Measures of body fatness and height in early and mid-to-late adulthood and prostate cancer: risk and mortality in The Pooling Project of Prospective Studies of Diet and Cancer.

BACKGROUND: Advanced prostate cancer etiology is poorly understood. Few studies have examined associations of anthropometric factors (e.g. early adulthood obesity) with advanced prostate cancer risk. PATIENTS AND METHODS: We carried out pooled analyses to examine associations between body fatness, height, and prostate cancer risk. Among 830 772 men, 51 734 incident prostate cancer cases were identified, including 4762 advanced (T4/N1/M1 or prostate cancer deaths) cases, 2915 advanced restricted (same as advanced, but excluding localized cancers that resulted in death) cases, 9489 high-grade cases, and 3027 prostate cancer deaths. Cox proportional hazards models were used to calculate study-specific hazard ratios (HR) and 95% confidence intervals (CI); results were pooled using random effects models. RESULTS: No statistically significant associations were observed for body mass index (BMI) in early adulthood for advanced, advanced restricted, and high-grade prostate cancer, and prostate cancer mortality. Positive associations were shown for BMI at baseline with advanced prostate cancer (HR = 1.30, 95% CI = 0.95-1.78) and prostate cancer mortality (HR = 1.52, 95% CI = 1.12-2.07) comparing BMI ≥35.0 kg/m2 with 21-22.9 kg/m2. When considering early adulthood and baseline BMI together, a 27% higher prostate cancer mortality risk (95% CI = 9% to 49%) was observed for men with BMI <25.0 kg/m2 in early adulthood and BMI ≥30.0 kg/m2 at baseline compared with BMI <25.0 kg/m2 in early adulthood and BMI <30.0 kg/m2 at baseline. Baseline waist circumference, comparing ≥110 cm with <90 cm, and waist-to-hip ratio, comparing ≥1.00 with <0.90, were associated with significant 14%-16% increases in high-grade prostate cancer risk and suggestive or significant 20%-39% increases in prostate cancer mortality risk. Height was associated with suggestive or significant 33%-56% risks of advanced or advanced restricted prostate cancer and prostate cancer mortality, comparing ≥1.90 m with <1.65 m. CONCLUSION: Our findings suggest that height and total and central adiposity in mid-to-later adulthood, but not early adulthood adiposity, are associated with risk of advanced forms of prostate cancer. Thus, maintenance of healthy weight may help prevent advanced prostate cancer.

Weight change in older adults and mortality: the Multiethnic Cohort Study.

OBJECTIVE: To investigate the association between weight change in older adults and mortality in a multiethnic population. METHODS: We performed a prospective analysis using data on weight change between the baseline (1993-1996) and the 10-year follow-up (2003-2007) surveys in relation to subsequent mortality among 63 040 participants in the Multiethnic Cohort Study in Hawaii and California. The participants were African American, Native Hawaiian, Japanese American, Latino and white, aged 45-75 years at baseline, and did not report heart disease or cancer at either survey. RESULTS: During an average of 7.3 years of follow-up after the 10-year survey, 6623 deaths were identified. Compared with individuals whose weight remained stable (±2.5 kg), those who lost weight and those with the highest weight gain (>10 kg) were at increased risk of all-cause mortality, with the risks greater for the weight loss (hazard ratios (HR): 2.86; 95% confidence interval (95% CI): 2.62-3.11 for >10 kg) than the weight-gain group (HR: 1.25; 95% CI: 1.11-1.41 for >10 kg), thus resulting in a reverse J-shaped curve. Japanese Americans and Latinos had stronger associations of weight loss >10 kg with mortality than did African Americans, Native Hawaiians and whites. The increase in risk with weight gain >10 kg was greater for older (⩾55 years at baseline) than younger individuals, whereas the increase in mortality associated with weight loss was greater for the normal weight (<25 kg m-2 at baseline) participants and never smokers, compared with overweight/obese persons and current smokers, respectively. CONCLUSIONS: Our findings confirm the association between weight change and a higher mortality in a healthy, multiethnic population, with higher risks for weight loss than weight gain. On the basis of these observations, public health recommendation should focus on the prevention of weight loss, as well as weight stability within the non-obese range, for middle-aged and older adults.

Trans-ethnic analysis of metabochip data identifies two new loci associated with BMI.

