Kelly J. Hunt

European prospective investigation into cancer and nutrition (EPIC): study populations and data collection

The European Prospective Investigation into Cancer and Nutrition (EPIC) is an ongoing multi-centre prospective cohort study designed to investigate the relationship between nutrition and cancer, with the potential for studying other diseases as well. The study currently includes 519 978 participants (366 521 women and 153 457 men, mostly aged 35-70 years) in 23 centres located in 10 European countries, to be followed for cancer incidence and cause-specific mortality for several decades. At enrollment, which took place between 1992 and 2000 at each of the different centres, information was collected through a non-dietary questionnaire on lifestyle variables and through a dietary questionnaire addressing usual diet. Anthropometric measurements were performed and blood samples taken, from which plasma, serum, red cells and buffy coat fractions were separated and aliquoted for long-term storage, mostly in liquid nitrogen. To calibrate dietary measurements, a standardised, computer-assisted 24-hour dietary recall was implemented at each centre on stratified random samples of the participants, for a total of 36 900 subjects. EPIC represents the largest single resource available today world-wide for prospective investigations on the aetiology of cancers (and other diseases) that can integrate questionnaire data on lifestyle and diet, biomarkers of diet and of endogenous metabolism (e.g. hormones and growth factors) and genetic polymorphisms. First results of case-control studies nested within the cohort are expected early in 2003. The present paper provides a description of the EPIC study, with the aim of simplifying reference to it in future papers reporting substantive or methodological studies carried out in the EPIC cohort.

National Cholesterol Education Program Versus World Health Organization Metabolic Syndrome in Relation to All-Cause and Cardiovascular Mortality in the San Antonio Heart Study

Background—To assess the utility of clinical definitions of the metabolic syndrome (MetS) to identify individuals with increased cardiovascular risk, we examined the relation between the MetS, using both the National Cholesterol Education Program (NCEP) and the World Health Organization definitions, and all-cause and cardiovascular mortality in San Antonio Heart Study participants enrolled between 1984 and 1988. Methods and Results—Among 2815 participants, 25 to 64 years of age at enrollment, 509 met both criteria, 197 met NCEP criteria only, and 199 met WHO criteria only. Over an average of 12.7 years, 229 deaths occurred (117 from cardiovascular disease). Moreover, in the primary prevention population of 2372 participants (ie, those without diabetes or cardiovascular disease at baseline), 132 deaths occurred (50 from cardiovascular disease). In the primary prevention population, the only significant association adjusted for age, gender, and ethnic group was between NCEP-MetS and cardiovascular mortality (hazard ratio [HR], 2.01; 95% CI, 1.13–3.57). In the general population, all-cause mortality HRs were 1.47 (95% CI, 1.13–1.92) for NCEP-MetS and 1.27 (95% CI, 0.97–1.66) for WHO-MetS. Furthermore, for cardiovascular mortality, there was evidence that gender modified the predictive ability of the MetS. For women and men, respectively, HRs for NCEP-MetS were 4.65 (95% CI, 2.35–9.21) and 1.82 (95% CI, 1.14–2.91), whereas HRs for WHO-MetS were 2.83 (95% CI, 1.55–5.17) and 1.15 (95% CI, 0.72–1.86). Conclusions—In summary, although both definitions were predictive in the general population, the simpler NCEP definition tended to be more predictive in lower-risk subjects.

Fueling the Obesity Epidemic? Artificially Sweetened Beverage Use and Long-term Weight Gain

We have examined the relationship between artificially sweetened beverage (ASB) consumption and long‐term weight gain in the San Antonio Heart Study. From 1979 to 1988, height, weight, and ASB consumption were measured among 5,158 adult residents of San Antonio, Texas. Seven to eight years later, 3,682 participants (74% of survivors) were re‐examined. Outcome measures were incidence of overweight/obesity (OW/OBinc) and obesity (OBinc) (BMI ≥ 25 and ≥ 30 kg/m2, respectively), and BMI change by follow‐up (ΔBMI, kg/m2). A significant positive dose‐response relationship emerged between baseline ASB consumption and all outcome measures, adjusted for baseline BMI and demographic/behavioral characteristics. Consuming >21 ASBs/week (vs. none) was associated with almost‐doubled risk of OW/OB (odds ratio (OR) = 1.93, P = 0.007) among 1,250 baseline normal‐weight (NW) individuals, and doubled risk of obesity (OR = 2.03, P = 0.0005) among 2,571 individuals with baseline BMIs <30 kg/m2. Compared with nonusers (+1.01 kg/m2), ΔBMIs were significantly higher for ASB quartiles 2–4: +1.46 (P = 0.003), +1.50 (P = 0.002), and +1.78 kg/m2 (P < 0.0001), respectively. Overall, adjusted ΔBMIs were 47% greater among artificial sweetner (AS) users than nonusers (+1.48 kg/m2 vs. +1.01 kg/m2, respectively, P < 0.0001). In separate analyses—stratified by gender; ethnicity; baseline weight category, dieting, or diabetes status; or exercise‐change category—ΔBMIs were consistently greater among AS users. These differences, though not significant among exercise increasers, or those with baseline diabetes or BMI >30 kg/m2 (P = 0.069), were significant in all 13 remaining strata. These findings raise the question whether AS use might be fueling—rather than fighting—our escalating obesity epidemic.

