Energy balance and colon cancer--beyond physical activity.

Low levels of physical activity and high levels of energy intake and body mass have all been directly associated with colon cancer. The purpose of this study was to determine how physical inactivity interacts with other components of energy balance (energy intake and body mass) in determining colon cancer risk. Data were obtained from 2073 first primary cases of colon cancer and 2466 age- and sex-matched controls identified from 8 counties in Utah, the Northern California Kaiser Permanente Medical Care Program, and the Twin Cities metropolitan area in Minnesota. Recent and lifetime physical activity was assessed by intensity of activities performed at home, leisure, and at work; energy intake was estimated from an extensive diet history questionnaire; and body mass index (BMI) was calculated from measured height at the time of interview and reported weight for the referent year. For both men and women, lack of lifetime vigorous leisure-time activity was associated with increased risk of colon cancer [odds ratio (OR), 1.63 and 95% confidence interval (CI), 1.26-2.12 for men and OR, 1.59 and 95% CI, 1.21-2.10 for women, comparing the lowest to highest level of activity]. There were no differences in risk associated with physical activity by tumor site within the colon or by age at diagnosis. High levels of energy intake were also associated with increased risk of colon cancer in men and women (OR, 1.74 and 95% CI, 1.14-2.67 for men and OR, 1.70 and 95% CI, 1.07-2.70 for women). A large BMI was more associated with increased risk in men (OR, 1.94 and 95% CI, 1.49-2.54) than in women (OR, 1.45 and 95% CI, 1.08-1.94). Those at greatest risk of colon cancer were those who had the most unfavorable energy balance in that they were physically inactive, had high energy intakes, and had a large BMI (OR, 3.35 and 95% CI, 2.09-5.35). However, when physical activity was high, having a high energy intake and large BMI resulted in a nonsignificant increased colon cancer risk (OR, 1.28 and 95% CI, 0.81-2.03). This pattern was consistent between the sexes, but there was some evidence that men may be at higher risk than women, especially older women, as a result of unfavorable energy balance. These results support previous findings that physical inactivity, high energy intake, and large body mass are associated with increased risk of developing colon cancer. However, energy balance as a whole seems to be associated with risk of colon cancer. These findings suggest systemic metabolic influences on carcinogenesis and have important implications for prevention.

Genetic traits related to hypertension and electrolyte metabolism.

The genetic and cultural heritability and intercorrelation of traits related to hypertension have been carried out in 98 Utah pedigrees (2,500 person) and 58 sibships with two or more hypertensive persons (131 hypertensive persons). Although none of these traits has been established as a marker for "sodium-sensitive hypertension," many of them are related at least indirectly to both electrolyte metabolism and risk of hypertension. Significant recessive monogenic effects and high total heritability (52-84%) were found for urinary kallikrein, high fat pattern index, intraerythrocytic sodium, Na-Li countertransport, and ouabain binding sites. Familial correlations more strongly attributable to shared environment than to genetic effects were found for Na,K-ATPase pump activity, intraerythrocytic magnesium, plasma digoxin-like factor, plasma renin activity, and plasma sodium concentration. All anthropometric variables tested showed highly significant genetic heritability with low and insignificant shared family environmental effects. Several of the genetically determined cellular cation tests also correlated with other genetic traits including plasma lipids, anthropometric measurements, and other cellular cation tests. Among hypertensive individuals with familial dyslipidemic hypertension, plasma insulin levels correlated with obesity and lipid abnormalities and with several cellular cation flux tests associated with hypertension.

A gene for high urinary kallikrein may protect against hypertension in Utah kindreds.

The inheritance of 12-hour overnight total urinary kallikrein excretion and its association with family history of essential hypertension were studied in 405 normotensive adults and 391 youths in 57 Utah pedigrees. Total urinary kallikrein excretion was highly familial with 51% of the total variance attributable to a dominant allele for high total urinary kallikrein excretion and 27% attributable to the combined effects of polygenes and shared family environment. An estimated 28% of the population has one or two copies of the dominant allele for high total urinary kallikrein excretion (2.3 SD units higher than the low homozygotes). About 83% of the population could be assigned to one of the two genotypic populations. Individuals with the high total urinary kallikrein excretion genotype were significantly less likely to have one or two hypertensive parents (relative odds = 0.56, p = 0.042). We conclude that a dominant allele expressed as high total urinary kallikrein excretion may be associated with decreased risk of essential hypertension. Further studies should be performed to confirm this finding and to test for interactions between this apparently protective gene and other genetic and environmental determinants of essential hypertension.