OBJECTIVE: Body mass index (BMI) is commonly used to assess obesity, which is associated with numerous diseases and negative health outcomes. BMI has been shown to be a heritable, polygenic trait, with close to 100 loci previously identified and replicated in multiple populations. We aim to replicate known BMI loci and identify novel associations in a trans-ethnic study population. SUBJECTS: Using eligible participants from the Population Architecture using Genomics and Epidemiology consortium, we conducted a trans-ethnic meta-analysis of 102 514 African Americans, Hispanics, Asian/Native Hawaiian, Native Americans and European Americans. Participants were genotyped on over 200 000 SNPs on the Illumina Metabochip custom array, or imputed into the 1000 Genomes Project (Phase I). Linear regression of the natural log of BMI, adjusting for age, sex, study site (if applicable), and ancestry principal components, was conducted for each race/ethnicity within each study cohort. Race/ethnicity-specific, and combined meta-analyses used fixed-effects models. RESULTS: We replicated 15 of 21 BMI loci included on the Metabochip, and identified two novel BMI loci at 1q41 (rs2820436) and 2q31.1 (rs10930502) at the Metabochip-wide significance threshold (P<2.5 × 10-7). Bioinformatic functional investigation of SNPs at these loci suggests a possible impact on pathways that regulate metabolism and adipose tissue. CONCLUSION: Conducting studies in genetically diverse populations continues to be a valuable strategy for replicating known loci and uncovering novel BMI associations.

Ethnic differences in serum adipokine and C-reactive protein levels: the multiethnic cohort.

BACKGROUND: Ethnic disparities in metabolic disease risk may be the result of differences in circulating adipokines and inflammatory markers related to ethnic variations in obesity and body fat distribution. SUBJECTS/METHODS: In a cross-sectional design, we compared serum levels of leptin, adiponectin, C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in control subjects (321 men and 930 women) from two nested case-control studies conducted within the Multiethnic Cohort Study consisting of whites, Japanese Americans (JA), Latinos, African Americans (AA) and Native Hawaiians (NH). General linear models were applied to evaluate ethnic differences in log-transformed serum biomarker levels before and after adjusting for body mass index (BMI) at cohort entry. RESULTS: In comparison to whites, significant ethnic differences were observed for all biomarkers except TNF-α. JA men and women had significantly lower leptin and CRP levels than whites, and JA women also had lower adiponectin levels. Leptin was significantly higher in AA women (P < 0.01), adiponectin was significantly lower in AA men and women (P = 0.02 and P < 0.001), and CRP and IL-6 were significantly higher in AA men and women. Lower adiponectin (P < 0.0001) and CRP (P = 0.03) levels were the only biomarkers in NH women that differed from whites; no statistically significant differences were seen for NH men and for Latino men and women. When adjusted for BMI at cohort entry, the differences between the lowest and the highest values across ethnic groups decreased for all biomarkers except adiponectin in men indicating that ethnic differences were partially due to weight status. CONCLUSIONS: These findings demonstrate the ethnic variations in circulating adipokine and CRP levels before and after adjustment for BMI. Given the limitation of BMI as a general measure of obesity, further investigation with visceral and subcutaneous adiposity measures are warranted to elucidate ethnicity-related differences in adiposity in relation to disparities in obesity-related disease risk.

The use of phenome-wide association studies (PheWAS) for exploration of novel genotype-phenotype relationships and pleiotropy discovery.

The field of phenomics has been investigating network structure among large arrays of phenotypes, and genome-wide association studies (GWAS) have been used to investigate the relationship between genetic variation and single diseases/outcomes. A novel approach has emerged combining both the exploration of phenotypic structure and genotypic variation, known as the phenome-wide association study (PheWAS). The Population Architecture using Genomics and Epidemiology (PAGE) network is a National Human Genome Research Institute (NHGRI)-supported collaboration of four groups accessing eight extensively characterized epidemiologic studies. The primary focus of PAGE is deep characterization of well-replicated GWAS variants and their relationships to various phenotypes and traits in diverse epidemiologic studies that include European Americans, African Americans, Mexican Americans/Hispanics, Asians/Pacific Islanders, and Native Americans. The rich phenotypic resources of PAGE studies provide a unique opportunity for PheWAS as each genotyped variant can be tested for an association with the wide array of phenotypic measurements available within the studies of PAGE, including prevalent and incident status for multiple common clinical conditions and risk factors, as well as clinical parameters and intermediate biomarkers. The results of PheWAS can be used to discover novel relationships between SNPs, phenotypes, and networks of interrelated phenotypes; identify pleiotropy; provide novel mechanistic insights; and foster hypothesis generation. The PAGE network has developed infrastructure to support and perform PheWAS in a high-throughput manner. As implementing the PheWAS approach has presented several challenges, the infrastructure and methodology, as well as insights gained in this project, are presented herein to benefit the larger scientific community.

