Eunyoung Cho

Fish and Long-Chain ω-3 Fatty Acid Intake and Risk of Coronary Heart Disease and Total Mortality in Diabetic Women

Background—Although several prospective cohort studies have found an inverse association between fish consumption and risk of coronary heart disease (CHD) or sudden cardiac death in the general population, limited data are available among diabetic patients. Methods and Results—We examined prospectively the association between intake of fish and &ohgr;-3 fatty acids and risk of CHD and total mortality among 5103 female nurses with diagnosed type 2 diabetes but free of cardiovascular disease or cancer at baseline. Between 1980 and 1996 (45 845 person-years of follow-up), we documented 362 incident cases of CHD (141 CHD deaths and 221 nonfatal myocardial infarctions) and 468 deaths from all causes. Compared with women who seldom consumed fish (<1 serving/mo), the relative risks (RRs) (95% CI) of CHD adjusted for age, smoking, and other established coronary risk factors were 0.70 (0.48 to 1.03) for fish consumption 1 to 3 times per month, 0.60 (0.42 to 0.85) for once per week, 0.64 (0.42 to 0.99) for 2 to 4 times per week, and 0.36 (0.20 to 0.66) for 5 or more times per week (P for trend=0.002). Higher consumption of fish was also associated with a significantly lower total mortality (multivariate RR=0.48 [0.29 to 0.80] for ≥5 times per week [P for trend=0.005]). Higher consumption of long-chain &ohgr;-3 fatty acids was associated with a trend toward lower incidence of CHD (RR=0.69 [95% CI 0.47 to 1.03], P for trend=0.10) and total mortality (RR=0.63 [95% CI, 0.45 to 0.88], P for trend=0.02). Conclusions—A higher consumption of fish and long-chain &ohgr;-3 fatty acids was associated with a lower CHD incidence and total mortality among diabetic women.

The impact of diabetes mellitus and prior myocardial infarction on mortality from all causes and from coronary heart disease in men

OBJECTIVES The goal of this study was to examine the impact of diabetes and prior myocardial infarction (MI) on mortality in men. BACKGROUND Previous studies have suggested that a history of diabetes and a prior MI confer similar risk for subsequent fatal coronary heart disease (CHD). Few studies have examined duration of diabetes in relation to mortality. METHODS We examined type 2 diabetes and prior MI in relation to mortality among 51,316 men aged 40 to 75 years in the Health Professionals Follow-up Study. RESULTS During 10 years of follow-up, we documented 4,150 deaths from all causes, including 1,124 deaths from CHD. Compared with men without diabetes or prior MI at baseline, the multivariate relative risks (RRs) for fatal CHD were 3.84 (95% confidence interval [CI], 3.12 to 4.71) for those with diabetes only, 7.88 (95% CI, 6.86 to 9.05) for those with MI only, and 13.41 (95% CI, 10.49 to 17.16) for those with both diabetes and MI. The corresponding RRs for total mortality were 1.91 (95% CI, 1.70 to 2.15), 2.23 (95% CI, 2.03 to 2.45), and 3.13 (95% CI, 2.56 to 3.84), respectively. Duration of diabetes was an independent risk factor for total as well as CHD mortality; the multivariate RRs of CHD mortality for increasing duration of diabetes (< or = 5 years, 6 to 10 years, 11 to 15 years, 16 to 25 years, 26+ years) were 1.63, 1.93, 2.35, 2.31, and 3.87, respectively (p for trend <0.001), compared with nondiabetic participants. CONCLUSIONS These findings support that both diabetes and MI are associated with elevated total and CHD mortality, and having both conditions is particularly hazardous. Longer duration of diabetes is a strong predictor of death among diabetic men.

Risk Factors and Individual Probabilities of Melanoma for Whites

PURPOSE Incidence and mortality of cutaneous melanoma is rising rapidly in the United States; therefore, identifying risk factors for melanoma and integrating them into a clinical and population risk estimation tool may help guide prevention efforts and identify participants for preventive interventions. METHODS We examined risk factors for melanoma in three large prospective studies of women and men. We observed 152,949 women and 25,206 men free of cancer at baseline for up to 14 years. RESULTS A total of 535 incident cases of invasive melanoma (444 women and 91 men) were included in the analysis. We combined the three studies to examine risk factors and to build a risk model to calculate melanoma risk score. Older age, male sex, family history of melanoma, higher number of nevi, history of severe sunburn, and light hair color were each associated with significantly elevated risk of melanoma and were included in the final risk prediction. Participants at the highest decile of risk had a more than three-fold increase in risk of melanoma compared with those in the lowest decile (observed relative risk, 3.61; expected relative risk, 4.20). The measure of discriminatory accuracy as summarized by an age-and sex-adjusted concordance statistic of 0.62 (95% CI, 0.58 to 0.65) indicated that the model had reasonable ability to differentiate those who will develop melanoma and those who will remain free from the disease. CONCLUSION We identified several risk factors for melanoma and developed statistical models with adequate performance and discriminatory accuracy.