Are there interactions and relations between genetic and environmental factors predisposing to high blood pressure?

An overview of published observations suggests that both genetic predisposition and environment work together to produce hypertension in most persons. High blood pressure before age 55 occurs 3.8 times more often among persons with a strong positive family history of high blood pressure. Much of the total variability in blood pressure in modern populations seems attributable to genetic factors. Estimates of the proportion of the variance attributable to all genetic factors (heritability [H2]) vary from 25% in pedigree studies to 65% in twin studies for sitting diastolic blood pressure. Several biochemical traits associated with high blood pressure are highly genetic (H2, 78-84%) and may help elucidate the pathophysiology of high blood pressure. While pertinent environmental factors such as salt intake, alcohol use, and amount of exercise also correlate significantly among relatives, only 7% of the total variance of diastolic blood pressure seems attributable to all shared environmental factors in family households. Thus most familial aggregation of high blood pressure appears to be due to genes rather than shared family environment. Practical benefit may result from identifying familial predisposition in multiple siblings with high blood pressure before age 55 and lipid abnormalities (labeled "familial dyslipidemic hypertension"). About 12% of high blood pressure patients have familial dyslipidemic hypertension and also have high risk of early coronary heart disease. Hyperinsulinemia and central obesity as well as high triglycerides and low high density lipoprotein cholesterol are prominent features of familial dyslipidemic hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary sugar and colon cancer.

It has been hypothesized that levels of triglycerides, glucose, and insulin are associated with risk of colon cancer and that diets high in simple sugars increase risk of colon cancer because of their impact on these factors. Limited epidemiological evidence supports the association between simple carbohydrates and risk of colon cancer. Using data from a population-based case-control study (n = 1993 cases and 2410 controls), we examined the associations between dietary sugars, foods containing high level of sugars, and dietary glycemic index (GI) and colon cancer. A dietary GI was developed to estimate metabolic response to a diet that may increase plasma glucose levels. Dietary data were obtained using a validated diet history questionnaire. High levels of sucrose intake were associated with increased risk of colon cancer among younger men [odds ratio (OR) for highest quintile relative to lowest, 1.59; 95% confidence interval (CI), 1.07-2.37]. There was also a trend of increasing colon cancer risk associated with a higher sucrose:dietary ratio for proximal tumors in both men and women. Individuals with proximal tumors who consumed a diet ranked as having a high GI were at increased risk (for men, comparing highest quintile to lowest quintile: OR, 1.58; 95% CI, 1.06-2.36; P trend 0.04; for women: OR, 1.72; 95% CI, 1.11-2.67; P trend 0.04). Those at greatest risk from a high dietary GI were those who were sedentary (for men, relative to those who were most active and had a low-GI diet: OR, 3.46; 95% CI, 1.78-6.70; for women: OR, 2.00; 95% CI, 0.98-4.07). We also observed that people who had a high sucrose: dietary fiber ration and who also were sedentary and had a large body mass index were at increased risk (OR, 4.58; 95% CI, 2.33-8.98) relative to those who had a low sucrose:dietary fiber ratio, were active, and had low body mass indices. These findings support previous reports that dietary sugars, especially diet high in simple carbohydrates relative to complex carbohydrates, increase risk of colon cancer, possibly through their impact on plasma glucose levels.

Statistical methods in epidemiology: a comparison of statistical methods to analyze dose-response and trend analysis in epidemiologic studies.