Evidence of an X-linked or recessive genetic component to prostate cancer risk.

We used data from a population-based cohort study of blacks, Hispanics, Japanese and whites to examine the frequency of prevalent prostate and breast cancer by family history status of first-degree relatives (parents and siblings). Independent of race, the age-adjusted relative risk for prevalent prostate cancer in subjects with affected brothers was approximately two times that in subjects with affected fathers (P < 0.00005). No such excess risk for breast cancer was observed among subjects with affected sisters compared to those with affected mothers (age- and race-adjusted relative risk = 1.10, P = 0.34). The magnitude of the relative risk for prostate cancer in sibling- versus parent-affected groups was significantly different from that of the comparable relative risk for breast cancer (P < 0.00005). An excess risk of prostate cancer in men with affected brothers compared to those with affected fathers is consistent with the hypothesis of an X-linked, or recessive, model of inheritance.

Urinary phytoestrogen excretion and prostate cancer risk: a nested case-control study in the Multiethnic Cohort.

BACKGROUND: Phytoestrogens are of special interest in prostate cancer research because populations in Asia with a high consumption of phytoestrogens have a lower incidence of the disease than comparable populations in Western countries. METHODS: This case-control study is nested within a large multiethnic cohort in Hawaii and California. Urine samples were analysed for daidzein, genistein, equol, and enterolactone among 249 incident prostate cancer cases and 404 controls matched on age, race/ethnicity, date/time of specimen collection, and fasting status. RESULTS: The median excretion of daidzein was 0.173 nmol mg(-1) creatinine in cases and 0.291 in controls (P=0.01), and the median excretion of genistein was 0.048 in cases and 0.078 in controls (P=0.05). An inverse association was seen for daidzein overall (odds ratio for the highest vs lowest quintile=0.55, 95% confidence interval=0.31-0.98, P(trend)=0.03) and seemed to apply to localized (P(trend)=0.08) as well as advanced or high-grade cancer (P(trend)=0.09). This association was consistent across the four ethnic groups examined. Although the relationship was weaker for genistein, the odds ratios and trends were similarly inverse. Urinary excretion of equol and enterolactone was not significantly related to prostate cancer risk. CONCLUSION: Our findings suggest that high intake of isoflavones, as reflected by urinary excretion of daidzein and genistein, may be protective against prostate cancer.

Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.

The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

Intake of flavonoids and lung cancer.

BACKGROUND: To investigate the possible relationship between intake of flavonoids-powerful dietary antioxidants that may also inhibit P450 enzymes-and lung cancer risk, we conducted a population-based, case-control study in Hawaii. METHODS: An in-person interview assessed smoking history and usual intake of 242 food items for 582 patients with incident lung cancer and 582 age-, sex-, and ethnicity-matched control subjects. Subjects who donated a blood sample were genotyped for the P450 enzyme variant allele CYP1A1*2 by use of a polymerase chain reaction-based method. Logistic regression analysis was used to compute odds ratios (ORs) and 95% confidence intervals (CIs). All P values are two-sided. RESULTS: After adjusting for smoking and intakes of saturated fat and beta-carotene, we found statistically significant inverse associations between lung cancer risk and the main food sources of the flavonoids quercetin (onions and apples) and naringin (white grapefruit). The lung cancer OR for the highest compared with the lowest quartile of intake was 0.5 (95% CI = 0.3-0.9) for onions (P for trend =.001) and 0.6 (95% CI = 0.4-1.0) for apples (P for trend =.03). The OR for the highest compared with the lowest tertile of intake for white grapefruit was 0.5 (95% CI = 0.2-0.9) (P for trend =.02). No association was found for important food sources of other flavonoids. Using published food-composition data for flavonoids, we found an inverse association between intake of quercetin and risk of lung cancer (P for trend =.07) that appears consistent with associations for its food sources. The effect of onions was particularly strong against squamous cell carcinoma (a cell type specifically associated with CYP1A1*2 in our study) and was modified by the CYP1A1 genotype, suggesting that CYP1A1 may play a role in this association. CONCLUSION: If replicated, particularly in prospective studies, these findings would suggest that foods rich in certain flavonoids may protect against certain forms of lung cancer and that decreased bioactivation of carcinogens by inhibition of CYP1A1 should be explored as underlying mechanisms.