Molecular pathological epidemiology of epigenetics: emerging integrative science to analyze environment, host, and disease

Epigenetics acts as an interface between environmental/exogenous factors, cellular responses, and pathological processes. Aberrant epigenetic signatures are a hallmark of complex multifactorial diseases (including neoplasms and malignancies such as leukemias, lymphomas, sarcomas, and breast, lung, prostate, liver, and colorectal cancers). Epigenetic signatures (DNA methylation, mRNA and microRNA expression, etc) may serve as biomarkers for risk stratification, early detection, and disease classification, as well as targets for therapy and chemoprevention. In particular, DNA methylation assays are widely applied to formalin-fixed, paraffin-embedded archival tissue specimens as clinical pathology tests. To better understand the interplay between etiological factors, cellular molecular characteristics, and disease evolution, the field of ‘molecular pathological epidemiology (MPE)’ has emerged as an interdisciplinary integration of ‘molecular pathology’ and ‘epidemiology’. In contrast to traditional epidemiological research including genome-wide association studies (GWAS), MPE is founded on the unique disease principle, that is, each disease process results from unique profiles of exposomes, epigenomes, transcriptomes, proteomes, metabolomes, microbiomes, and interactomes in relation to the macroenvironment and tissue microenvironment. MPE may represent a logical evolution of GWAS, termed ‘GWAS-MPE approach’. Although epigenome-wide association study attracts increasing attention, currently, it has a fundamental problem in that each cell within one individual has a unique, time-varying epigenome. Having a similar conceptual framework to systems biology, the holistic MPE approach enables us to link potential etiological factors to specific molecular pathology, and gain novel pathogenic insights on causality. The widespread application of epigenome (eg, methylome) analyses will enhance our understanding of disease heterogeneity, epigenotypes (CpG island methylator phenotype, LINE-1 (long interspersed nucleotide element-1; also called long interspersed nuclear element-1; long interspersed element-1; L1) hypomethylation, etc), and host–disease interactions. In this article, we illustrate increasing contribution of modern pathology to broader public health sciences, which attests pivotal roles of pathologists in the new integrated MPE science towards our ultimate goal of personalized medicine and prevention.

Adolescent diet and risk of breast cancer

Objectives: To investigate the components of adolescent diet that may influence risk of breast cancer as an adult. Methods: Retrospective cohort study among 47,355 participants in the Nurses Health Study II who answered a 131-item food frequency questionnaire about diet during high school. Cox proportional hazards regression was used to estimate relative risks and 95% confidence intervals among incident cases of breast cancer between 1989 (inception of the study) and 1998 (when high school diet was assessed). Results: Intakes of fat and fiber were not significantly related to risk of breast cancer in multivariate analysis, but increased intake of vegetable fat (Q5versusQ1 multivariate RR = 0.58, 95% CI (0.38–0.86); test for trend p = 0.005) and vitamin E (Q5versusQ1 multivariate RR = 0.61, 95% CI (0.42–0.89); test for trend p = 0.003) were associated with a lower risk. A higher dietary glycemic index (Q5versusQ1 multivariate RR = 1.47, 95% CI (1.04–2.08); test for trend p = 0.01) was associated with increased risk of breast cancer. Conclusions: The apparent protective effects of vegetable fat and vitamin E and adverse effect of high glycemic foods on risk of breast cancer need confirmation in prospective analyses.