Evaluation of various statistical methods to describe accurately associations between exposures and disease are constantly being explored. Spline regression has been suggested as an alternative to using categorized variables in studies of disease etiology, as it uses all data points to estimate the shape of the association between a given exposure and disease outcome. It has been proposed that this method is especially beneficial when associations are concentrated in a small range of the overall distribution of the exposure. In this study, we use data from a large case-control study of colon cancer to evaluate associations obtained from logistic regression models that use spline regression for main exposure and confounder effects with those that use categorized variables for main exposure. Our results show that for variables for which the association appears to be linear, such as body size and dietary intake of calcium, fiber, and cholesterol, associations are similar when estimates are generated from spline or categorized variable models. For other variables, such as total energy intake, for which associations appear to be strongest in the upper end of the distribution, estimates of association appear to be conservative when using categorized variables. The data also suggest that selection of cut points for the categorized variables may have an impact on the associations observed. Spline regression appears to be useful to estimate the shape of the association between a given exposure and disease and may provide guidance as to the appropriateness of using categorized variables. The risk estimates from spline regression appear to be similar to those from traditional categorical methods. When effects are large or rapidly changing, spline models may more appropriately describe the association.

Genetic basis of familial dyslipidemia and hypertension: 15-year results from Utah.

The genetic and environmental determinants of hypertension, lipid abnormalities, and coronary artery disease (CAD) have been studied for 15 years in Utah in population-based multigenerational pedigrees (2500 subjects among 98 pedigrees), twin pairs (74 monozygous and 78 dizygous), hypertensive siblings (131 sibships), siblings with CAD before age 55 (45 sibships), and anecdotally ascertained pedigrees with type II diabetes (271 subjects among 16 pedigrees), lipoprotein lipase deficiency (106 subjects in a single pedigree), and familial hypercholesterolemia (502 heterozygotes among 50 pedigrees). Estimates of heritability ranged from 20 to 75% for blood pressures and blood lipids. A strong positive family history predicts a future occurrence of hypertension (relative risk [RR] = 3.8) and CAD (RR = 12.7). Segregating single-gene effects were found for several 'intermediate phenotypes' associated with hypertension (erythrocyte sodium-lithium countertransport, intraerythrocytic sodium, a relative fat pattern, total urinary kallikrein excretion, and fasting insulin levels). Strong single-gene effects in segregation analysis were also found for low-density lipoprotein (LDL) cholesterol, lipoprotein (a) (Lp[a]), low high-density lipoprotein (HDL) cholesterol, and high apolipoprotein (apo) B. Deoxyribonucleic acid (DNA) markers of lipid abnormalities or hypertension have included LDL-receptor defects, lipoprotein lipase deficiency, high Lp(a), familial defective apo B, decreased quantitative levels of apo B, apo E phenotype, angiotensinogen, and 'glucocorticoid remediable aldosteronism (GRA) hypertension.' Also tested in Utah studies, but not found to be DNA markers for hypertension, were the genetic loci for the structural genes for renin and angiotensin-converting enzyme, and the sodium antiport system. In addition, important gene-gene interactions (LDL receptor with apo E2) and gene-environment interactions (kallikrein with potassium intake) were found.(ABSTRACT TRUNCATED AT 250 WORDS)

A computerized diet history questionnaire for epidemiologic studies.

OBJECTIVE: To describe methods used to computerize the diet history questionnaire developed for the Coronary Artery Risk Factor Development in Young Adult (CARDIA) study and to describe quality-control procedures used in conjunction with dietary assessment. DESIGN: The computerized diet history is being used in a case-control study. Because of the computerized nature of the questionnaire, we developed quality-control procedures that incorporate listening to an audiotape of the interview while visually reviewing recorded data. SETTING: Three centers involved in a population-based epidemiologic study of colon cancer. SUBJECTS: Men and women between the ages of 30 and 79 years. RESULTS: Quality-control results showed that 100% of the computerized forms would be free of errors if the data were subjected to visual review only. Probing errors, which accounted for 47.3% of all errors, were the most commonly encountered errors. In probing errors the interviewer did not probe in a nondirective manner, or the interviewer failed to verify responses that might be considered questionable. APPLICATIONS: The CARDIA diet history was computerized for use in epidemiologic studies of the association between diet and disease. Review of the audiotapes of the interviews showed that most errors made in obtaining a dietary assessment were not detectable from visual review of the data. Although the quality-control procedures were developed for a computerized diet history questionnaire, they are applicable to other dietary assessment methods.

A nationwide survey of self-reported red light running: measuring prevalence, predictors, and perceived consequences.