Association of the NAD(P)H:quinone oxidoreductase 609C-->T polymorphism with a decreased lung cancer risk.

The NAD(P)H:quinone oxidoreductase gene, NQO1, often carries a C-->T transition at bp 609, which has been associated with a reduced enzymatic activity and which may result in altered metabolic activation of tobacco smoke procarcinogens. We tested the association of this polymorphism with lung cancer risk in a population-based case-control study of 327 cases and 440 controls of Caucasian, Japanese, or Native Hawaiian ancestry in Hawaii. We found a notable difference in the frequency of the variant allele among Japanese (38%), Caucasians (20%), and Hawaiians (22%). Overall, the variant allele was less frequent in cases than in controls (P = 0.03). A significant inverse association was found in Japanese, with adjusted odds ratios of 0.8 (95% confidence interval, 0.4-1.5) and 0.3 (0.1-0.7) for the heterozygous and homozygous variant genotypes, respectively, compared with the homozygous wild-type genotype (P for genetic trend, 0.02). The association did not reach statistical significance in Caucasians and Hawaiians but was in the same direction.

CYP1A1 genetic polymorphisms and in situ colorectal cancer.

Numerous studies have associated colorectal adenoma with smoking and large bowel cancer with consumption of foods potentially containing polycyclic aromatic hydrocarbons. Enhanced metabolic activation of polycyclic aromatic hydrocarbons has recently been observed in homozygotes for a MspI mutation in the 3'-end of CYP1A1. We conducted a population-based case-control study to investigate whether CYP1A1 polymorphisms were related to colorectal cancer risk. Using polymerase chain reaction-based methods, we assessed the frequency of the MspI polymorphism in the 3'-end of CYP1A1 and another mutation in exon 7 of the gene (Ile-Val polymorphism) among 43 patients with in situ adenocarcinoma of the large bowel and 129 population controls. Homozygosity for the MspI mutant genotype was found to be positively associated with in situ colorectal cancer in Japanese (P = 0.008) and Hawaiians/part-Hawaiians (P < 0.001), whereas the study lacked power to detect a similar association in Caucasians. The odds ratio for the homozygous variant genotype compared to the heterozygous and wild-type genotypes was 7.9 (95% confidence interval, 1.4-44.4) in Japanese. A similar association was suggested for the exon 7 mutation homozygosity in Japanese, as the two polymorphisms are in genetic disequilibrium. Thus, this study suggests a potentially important role for CYP1A1 and polycyclic aromatic hydrocarbons in the etiology of colorectal cancer in populations with a high gene frequency.

Associations of sedentary lifestyle, obesity, smoking, alcohol use, and diabetes with the risk of colorectal cancer.

Variation in colorectal cancer rates between countries and within ethnic groups upon migration and/or Westernization suggests a role for some aspects of Western lifestyle in the etiology of this disease. We conducted a population-based case-control study in the multiethnic population of Hawaii to evaluate associations between colorectal cancer and a number of characteristics of the Western lifestyle (high caloric intake, physical inactivity, obesity, smoking, and drinking) and some of their associated diseases. We interviewed in person 698 male and 494 female United States-born or immigrant Japanese, Caucasian, Filipino, Hawaiian, and Chinese patients diagnosed in 1987-1991 with colorectal cancer and 1192 population controls matched on age, sex, and ethnicity. Conditional logistic regression was used to estimate odds ratios adjusting for dietary and nondietary risk factors. Place of birth and duration of residence in the United States were unrelated to colorectal cancer risk. Energy intake (independent of the calorie source) and body mass index were directly associated with risk, and lifetime recreational physical activity was inversely associated with risk. The associations with these factors were independent of each other, additive (on the logistic scale) and stronger in men. When individuals were cross-categorized in relation to the medians of these variables, those with the higher energy intake and body mass index and lower physical activity were at the highest risk (for males, OR, 3.0; 95% confidence interval, 1.8-5.0, and for females, OR, 1.7; 95% confidence interval, 1.0-3.2). Smoking in the distant, as well as recent, past and alcohol use were directly associated with colorectal cancer in both sexes. Individuals with a history of diabetes or frequent constipation were at increased risk for this cancer, whereas past diagnosis of hypercholesterolemia was inversely associated with risk. The findings were consistent between sexes, among ethnic groups, and across stages at diagnosis, making bias an unlikely explanation. These results confirm the data from immigrant studies that suggest that the increase in colorectal cancer risk experienced by Asian immigrants to the United States occurred in the first generation because we found no difference in risk between the immigrants themselves and subsequent generations. They also agree with recent findings that suggest that high energy intake, large body mass, and physical inactivity independently increase risk of this disease and that a nutritional imbalance, similar to the one involved in diabetes, may lead to colorectal cancer.