Dietary flavonols and flavonol-rich foods intake and the risk of breast cancer

Laboratory and animal studies suggest that dietary flavonols may reduce breast cancer risk but there are limited epidemiological studies. We computed flavonol intakes from dietary data collected by validated food frequency questionnaires in 1991 and 1995 from 90,630 women in the Nurses Health Study II. Using multivariate relative risks (RR) and 95% confidence intervals (95% CI), we evaluated the association of flavonol intake with breast cancer risk in women who were premenopausal and aged between 26 and 46 years at baseline in 1991. During 8 years of follow‐up, we documented 710 cases of invasive breast cancer. The multivariate RR (95% CI), comparing highest to lowest quintiles of cumulative average intake, was 1.05 (0.83, 1.34; p‐value for test of trend = 0.96) for the sum of flavonols and there were no associations seen between individual flavonols such as kaempferol, quercetin and myricetin and breast cancer risk. The multivariate RR (95% CI), comparing highest to lowest quintiles of cumulative average intake, was 0.94 (0.72, 1.22; p‐value for test of trend = 0.54) for sum of flavonol‐rich foods. Among the major food sources of flavonols, we found a significant inverse association with intake of beans or lentils but not with tea, onions, apples, string beans, broccoli, green pepper and blueberries. The multivariate RR (95% CI), comparing the highest category (2 or more times a week) of cumulative average beans or lentils intake with the lowest category (less than once a month), was 0.76 (0.57, 1.00; p‐value for test of trend = 0.03). While we found no overall association between intake of flavonols and risk of breast cancer, there was an inverse association with intake of beans or lentils that merits further evaluation.

Intakes of vitamins A, C and E and folate and multivitamins and lung cancer: A pooled analysis of 8 prospective studies

Intakes of vitamins A, C and E and folate have been hypothesized to reduce lung cancer risk. We examined these associations in a pooled analysis of the primary data from 8 prospective studies from North America and Europe. Baseline vitamin intake was assessed using a validated food‐frequency questionnaire, in each study. We calculated study‐specific associations and pooled them using a random‐effects model. During follow‐up of 430,281 persons over a maximum of 6–16 years in the studies, 3,206 incident lung cancer cases were documented. Vitamin intakes were inversely associated with lung cancer risk in age‐adjusted analyses; the associations were greatly attenuated after adjusting for smoking and other risk factors for lung cancer. The pooled multivariate relative risks, comparing the highest vs. lowest quintile of intake from food‐only, were 0.96 (95% confidence interval (CI) 0.83–1.11) for vitamin A, 0.80 (95% CI 0.71–0.91) for vitamin C, 0.86 (95% CI 0.76–0.99) for vitamin E and 0.88 (95% CI 0.74–1.04) for folate. The association with vitamin C was not independent of our previously reported inverse association with β‐cryptoxanthin. Further, vitamin intakes from foods plus supplements were not associated with a reduced risk of lung cancer in multivariate analyses, and use of multivitamins and specific vitamin supplements was not significantly associated with lung cancer risk. The results generally did not differ across studies or by sex, smoking habits and lung cancer cell type. In conclusion, these data do not support the hypothesis that intakes of vitamins A, C and E and folate reduce lung cancer risk.

Risk Factors for Melanoma by Body Site

It has been hypothesized that cutaneous melanoma at different anatomic sites develops through divergent pathways. We examined this hypothesis prospectively. We followed 152,949 women and 25,204 men free of cancer at baseline for up to 14 years in three large prospective studies. We examined risk factors for melanoma by anatomic location (head or neck, trunk, upper extremity, and lower extremity). Polytomous logistic regression was used to test the difference among risk factors by location of melanoma. A total of 511 incident cases of invasive melanoma (49 head or neck, 188 trunk, 98 upper extremity, and 176 lower extremity) were included in the analysis. Compared with females, males had a higher risk of developing melanoma on the head or neck and trunk. History of severe and painful sunburn was most strongly related to melanoma of upper extremity; individuals with >10 burns had a 6.86-fold (95% confidence interval, 2.62-18.00) higher risk of melanoma of upper extremity compared with those with no burns (P for trend < 0.0001; P for difference by body site = 0.04). Number of moles was most strongly related to melanoma of the trunk; the multivariate relative risk for having >10 moles was 4.67 (95% confidence interval, 3.07-7.11) compared with having no moles (P for trend < 0.0001; P for difference by body site = 0.04). Age, family history of melanoma, and hair color did not statistically differ by anatomic site of the cancer. These data support divergent etiologic pathways of melanoma development by anatomic sites.