A United States probability sample of 880 licensed drivers participated in a telephone survey of red light running perceptions and behaviors. Despite most drivers believing red light running was problematic and dangerous, approximately one in five respondents reported running one or more red lights when entering the last ten signalized intersections. Among several demographic and attitude variables, only age group predicted recent red light running. Specifically, younger respondents were more likely to be violators. Drivers also reported being more likely to run red lights when alone, and were typically in a hurry when speeding up to be beat red lights. Contrary to expectations, frustration was not as important for predicting red light running as it was for other driving behaviors, such as speeding, tailgating, weaving, and gesturing angrily at others. Additionally, drivers perceived and received few consequences for running red lights. Less than 6% had received a traffic ticket for red light running and most believed that police would catch less than 20% of violators. Slightly more than one in ten had been involved in a red light running crash. Respondents most commonly suggested legal initiatives to reduce red light running. Accordingly, we recommend traffic safety experts pursue interventions that apply immediate and consistent negative consequences to violators to change the public's red light running perceptions and behavior.

A single-subject approach to evaluating vehicle safety belt reminders: Back to basics.

A single-subject ABA reversal design was applied to evaluate the effectiveness of a limited 8-s safety belt reminder system and two modified reminder systems (a delayed and second reminder) to increase the safety belt use of 13 drivers. The research was conducted with a specially equipped research vehicle that permitted the manipulation of different safety belt reminder stimuli and the unobtrusive recording of a driver's belt use. For 2 subjects, the limited 8-s reminder increased safety belt use. For another 2 subjects, the second reminder markedly increased belt use. Some subjects were uninfluenced by the reminder systems presented; others always buckled up during both baseline and intervention conditions. The approach and results are discussed with regard to the application of behavior analysis methodologies (e.g., cumulative records) and principles (e.g., schedules of reinforcement) to advance the utility and investigation of safety belt reminder systems.

Multigenic human hypertension: evidence for subtypes and hope for haplotypes.

Hypertension that occurs before the age of 60 years is strongly aggregated in families, mostly due to genetic factors with weaker contributions from a shared family environment. Hypertension is probably a heterogeneous collection of overlapping subsets of pathophysiological mechanisms, such as dyslipidemia, obesity, hyperinsulinemia and cation metabolism. Highly heritable traits such as sodium-lithium countertransport, urinary kallikrein excretion and a body fat pattern index show evidence of major gene segregation in families with hypertension. They are thought to be intermediate phenotypes in the chain of pathophysiological events leading from specific genes to the distant phenotype of hypertension. They provide evidence of measurable contributions from single gene traits to the susceptibility to hypertension. Genetic linkage studies have suggested that other specific loci (e.g. histocompatibility leukocyte antigen, blood group MN and the haptoglobin protein) contribute to the susceptibility to hypertension. DNA sequencing has shown a point mutation for lipoprotein lipase that conveys susceptibility to lipid abnormalities, and possibly also hypertension, as seen in families with dyslipidemic hypertension. Further application of these approaches, especially in families that include multiple siblings with hypertension, shows promise of a true understanding of how the combined effects of a few specific genes, the polygenic background and selected environmental factors can lead to essential hypertension. This understanding should foster better tailored and more effective approaches to the prevention, diagnosis and treatment of hypertension.

Current knowledge regarding the genetics of human hypertension.

Observations over 11 years from the University of Utah Cardiovascular Genetics Research Clinic and published data from other studies are reviewed to illustrate research approaches, developing results and prospects for future studies. Strong associations with hypertension have been found for several biochemical tests that show substantial genetic determination. Suggestions of recessive major gene effects and significant polygenic background determinations have been found for several variables, including urinary kallikrein excretion, intracellular sodium concentration, sodium-lithium countertransport and sodium-potassium cotransport. Each of these variables is related in some way to sodium or potassium metabolism, or both, and may help to improve the understanding of a possibly inherited susceptibility to hypertension that is related to dietary electrolyte intake. A second major group of factors involving familial predisposition to hypertension include lipid abnormalities (increased very-low- and low-density lipoprotein cholesterol and decreased high-density lipoprotein cholesterol); increased fasting insulin levels or insulin resistance, or both; obesity (especially central or upper body obesity); and multiple environmental factors influencing these metabolic systems, including dietary fat, carbohydrate and calorie intake; physical exercise; and certain antihypertensive medications that adversely affect lipid metabolism and glucose tolerance. Some studies even suggest a possible link between these two large groups of factors (electrolyte metabolism and lipid-insulin metabolism). Hypertriglyceridaemia and hyperinsulinaemia are both significantly correlated with increased levels of several cation-flux tests. It is recommended that studies of human hypertension apply these biochemical profiles to study sibships with two or more hypertensive siblings as a cost-effective initial approach.(ABSTRACT TRUNCATED AT 250 WORDS)

