The authors describe the design and implementation of a large multiethnic cohort established to study diet and cancer in the United States. They detail the source of the subjects, sample size, questionnaire development, pilot work, and approaches to future analyses. The cohort consists of 215,251 adult men and women (age 45-75 years at baseline) living in Hawaii and in California (primarily Los Angeles County) with the following ethnic distribution: African-American (16.3%), Latino (22.0%), Japanese-American (26.4%), Native Hawaiian (6.5%), White (22.9%), and other ancestry (5.8%). From 1993 to 1996, participants entered the cohort by completing a 26-page, self-administered mail questionnaire that elicited a quantitative food frequency history, along with demographic and other information. Response rates ranged from 20% in Latinos to 49% in Japanese-Americans. As expected, both within and among ethnic groups, the questionnaire data show substantial variations in dietary intakes (nutrients as well as foods) and in the distributions of non-dietary risk factors (including smoking, alcohol consumption, obesity, and physical activity). When compared with corresponding ethnic-specific cancer incidence rates, the findings provide tentative support for several current dietary hypotheses. As sufficient numbers of cancer cases are identified through surveillance of the cohort, dietary and other hypotheses will be tested in prospective analyses. Keywords alcohol drinking; cohort studies; diet; ethnic groups; obesity; physical fitness; prospective studies; smoking Ethnic minorities in the United States have not been well represented in epidemiologic research on diet and cancer, especially in prospective cohort studies. Thus, little is known about the relation of dietary factors to cancer risk in these groups. Furthermore, while diet and other external factors are the predominant determinants of cancer risk in all these groups (1), the extent to which environmental exposures explain interethnic differences in incidence Reprint requests to Dr. Laurence Kolonel, Cancer Research Center of Hawaii, 1236 Lauhala Street, Honolulu, HI 96813. HHS Public Access Author Manuscript Author Manuscript Author ManuscriptAuthor Manuscript is not known. By including a variety of ethnic groups within a single study, and by using a common data collection methodology in all groups, interethnic comparisons of exposuredisease relations can readily be made.Hawaii has long presented special opportunities for epidemiologic research because of its diverse ethnic/cultural environment. Over the past two decades, the Los Angeles basin has also attracted large ethnic populations, including a variety of groups from Asia, and Latino migrants from Mexico and Central and South America. Together, these two areas now provide an unmatched resource for epidemiologic initiatives.Recognizing the need for dietary studies of ethnic minorities in the United States, the unique opportunities offered by Hawaii and southern California for conducting cross-ethnic a...

Clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) was detected using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells (>5–10%) with the same abnormal karyotype (presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rises rapidly to 2–3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions that pinpoint the locations of genes previously associated with hematological cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer prior to DNA sampling, those without a prior diagnosis have an estimated 10-fold higher risk of a subsequent hematological cancer (95% confidence interval = 6–18).

The performance of the dietary questionnaire used in a multiethnic cohort study in Hawaii and Los Angeles was assessed in a calibration substudy that compared diet reported from the questionnaire with three 24-hour dietary recalls. For the calibration substudy, subjects from each of eight subgroups defined by sex and ethnic group (African-American, Japanese-American, Latino, and White) were chosen randomly from among the cohort members, and each participant's previous day's diet was assessed by telephone recall on three occasions over approximately 2 months. After completing the three 24-hour recalls, each calibration subject was sent a second questionnaire; 1,606 persons completed three recalls and a second questionnaire (127 to 267 per ethnic-sex group). This report describes correlation coefficients and calibration slopes for the relation between the 24-hour recalls and second questionnaire values for a selected set of macro- and micronutrients, as absolute intakes, nutrient densities, and calorie-adjusted nutrients. In all subgroups, estimates of the correlation between the questionnaire and 24-hour recalls were greater after energy adjustment (average correlations ranged from 0.57-0.74 for nutrient densities and from 0.55-0.74 for calorie-adjusted nutrients) than when absolute nutrient values were used (average range 0.26-0.57). For absolute nutrient intakes, the correlations were greatest for Whites, somewhat lower for Japanese-Americans and Latinos, and lowest for African-Americans. After energy adjustment, the difference between subgroups were diminished, and the correlations were generally highly satisfactory.

Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others1, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. We analyzed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and Latin Americans: 3,848 with type 2 diabetes (T2D) and 4,366 non-diabetic controls. In addition to replicating previous findings2–4, we identified a novel locus associated with T2D at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P=3.9×10−13; odds ratio (OR)=1.29). The association was stronger in younger, leaner people with T2D, and replicated in independent samples (P=1.1×10−4; OR=1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at ≈50% frequency in Native American samples and ≈10% in East Asian, but rare in European and African samples. Analysis of an archaic genome sequence indicated the risk haplotype introgressed into modern humans via admixture with Neandertals. The SLC16A11 mRNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite T2D having been well studied by genome-wide association studies (GWAS) in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for T2D with a possible role in triacylglycerol metabolism.

Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry, and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one novel locus at 5q33 (GALNT10, rs7708584, p=3.4×10−11) and another at 7p15 when combined with data from the Giant consortium (MIR148A/NFE2L3, rs10261878, p=1.2×10−10). We also found suggestive evidence of an association at a third locus at 6q16 in the African ancestry sample (KLHL32, rs974417, p=6.9×10−8). Thirty-two of the 36 previously established BMI variants displayed directionally consistent effect estimates in our GWAS (binomial p=9.7×10−7), of which five reached genome-wide significance. These findings provide strong support for shared BMI loci across populations as well as for the utility of studying ancestrally diverse populations.

In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study (GWAS), with 1,047,986 single nucleotide polymorphism (SNP) markers examined in 3,425 African American prostate cancer cases and 3,290 African American male controls. The most significant 17 novel associations in stage 1 were followed-up in 1,844 cases and 3,269 controls of African ancestry. We identified a novel risk variant on chromosome 17q21 (rs7210100; odds ratio per allele=1.51; p=3.4×10−13). The frequency of the risk allele is ~5% in men of African descent while it is rare in other populations (<1%). Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. These findings emphasize the importance of conducting GWAS in diverse populations.

Prospective data on ethnic differences in hormone receptor-defined subtypes of breast cancer and their risk factor profiles are scarce. The authors examined the joint distributions of estrogen receptor (ER) and progesterone receptor (PR) status across 5 ethnic groups and the associations of established risk factors with ER/PR status in the Multiethnic Cohort Study (Hawaii and Los Angeles, California). During an average of 10.4 years of follow-up of 84,427 women between 1993-1996 and 2004/2005, 2,543 breast cancer cases with data on ER/PR status were identified: 1,672 estrogen receptor-positive (ER+)/progesterone receptor-positive (PR+); 303 ER+/progesterone receptor-negative (PR-); 77 estrogen receptor-negative (ER-)/PR+; and 491 ER-/PR-. ER/PR status varied significantly across racial/ethnic groups even within the same tumor stage (for localized tumors, P < 0.0001; for advanced tumors, P = 0.01). The highest fraction of ER-/PR- tumors was observed in African Americans (31%), followed by Latinas (25%), Whites (18%), Japanese (14%), and Native Hawaiians (14%). Associations differed between ER+/PR+ and ER-/PR- cases for postmenopausal obesity (P = 0.02), age at menarche (P = 0.05), age at first birth (P = 0.04), and postmenopausal hormone use (P < 0.0001). African Americans are more likely to be diagnosed with ER-/PR- tumors independently of stage at diagnosis, and there are disparate risk factor profiles across the ER/PR subtypes of breast cancer.

It has been recently hypothesized that many of the signals detected in genome-wide association studies (GWAS) to T2D and other diseases, despite being observed to common variants, might in fact result from causal mutations that are rare. One prediction of this hypothesis is that the allelic associations should be population-specific, as the causal mutations arose after the migrations that established different populations around the world. We selected 19 common variants found to be reproducibly associated to T2D risk in European populations and studied them in a large multiethnic case-control study (6,142 cases and 7,403 controls) among men and women from 5 racial/ethnic groups (European Americans, African Americans, Latinos, Japanese Americans, and Native Hawaiians). In analysis pooled across ethnic groups, the allelic associations were in the same direction as the original report for all 19 variants, and 14 of the 19 were significantly associated with risk. In summing the number of risk alleles for each individual, the per-allele associations were highly statistically significant (P<10−4) and similar in all populations (odds ratios 1.09–1.12) except in Japanese Americans the estimated effect per allele was larger than in the other populations (1.20; Phet = 3.8×10−4). We did not observe ethnic differences in the distribution of risk that would explain the increased prevalence of type 2 diabetes in these groups as compared to European Americans. The consistency of allelic associations in diverse racial/ethnic groups is not predicted under the hypothesis of Goldstein regarding “synthetic associations” of rare mutations in T2D.