Intakes of Fruit, Vegetables, and Carotenoids and Renal Cell Cancer Risk: A Pooled Analysis of 13 Prospective Studies

Fruit and vegetable consumption has been hypothesized to reduce the risk of renal cell cancer. We conducted a pooled analysis of 13 prospective studies, including 1,478 incident cases of renal cell cancer (709 women and 769 men) among 530,469 women and 244,483 men followed for up to 7 to 20 years. Participants completed a validated food-frequency questionnaire at baseline. Using the primary data from each study, the study-specific relative risks (RR) were calculated using the Cox proportional hazards model and then pooled using a random effects model. We found that fruit and vegetable consumption was associated with a reduced risk of renal cell cancer. Compared with <200 g/d of fruit and vegetable intake, the pooled multivariate RR for ≥600 g/d was 0.68 [95% confidence interval (95% CI) = 0.54-0.87; P for between-studies heterogeneity = 0.86; P for trend = 0.001]. Compared with <100 g/d, the pooled multivariate RRs (95% CI) for ≥400 g/d were 0.79 (0.63-0.99; P for trend = 0.03) for total fruit and 0.72 (0.48-1.08; P for trend = 0.07) for total vegetables. For specific carotenoids, the pooled multivariate RRs (95% CIs) comparing the highest and lowest quintiles were 0.87 (0.73-1.03) for α-carotene, 0.82 (0.69-0.98) for β-carotene, 0.86 (0.73-1.01) for β-cryptoxanthin, 0.82 (0.64-1.06) for lutein/zeaxanthin, and 1.13 (0.95-1.34) for lycopene. In conclusion, increasing fruit and vegetable consumption is associated with decreasing risk of renal cell cancer; carotenoids present in fruit and vegetables may partly contribute to this protection. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1730–9)

Aspirin and the Risk of Colorectal Cancer in Relation to the Expression of 15-Hydroxyprostaglandin Dehydrogenase (HPGD)

Aspirin use is associated with a lower risk of colorectal cancer arising in association with high expression of 15-PGDH (HPGD) in normal colon mucosa. An Aspirin a Day May Keep Colon Cancer Away Aspirin, the ubiquitous drug that people use for everything, ranging from fever and headache to prevention of heart disease and colon cancer, is not without its drawbacks. Especially at high doses, aspirin increases the risk of gastrointestinal problems, such as bleeding and ulcers, in addition to other side effects such as bruising. Thus, it would be nice to know which patients are most likely to derive a benefit from aspirin treatment, and to avoid exposing everyone else to unnecessary adverse effects. Fink and coauthors analyzed two large studies totaling more than 100,000 participants and discovered that patients who used aspirin for colon cancer prevention were less likely to develop colon cancer with a high expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Conversely, colon cancers expressing low amounts of 15-PGDH were equally common in patients who used aspirin and those who didn’t. The applicability of these results for preventative medicine will still need to be confirmed in prospective trials, to determine whether the concentration of 15-PGDH (determined in advance, perhaps during routine colonoscopy) can predict which patients would benefit from using aspirin to prevent colon cancer. The current paper lays the groundwork for such studies and provides hope that we may someday be able to maximize the benefits of aspirin and use it for targeted efforts at cancer prevention. Aspirin use reduces the risk of colorectal neoplasia, at least in part, through inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase 2)–related pathways. Hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide) (15-PGDH, HPGD) is down-regulated in colorectal cancers and functions as a metabolic antagonist of PTGS2. We hypothesized that the effect of aspirin may be antagonized by low 15-PGDH expression in the normal colon. In the Nurses’ Health Study and the Health Professionals Follow-Up Study, we collected data on aspirin use every 2 years and followed up participants for diagnoses of colorectal cancer. Duplication-method Cox proportional, multivariable-adjusted, cause-specific hazards regression for competing risks data was used to compute hazard ratios (HRs) for incident colorectal cancer according to 15-PGDH mRNA expression level measured in normal mucosa from colorectal cancer resections. Among 127,865 participants, we documented 270 colorectal cancer cases from which we could assess 15-PGDH expression. Compared with nonuse, regular aspirin use was associated with lower risk of colorectal cancer that developed within a background of colonic mucosa with high 15-PGDH expression [multivariable HR, 0.49; 95% confidence interval (CI), 0.34 to 0.71], but not with low 15-PGDH expression (multivariable HR, 0.90; 95% CI, 0.63 to 1.27) (P for heterogeneity = 0.018). Regular aspirin use was associated with lower incidence of colorectal cancers arising in association with high 15-PGDH expression, but not with low 15-PGDH expression in normal colon mucosa. This suggests that 15-PGDH expression level in normal colon mucosa may serve as a biomarker that may predict stronger benefit from aspirin chemoprevention.