Associations of CYP1A1, GSTM1, and CYP2E1 polymorphisms with lung cancer suggest cell type specificities to tobacco carcinogens.

The dramatic shift in the pathological presentation of lung cancer [the proportional decrease in squamous cell carcinoma (SCC) and increase in adenocarcinoma (AC)] observed in the United States after the 1950s may have taken place as the result of the reduction in polycyclic aromatic hydrocarbons (PAHs) and the increase in N-nitrosamines in inhaled smoke from filtered low-yield cigarettes. The predominant mutation patterns of these tumors also suggest differences in their etiology. We tested the hypothesis that genetic susceptibility to PAHs, as determined by polymorphisms in CYP1A1 and GSTM1, predominantly causes lung SCCs, and susceptibility to nitrosamines, as determined by polymorphisms in CYP2E1, predominantly causes lung ACs. CYP1A1 and GSTM1 play a major role in the metabolic activation and detoxification of PAHs, respectively, and CYP2E1 plays a major role in the metabolic activation of nitrosamines. We conducted a population-based case-control study among 341 incident lung cancer cases and 456 controls of Caucasian, Japanese, or Hawaiian origin. In-person interviews collected detailed information on lifestyle risk factors, and DNA extracted from peripheral leukocytes was used in PCR-based genotyping assays. Logistic regression analyses were used to compute odds ratios and 95% confidence intervals (CIs) for each cell type, adjusting for smoking and dietary variables. The presence of at least one copy of the CYP1A1 MspI variant allele was found to be associated with a 2.4-fold (95% CI, 1.2-4.7) increase in the risk of SCC when this gene was considered singly and a 3.1-fold (95% CI, 1.2-7.9) increase in the risk of SCC when combined with a GSTM1 deletion. No significant association was found between MspI and all lung cancers or other cell types or with the CYP1A1 exon 7 polymorphism. In contrast, the CYP2E1 RsaI and DraI polymorphisms were not clearly related to SCC risk, but these homozygous variant genotypes were associated with a 10-fold (95% CI, 0.0-0.5) decrease in the risk of overall lung cancer (RsaI variant) and AC (DraI variant) compared to the homozygous wild-type genotypes. Inverse associations with these two closely linked CYP2E1 polymorphisms were also suggested for small cell carcinoma. In agreement with past experimental and epidemiological data, the associations found in this study between CYP1A1 and lung SCC and between CYP2E1 and lung AC suggest a certain specificity of tobacco smoke PAHs for lung SCC and tobacco-specific nitrosamines for lung ACs.

Diet, body size, physical activity, and the risk of endometrial cancer.