Who returns for postpartum glucose screening following gestational diabetes mellitus

OBJECTIVE The objective of the study was to determine the prevalence of postpartum impaired glucose regulation (IGR) and factors associated with glucose screening following gestational diabetes mellitus (GDM). STUDY DESIGN This was a prospective cohort study of 707 women with GDM who delivered at the University Hospital (San Antonio, TX). RESULTS A total of 35.5% of 400 women with any postpartum glucose testing had IGR postpartum, and 40.6% of 288 women who completed an oral glucose tolerance test had IGR, one-third of whom had isolated elevated 2-hour glucose levels. Women who failed to return for postpartum glucose testing (n = 307) were more likely to report prior GDM, have higher diagnostic glucose levels, and require insulin during pregnancy than women who returned for postpartum glucose testing. CONCLUSION Women who returned for postpartum glucose testing had less severe GDM than women who failed to return, suggesting that the true prevalence of postpartum IGR may be even higher than identified in our population.

Haplotypes of Transcription Factor 7–Like 2 (TCF7L2) Gene and Its Upstream Region Are Associated With Type 2 Diabetes and Age of Onset in Mexican Americans

TCF7L2 acts as both a repressor and transactivator of genes, as directed by the Wnt signaling pathway. Recently, several highly correlated sequence variants located within a haplotype block of the TCF7L2 gene were observed to associate with type 2 diabetes in three Caucasian cohorts. We previously reported linkage of type 2 diabetes in the San Antonio Family Diabetes Study (SAFADS) cohort consisting of extended pedigrees of Mexican Americans to the region of chromosome 10q harboring TCF7L2. We therefore genotyped 11 single nucleotide polymorphisms (SNPs) from nine haplotype blocks across the gene in 545 SAFADS subjects (178 diabetic) to investigate their role in diabetes pathogenesis. We observed nominal association between four SNPs (rs10885390, rs7903146, rs12255372, and rs3814573) in three haplotype blocks and type 2 diabetes, age at diagnosis, and 2-h glucose levels (P = 0.001–0.055). Furthermore, we identified a common protective haplotype defined by these four SNPs that was significantly associated with type 2 diabetes and age at diagnosis (P = 4.2 × 10−5, relative risk [RR] 0.69; P = 6.7 × 10−6, respectively) and a haplotype that confers diabetes risk that contains the rare alleles at SNPs rs10885390 and rs12255372 (P = 0.02, RR 1.64). These data provide evidence that variation in the TCF7L2 genomic region may affect risk for type 2 diabetes in Mexican Americans, but the attributable risk may be lower than in Caucasian populations.

A cross-sectional study of IGF-I determinants in women

Evidence is accumulating that elevated circulating insulin-like growth factor I (IGF-I) is related to increased cancer risk. The identification of hormonal, reproductive and lifestyle characteristics influencing its synthesis and bioavailability is of particular interest. Data from 400 women, who served as controls in two case–control studies nested within the same prospective cohort study, were combined. IGF-I, IGF-binding proteins 1, 2 and 3 (IGFBP-1, -2, -3) and insulin were measured in serum samples from all subjects and cotinine in 186 samples. Age appears to be the most important determinant of total IGF-I levels in women. Anthropometric measures, such as body mass index (BMI) or waist-to-hip ratio (WHR) do not seem to influence total IGF-I concentrations in peripheral blood, but may modulate IGF-I bioavailability through insulin-dependent changes in IGFBP-1 and -2 concentrations. Age at menarche, phase of the menstrual cycle at blood draw, parity, menopause, past oral contraceptive or hormone replacement therapy use, and tobacco smoking do not appear to exert an independent effect on IGF-I and its binding proteins. There was some suggestion that regular physical activity may increase total IGF-I and that women with positive family history of breast cancer might have higher IGF-I levels than those without such diagnosis in their relatives.

Levels of Oxidized LDL and Advanced Glycation End Products–Modified LDL in Circulating Immune Complexes Are Strongly Associated With Increased Levels of Carotid Intima-Media Thickness and Its Progression in Type 1 Diabetes