Identification of uterine leiomyoma genes developmentally reprogrammed by neonatal exposure to diethylstilbestrol.

Environmental exposures during development can alter susceptibility later in life to adult diseases including uterine leiomyoma, a phenomenon termed developmental reprogramming. The goal of this study was to identify genes developmentally reprogrammed by diethylstilbestrol (DES) and aberrantly expressed in leiomyomas. Transcriptional profiling identified 171 genes differentially expressed in leiomyomas relative to normal myometrium, of which 6/18 genes with putative estrogen responsive elements and confirmed to be estrogen-responsive in neonatal uteri were reprogrammed by neonatal DES exposure. Calbindin D9k and Dio2, normally induced by estrogen, exhibited elevated expression in DES-exposed animals during both phases of the estrus cycle. Gdf10, Car8, Gria2, and Mmp3, genes normally repressed by estrogen, exhibited elevated expression in DES-exposed animals during the proliferative phase, when estrogen is highest. These data demonstrate that neonatal DES exposure causes reprogramming of estrogen-responsive genes expressed in uterine leiomyomas, leading to over-expression of these genes in the myometrium of exposed animals prior to the onset of tumorigenesis.

Is survival among women diagnosed with breast cancer influenced by family history of breast cancer?

In this study, we examine the association between having a family history of breast cancer and survival after diagnosis with breast cancer. Data for this study were from the Utah Population Database, a linked database consisting of genealogy data of Mormon pioneer families, Utah Cancer Registry data, and Vital Statistics data. We observed that women who had a mother with breast cancer were more likely to die of any cause than women without a mother with breast cancer [hazard rate ratio (HRR) = 1.36, 95% confidence limits (CL) = 1.04, 1.79], as were women with over 30 female relatives with breast cancer (HRR = 1.69, 95% CL = 1.16, 2.45). Similar findings were observed for women dying of breast cancer. Other indicators of family history were not associated with survival except within specific age groups. Women diagnosed with breast cancer at age 50 or before had poorer survival if they had a family history of breast cancer. Relative risk estimates were 1.54 (95% CL = 0.98, 2.41) for first degree relative, 1.55 (95% CL = 0.87, 2.78) for mother, and 2.65 (95% CL = 1.23, 5.74) for more than 30 female relatives with breast cancer.

Diet diversity, diet composition, and risk of colon cancer (United States).

In this study, we evaluate diet diversity, diet composition, and risk of colon cancer in an incident population-based study of 1,993 cases and 2,410 controls in the Kaiser Permanente Medical Care Program of Northern California, eight counties in Utah, and the Twin Cities area of Minnesota (United States). Ninety-one and one-half percent of the population were non-Hispanic White. Dietary intake was obtained using an adaptation of the CARDIA diet-history questionnaire. Diet diversity was defined as the number of unique food items reported; diversity also was explored within six major food groups. Composition of the diet was described by estimating the proportion of total number of food items contributed by major food groups. Younger individuals, higher educated individuals, and those who lived in larger households reported eating the most diverse diet. Total diet diversity was not associated with colon cancer. However, eating a diet with greater diversity of meats, poultry, fish, and eggs, was associated with a 50 percent increase in risk among all men (95 percent confidence interval [CI] = 1.1-2.0; P trend = 0.01), with slightly stronger associations for younger men and men with distal tumors. A diet with a greater number of refined grain products also was associated with increased risk among men (odds ratio [OR] = 1.7, CI = 1.3-2.3). Women who ate a diet with a more diverse pattern of vegetables were at approximately a 20 percent lower risk than women who had the least diverse diet in vegetables. Assessment of diet composition showed that men who consumed a large proportion of their food items from meat, fish, poultry, and eggs were at an increased risk, with the most marked association being for distal tumors (OR = 1.7, CI = 1.2-2.5). Women who consumed the largest percentage of their food items in the form of plant foods (fruits, vegetables, or whole grains) were at a reduced risk of developing colon cancer (OR = 0.7, CI = 0.5-1.0).