Endometrial cancer is associated with increased weight and body size, diabetes, and other conditions that may result from an excess in calories or lack of physical activity. Although a few studies have explored the effect of dietary constituents on the risk of endometrial cancer, the nature of the joint association of these constituents and obesity, energy intake, or energy expenditure with risk is unknown. A population-based case-control study was conducted in Hawaii to examine the association of diet, body size, and physical activity with the risk of endometrial cancer. Subjects included 332 histologically confirmed, primary endometrial cancer cases and 511 controls identified between 1985 and 1993. Cases and controls were residents of Oahu, Hawaii who were between 18 and 84 years of age and were from one of the following ethnic groups: Japanese, Caucasian, Native Hawaiian, Filipino, and Chinese. Cases were identified through the Hawaii Tumor Registry and matched to the controls on age (+/-2.5 years) and ethnicity. In-person interviews, conducted in the subjects' homes, included dietary, reproductive, menstrual, and medical histories and use of exogenous hormones, physical activity, and other lifestyle variables. Weight, girth, and skinfold measurements were taken at the time of the interview. We found a strong dose-response relation of increased body size to the development of endometrial cancer after adjustment for energy intake. The odds ratio (OR) for endometrial cancer among women in the highest quartile of body mass index (BMI; kg/m2) was more than four times that among women in the lowest quartile. Waist, hip, midarm, and wrist girths were positively associated with the estimated risk of endometrial cancer after adjustment for total calories and other nondietary risk factors, although the trends in the ORs were attenuated after adjustment for BMI. Physically active women had a modest reduction in their risk of disease compared with inactive women. Cases consumed a greater percentage of their calories from fat and a lower percentage of their calories from carbohydrates than did controls. Adjustment for BMI reduced the ORs for the highest compared with the lowest quartile of fat calorie intake from 2.0 (95% confidence interval, 1.3-3.2) to 1.6 (95% confidence interval, 1.0-2.6), suggesting that part of the association is explained by obesity. There was a differential effect of fat on endometrial cancer according to BMI. For all components of fat, the associations with endometrial cancer were either minimal or absent among leaner women (i.e., those with BMI below the median), whereas, among more obese women, two-fold differences in risk were observed between women above and below the median of fat intake. Foods that are high in fat and cholesterol, such as red meat, margarine, and eggs, were positively associated with endometrial cancer, whereas cereals, legumes, vegetables, and fruits, particularly those high in lutein, were inversely associated. These findings suggest that women who avoid being overweight and who consume a diet low in plant and animal fats and high in complex carbohydrates are at a reduced risk of endometrial cancer.

Nutritional factors and non-Hodgkin lymphoma survival in an ethnically diverse population: the Multiethnic Cohort.

BACKGROUND/OBJECTIVES: To understand the possible effect of modifiable health behaviors on the prognosis of the increasing number of non-Hodgkin lymphoma (NHL) survivors, we examined the pre-diagnostic intake of major food groups with all-cause and NHL-specific survival in the Multiethnic Cohort (MEC). SUBJECTS/METHODS: This analysis included 2339 participants free of NHL at cohort entry and diagnosed with NHL as identified by cancer registries during follow-up. Deaths were ascertained through routine linkages to state and national death registries. Cox proportional hazards regression was applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for overall and NHL-specific mortality according to pre-diagnostic intake of vegetables, fruits, red meat, processed meat, fish, legumes, dietary fiber, dairy products and soy foods assessed by food frequency questionnaire. RESULTS: The mean age at diagnosis was 71.8±8.5 years. During 4.5±4.1 years of follow-up, 1348 deaths, including 903 NHL-specific deaths, occurred. In multivariable models, dairy intake was associated with higher all-cause mortality (highest vs lowest tertile: HR=1.14, 95% CI 1.00-1.31, Ptrend=0.03) and NHL-specific (HR=1.16, 95% CI 0.98-1.37) mortality. Legume intake above the lowest tertile was related to significant 13-16% lower all-cause and NHL-specific mortality, whereas red meat and fish intake in the intermediate tertiles was associated with lower NHL-specific mortality. No association with survival was detected for the other food groups. CONCLUSIONS: These data suggest that pre-diagnostic dietary intake may not appreciably contribute to NHL survival, although the higher mortality for dairy products and the better prognosis associated with legumes agree with known biologic effects of these foods.

Lifestyle and nutritional correlates of cytochrome CYP1A2 activity: inverse associations with plasma lutein and alpha-tocopherol.

Cytochrome CYP1A2, a liver enzyme responsible for the metabolic activation of a number of putative human carcinogens, exhibits wide inter-individual differences in activity. In order to characterize sources of variability in CYP1A2 activity, we phenotyped (with the caffeine test) 90 subjects of various ethnic backgrounds in Hawaii. Forty-three subjects were patients with in-situ colorectal cancer treated by polypectomy and 47 were healthy population controls. Subjects were also administered a detailed lifestyle questionnaire, including a quantitative food frequency questionnaire, and were assessed for plasma levels of carotenoids, tocopherols, retinol, ascorbic acid, cholesterol and triglycerides. In a stepwise multiple regression, 27% of the overall variation in CYP1A2 activity was explained by seven variables. Plasma lutein explained the largest portion of the variance (7%) and was negatively associated with CYP1A2 activity (p < 0.01), as were use of menopausal replacement estrogens (p = 0.04), plasma alpha-tocopherol (p = 0.05) and alcohol consumption (p = < 0.01). Acetaminophen use (p = 0.05), coffee consumption (p = 0.05) and plasma lycopene (p = 0.06) were positively associated with CYP1A2 activity. After adjustment for these variables, no association was found between CYP1A2 activity and sex, race, age, education, smoking, physical activity, weight, vitamin E supplements, the other plasma micronutrients measured, and dietary intakes of red meat, processed meat and cruciferous vegetables. Results were similar for colorectal cancer cases and controls. Almost two-thirds (73%) of the variability in CYP1A2 activity remained unexplained. This study confirms an enhancing effect of acetaminophen and coffee on CYP1A2 activity and suggests and inhibitory effect of estrogens, alcohol and food sources of lutein and alpha-tocopherol on this enzyme.