OBJECTIVE High cholesterol levels in circulating immune complexes (IC), surrogate markers of modified LDL, are associated with increased carotid intima-media thickness (IMT) and cardiovascular events in type 1 diabetes. Different modifications of LDL are involved in IC formation, but which of these are predictive of vascular events is not known. Therefore, we measured oxidized LDL (oxLDL), advanced glycation end products–modified LDL (AGE-LDL), and malondialdehyde-modified LDL (MDA-LDL) in IC and determined their relationship with increased carotid IMT and compared the strength of the association with that observed with conventional risk factors. RESEARCH DESIGN AND METHODS Levels of oxLDL, AGE-LDL, and MDA-LDL were measured in circulating IC isolated from sera of 479 patients of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort, collected at baseline. Internal and common carotid IMT were measured 8 and 14 years later by DCCT/EDIC. RESULTS OxLDL, AGE-LDL, and MDA-LDL levels in circulating IC were significantly correlated with diabetes duration, BMI, and lipid and blood pressure, but not with age. Multivariate logistic regression models indicated that individuals in the highest versus lowest quartile of oxLDL and AGE-LDL in IC had a 6.11-fold [confidence interval (CI) 2.51–14.8] and a 6.4-fold (CI 2.53–16.2) increase in the odds of having high carotid IMT, respectively, after adjusting for conventional risk factors. Parallel analyses resulted in odds ratios of 2.62 (CI 1.24, 5.55) for LDL-C, 1.45 (CI 0.69, 3.03) for diastolic blood pressure, and 2.33 (CI 1.09, 4.99) for A1C. CONCLUSIONS OxLDL and AGE-LDL in circulating IC were significantly associated with progression and increased levels of carotid IMT in type 1 diabetes.

Genetic Basis of Variation in Carotid Artery Plaque in the San Antonio Family Heart Study

Background and Purpose— In contrast to the commonly used quantitative marker of subclinical atherosclerosis, namely intima-media thickness, we investigated the extent to which the presence or absence of carotid artery plaque (CAP) was under genetic control. Methods— The study population consisted of 750 individuals distributed across 29 randomly ascertained extended Mexican American pedigrees who participated in the second examination cycle of the San Antonio Family Heart Study. Extracranial focal CAP was identified by B-mode ultrasound bilaterally in the internal carotid artery or the carotid bulb. Using a variance decomposition approach implemented in the SOLAR computer program, we performed genetic analysis on the discrete trait CAP (ie, liability to disease) using a threshold model. Covariates considered in the analysis included age, sex, diabetes, current smoking status, lipid levels, and markers of hypertension and obesity. Results— Fifty-one of 461 women and fifty-seven of 289 men with a mean age of 42.1 years had evidence of a plaque in the right and/or left carotid artery. The age- and sex-adjusted heritability (h2±SE) for CAP was significant (h2=0.28±0.15, P =0.01). Furthermore, after adjustment for additional covariates that contributed significantly to the model (P <0.05; diabetes, hypertension, body mass index, waist circumference, and smoking status), heritability remained significant (h2=0.23±0.15, P =0.03). Conclusions— Our data indicate that after established cardiovascular risk factors are controlled for, the variation of the discrete trait CAP is under appreciable additive genetic influences.

Elevated Carotid Artery Intima-Media Thickness Levels in Individuals Who Subsequently Develop Type 2 Diabetes

Objective—We examined whether B-mode ultrasound–detected carotid artery intima-media thickness (IMT) was elevated before the onset of clinical diabetes. Methods and Results—The study population for these analyses included 1127 nondiabetic participants, 66 prediabetic participants, and 303 diabetic participants with a mean age of 49.8 years who participated in the Mexico City Diabetes Study, a prospective cohort study. Common carotid artery (CCA) and internal carotid artery (ICA) IMTs were measured bilaterally by B-mode ultrasound. Age- and sex-adjusted mean ICA and CCA IMTs were both significantly higher among prediabetic individuals {0.81 mm [95% confidence interval (CI), 0.75–0.88] and 0.72 mm [95% CI, 0.69–0.75], respectively} than in individuals who remained free of diabetes [0.71 mm (95% CI, 0.69–0.72) and 0.69 mm (95% CI, 0.68–0.69), respectively]. However, after adjustment for established cardiovascular risk factors, ICA IMT, but not CCA IMT, remained significantly higher among prediabetic individuals [0.81 mm (95% CI, 0.75–0.88) and 0.71 mm (95% CI, 0.68–0.74)] than in individuals who remained free of diabetes [0.71 mm (95% CI, 0.69–0.72) and 0.69 mm (95% CI, 0.68–0.70)]. Conclusions—The present study provides direct evidence at the vascular level that atherosclerosis levels are elevated before the clinical onset of diabetes.

Acoustic shadowing on B-mode ultrasound of the carotid artery predicts CHD

The relationship between carotid artery lesions (CALs), with and without acoustic shadowing (AS) as an index of arterial mineralization, and incident coronary heart disease (CHD) was examined in the Atherosclerosis Risk in Communities study cohort. Among 12,375 individuals, ages 45-64 years, free of CHD at baseline, 399 CHD events occurred between 1987-1995. In a 3-cm segment centered at the carotid bifurcation, CALs with and without AS were identified by B-mode ultrasound (US). After adjustment for the major CHD risk factors, the CHD hazard ratio (HR) for women with CAL without AS compared to women without CAL was 1.78 (95% CI: 1.22, 2.60) and the HR comparing women with CAL with AS to women with CAL without AS was 1.73 (95% CI: 1.07, 2.80). Corresponding HRs for men were 1.59 (95% CI: 1.22, 2.07) and 1.04 (95% CI: 0.72, 1.51). CALs predicted CHD events; this association was stronger for mineralized CALs in women, but not men.