Dietary fats and colon cancer: assessment of risk associated with specific fatty acids.

There are many biological mechanisms whereby dietary fat and specific dietary fatty acids may alter risk of colon cancer in addition to their contribution to total energy intake. To evaluate these potential associations, we used detailed dietary intake data collected in a population-based study of 1,993 incident colon cancer cases and 2,410 controls conducted in 3 areas of the United States. The most commonly consumed fatty acid in the study population was oleic acid. One-third of dietary fats consumed came from additions to other foods at the table or from the preparation of other foods. After adjusting for total energy intake, physical activity and body size, neither total dietary fat nor specific fatty acids was associated with risk of colon cancer. However, among older women, fats from food preparation were associated with increased risk of colon cancer (OR 1.84, 95% CI 1.20-2.80), while fats from foods themselves or from additions to other foods were not. While dietary fats were not associated with colon cancer risk in the total population, subgroups of the population appeared to be at slightly greater risk if they consumed a high-fat diet. Women who consumed a diet high in mono-unsaturated fatty acids (MFAs) and poly-unsaturated fatty acids (PFAs) and who had a family history of colorectal cancer were at greater risk of colon cancer than those with similar intakes but without a family history of colorectal cancer. Similar associations with family history were noted among men diagnosed at younger ages for MFA, linolenic acid and 20-carbon PFA.

Objective system for interviewer performance evaluation for use in epidemiologic studies.

In this paper, the authors present an objective system to evaluate interviewer performance for use in epidemiologic studies. With this quality control system, all study interviews are audio-taped, and a random sample of interviews are coded according to interviewer behaviors, such as whether the interviewer asked the questions exactly as written and used the probes appropriately. With the use of data obtained from a large case-control study of colon cancer, the authors observed that 94.2% of all questions were asked in the same manner by all interviewers and that 89.5% of all probing behaviors were appropriate. They show that questions that required additional interviewer behaviors were more likely to result in variation in response that can be attributed to the interviewer. These findings have implications for study design and interpretation of study results. From simulations, the authors have estimated the impact of uncorrected interviewer variability on study power and ability to detect disease associations. Uncorrected interviewer variability could decrease study power from 84% to 56%. From simulations, the authors observed that odds ratios could be biased downward from 1.8 to 1.3. These findings illustrate the importance of using a continuous quality control program in epidemiologic research.

Detection of genetic heterogeneity among pedigrees through complex segregation analysis: an application to hypercholesterolemia.

Several methods for investigating genetic heterogeneity for extreme levels of a quantitative trait with hypothesized multiple genetic etiologies require a priori stratification of families and/or identification of distinct phenotypes among affected individuals. We present a statistical approach for detecting genetic heterogeneity that does not rely on either a priori stratification or discrete disease phenotypes. Complex segregation analysis was applied to total serum cholesterol measurements in 709 relatives of 98 healthy index cases selected from 3,666 school children surveyed for lipid levels in Rochester, Minnesota. Thirty-three of the index cases and 109 relatives had hypercholesterolemia (cholesterol levels greater than the 95th percentile for their age and sex). Through application of the mixed genetic model and then estimation of conditional probabilities for having the mutant allele at the major locus, genetic heterogeneity for hypercholesterolemia was indicated. In three of 70 pedigrees with one or more hypercholesterolemics, there is strong evidence for segregation at a major locus. In the remaining pedigrees, only polygene variation and/or environmental variation are associated with cholesterol variability. Grandparents in the three pedigrees that were segregating at the major locus had the highest rates of death due to coronary heart disease. This study establishes that the mixed model has the potential to identify pedigrees with different genetic etiologies for variability in quantitative traits.