Association of tocopherols with circulating autoantibody levels against an oxidized DNA nucleoside in humans.

Autoantibodies against oxidized DNA bases are found in vivo and have been used as an indicator of oxidative damage, yet little is known concerning their individual variation and relation to serum micronutrients. Human plasma anti-5-hydroxymethyl-2'-deoxyuridine (HMdU) autoantibody (aAb) levels were repeatedly determined in 41 women and 11 men, and found to have small within-individual variation over time, but large between-individual differences. A positive association in both women (r = .5762, p = .0001) and men (r = .415, p = .2) between plasma total tocopherols and antibody levels was observed. Autoantibody levels were lower in postmenopausal women (8.37 +/- 1.61 vs. 17.18 +/- 2.85 in premenopausal women, p < .01), independently of plasma tocopherol. However, aAb titers in postmenopausal women were still significantly associated with plasma tocopherol levels and adjustment for menopausal status in women yielded a highly significant correlation between HMdU aAb levels and total tocopherol (r = .7342, p = .0001). Plasma malondialdehyde equivalents (MDA), a measure of lipid peroxidation, were also higher in individuals with either high plasma alpha-tocopherol or high beta+gamma-tocopherol levels. The positive association of tocopherols with markers of oxidative damage may reflect a response to the generation of endogenous oxidants associated with enhanced immune function. The decrease in aAb level in postmenopausal women may similarly reflect decreased immune function associated with decreased estrogen levels.

Development and validation of dietary assessment methods for culturally diverse populations.

Culturally diverse populations with variable dietary and disease patterns provide a unique opportunity for conducting epidemiologic studies to identify the role of diet in the etiology of chronic diseases. The dietary method for epidemiologic studies, such as cohort or case-control studies, should generally be a diet history (or quantitative food frequency) of selected food items consumed during a usual month. Knowledge of the eating patterns of each ethnic group in the study is needed to develop an appropriate questionnaire. The diet history may be validated by collecting multiple 24-h recalls or food records from representative samples of each ethnic group and comparing the mean dietary intakes with the values obtained from the diet history. Examples of studies of culturally diverse populations and the development and validation of the dietary methods are discussed.

Use of breath hydrogen and methane as markers of colonic fermentation in epidemiological studies: variability in excretion.

Breath hydrogen and methane are specific end products of colonic fermentation, a process which may play a protective role against colon cancer. To assess the possibility of using these markers in epidemiological studies, we characterized the intra- and intersubject variability of breath hydrogen and methane excretion over 15 consecutive days among 32 men and women of various ethnic backgrounds (16 Asians, 8 Caucasians, 8 Hawaiians). Participants were asked to collect four end-expiratory samples each day, which we had shown previously would optimally characterize daily hydrogen excretion. There was substantial within-subject variation in breath hydrogen over the study, although breath methane levels were more constant over time. We found that about 4 days of measurement of breath hydrogen and 1 day of measurement for breath methane are required to correctly characterize individuals according to their long-term excretion of these gases. This was true for Asians and non-Asians. Although breath methane appears to be more practical to measure, it is a less sensitive marker of colonic fermentation than breath hydrogen. Whereas all subjects excreted hydrogen, only 28% of the subjects excreted methane, and methane excretor status of a few participants varied during the study. Because the breath test is noninvasive and reliable, we tested the multiple day collection protocol among colon cancer patients and controls and found it to be well accepted. We conclude that it is practical to measure breath hydrogen and methane in large epidemiological studies conducted at the individual level. The potential use for these markers is discussed.