino; admixture; principal component analysis
Genome-wide association studies have identified many common genetic variants that are associated with polygenic traits, and have typically been performed with individuals of recent European ancestry. In these populations, many common variants are tightly correlated, with the perfect or near-perfect proxies for the functional or true variant showing equivalent evidence of association, considerably limiting the resolution of fine mapping. Populations with recent African ancestry often have less extensive and/or different patterns of linkage disequilibrium (LD), and have been proposed to be useful in fine-mapping studies. Here, we strongly replicate and fine map in populations of predominantly African ancestry the association between variation at the FTO locus and body mass index (BMI) that is well established in populations of European ancestry. We genotyped single nucleotide polymorphisms that are correlated with the signal of association in individuals of European ancestry but that have varying degrees of correlation in African-derived individuals. Most of the variants, including one previously proposed as functionally important, have no significant association with BMI, but two variants, rs3751812 and rs9941349, show strong evidence of association (P = 2.58 × 10−6 and 3.61 × 10−6 in a meta-analysis of 9881 individuals). Thus, we have both strongly replicated this association in African-ancestry populations and narrowed the list of potentially causal variants to those that are correlated with rs3751812 and rs9941349 in African-derived populations. This study illustrates the potential of using populations with different LD patterns to fine map associations and helps pave the way for genetically guided functional studies at the FTO locus.
Prostate cancer (PC) is the most common male malignancy in the U.S. and disparities in risk exist among ethnic/racial groups. A high intake of well-done meat and the presence of the rapid NAT1 and slow NAT2 acetylator genotypes, as modifiers of the carcinogenic effect of heterocyclic amines, were hypothesized to increase PC risk and possibly explain these ethnic differences in risk.
This study examined the associations between well-done (red) meat consumption, NAT1 and NAT2 acetylator genotypes and PC risk among five ethnicities (African American, Native Hawaiian, Japanese American, Latino and Caucasian) in a case-control study of PC nested within the Multiethnic Cohort study. Cases (n=2,106) and controls (n=2,063) were genotyped for eight single nucleotide polymorphisms (SNPs) in NAT1 and seven SNPs in NAT2 that characterize all common alleles for these genes. Well-done meat intake was computed based on responses to a detailed food frequency questionnaire including a question on meat preference. Conditional logistic regression was used in the analysis.
There was no evidence of an increased risk associated with preference for well-done meat, intake of well-done meat and NAT1 or NAT2 genotypes (jointly or separately).
These results do not support the hypothesis that exposure to heterocyclic amines is associated with risk of PC. However, additional studies with more precise exposure measures are needed.
prostate cancer; well-done meat; N-acetyltransferase 1 (NAT1); N-acetyltransferase 2 (NAT2); the Multiethnic Cohort