Overview of the Type I Diabetes Genetics Consortium.

The Type I Diabetes Genetics Consortium (T1DGC) is an international, multicenter research program with two primary goals. The first goal is to identify genomic regions and candidate genes whose variants modify an individual's risk of type I diabetes (T1D) and help explain the clustering of the disease in families. The second goal is to make research data available to the research community and to establish resources that can be used by, and that are fully accessible to, the research community. To facilitate the access to these resources, the T1DGC has developed a Consortium Agreement (http://www.t1dgc.org) that specifies the rights and responsibilities of investigators who participate in Consortium activities. The T1DGC has assembled a resource of affected sib-pair families, parent-child trios, and case-control collections with banks of DNA, serum, plasma, and EBV-transformed cell lines. In addition, both candidate gene and genome-wide (linkage and association) studies have been performed and displayed in T1DBase (http://www.t1dbase.org) for all researchers to use in their own investigations. In this supplement, a subset of the T1DGC collection has been used to investigate earlier published candidate genes for T1D, to confirm the results from a genome-wide association scan for T1D, and to determine associations with candidate genes for other autoimmune diseases or with type II diabetes that may be involved with beta-cell function.

Current status and the future for the genetics of type I diabetes.

The Type I Diabetes Genetics Consortium (T1DGC) is an international collaboration whose primary goal is to identify genes whose variants modify an individual's risk of type I diabetes (T1D). An integral part of the T1DGC's mission is the establishment of clinical and data resources that can be used by, and that are fully accessible to, the T1D research community (http://www.t1dgc.org). The T1DGC has organized the collection and analyses of study samples and conducted several major research projects focused on T1D gene discovery: a genome-wide linkage scan, an intensive evaluation of the human major histocompatibility complex, a detailed examination of published candidate genes, and a genome-wide association scan. These studies have provided important information to the scientific community regarding the function of specific genes or chromosomal regions on T1D risk. The results are continually being updated and displayed (http://www.t1dbase.org). The T1DGC welcomes all investigators interested in using these data for scientific endeavors on T1D. The T1DGC resources provide a framework for future research projects, including examination of structural variation, re-sequencing of candidate regions in a search for T1D-associated genes and causal variants, correlation of T1D risk genotypes with biomarkers obtained from T1DGC serum and plasma samples, and in-depth bioinformatics analyses.

Overview of the Rapid Response data.

The Type I Diabetes Genetics Consortium (T1DGC) Rapid Response Workshop was established to evaluate published candidate gene associations in a large collection of affected sib-pair (ASP) families. We report on our quality control (QC) and preliminary family-based association analyses. A random sample of blind duplicates was analyzed for QC. Quality checks, including examination of plate-panel yield, marker yield, Hardy-Weinberg equilibrium, mismatch error rate, Mendelian error rate, and allele distribution across plates, were performed. Genotypes from 2324 families within nine cohorts were obtained from a panel of 21 candidate genes, including 384 single-nucleotide polymorphisms on two genotyping platforms performed at the Broad Institute Center for Genotyping and Analysis (Cambridge, MA, USA). The T1DGC Rapid Response project, following rigorous QC procedures, resulted in a 2297 family, 9688 genotyped individual database on a single-candidate gene panel. The available data include 9005 individuals with genotype data from both platforms and 683 individuals genotyped (276 in Illumina; 407 in Sequenom) on only one platform.

Overview of the MHC fine mapping data.

AIM: The aim of this study was to perform quality control (QC) and initial family-based association analyses on the major histocompatibility complex (MHC) single nucleotide polymorphism (SNP) and microsatellite marker data for the MHC Fine Mapping Workshop through the Type 1 Diabetes Genetics Consortium (T1DGC). METHODS: A random sample of blind duplicates was sent for analysis of QC. DNA samples collected from participants were shipped to the genotyping laboratory from several T1DGC DNA Repository sites. Quality checks including examination of plate-panel yield, marker yield, Hardy-Weinberg equilibrium, mismatch error rate, Mendelian error rate and allele distribution across plates were performed. RESULTS: Genotypes from 2325 families within nine cohorts were obtained and subjected to QC procedures. The MHC project consisted of three marker panels - two 1536 SNP sets (Illumina Golden Gate platform performed at the Wellcome Trust Sanger Institute, Cambridge, UK) and one 66 microsatellite marker panel (performed at deCODE). In the raw SNP data, the overall concordance rate was 99.1% (+/-0.02). CONCLUSIONS: The T1DGC MHC Fine Mapping project resulted in a 2300 family, 9992 genotyped individuals database comprising of two 1536 SNP panels and a 66 microsatellite panel to densely cover the 4 Mb MHC core region for use in statistical genetic analyses.

Associations of body fat and its distribution with dietary intake, physical activity, alcohol, and smoking in blacks and whites.

Cross-sectional associations between body fat and its distribution and environmental factors influencing energy balance were examined in 5115 young adults. Protein was directly associated with body mass index (BMI) in all race and sex groups (P less than 0.01) after age, education, cigarette-smoking status, alcohol intake, and physical activity were adjusted for. Carbohydrate intake was inversely associated with BMI in males (P = 0.02). Total physical activity was inversely associated with BMI in white women and with skinfold-thickness measures (P less than 0.01) in all groups. Waist-to-hip-circumference ratio (WHCR) was positively associated with total kilojoules (kilocalories) in women, inversely associated with percent of kilojoules (kilocalories) from carbohydrates in whites, grams of crude fiber/4184 kJ (1000 kcal) (except in black men), and physical activity (except in white women). WHCR was directly associated with cigarette smoking except in black men, and with total alcohol intake in men. Beer was consistently associated with WHCR in all race and sex groups.

Meat consumption and its associations with other diet and health factors in young adults: the CARDIA study.

Using cross-sectional data from the longitudinal Coronary Artery Risk Development in Young Adults (CARDIA) study, we assessed associations between meat consumption and other dietary- and health-status indicators. Less than one percent of this sample (n = 32) ate no red meat or poultry, and another 1% (n = 47) ate red meat or poultry less than once per week. Individuals who ate red meat and poultry less than once per week were less likely to drink alcohol (P = 0.003); reported more physical activity (P less than or equal to 0.001); had lower [corrected] Keys scores (P less than or equal to 0.001); consumed diets higher in carbohydrates, starch, fiber, vitamins A and C, and calcium and lower in energy, fat, and protein (P less than or equal to 0.001); had smaller body sizes as indicated by the body mass index [calculated as wt(kg)/ht(m2)] (P = 0.01); and had lower concentrations of total serum cholesterol (P = 0.001), low-density-lipoprotein cholesterol (P = 0.001), and triglycerides (P = 0.015) compared with individuals who consumed meat more frequently.

Seven-year trends in plasma low-density-lipoprotein-cholesterol in young adults: the CARDIA Study.

To identify determinants of recent secular trends in lipids and characterize their influence on age-related increases in LDL-cholesterol, we examined a cohort of black and white men and women aged 18-30 in 1985-1986. Secular trends were determined by comparing participants aged 25-30 at baseline with those aged 25-30 at year 7 (2788 and 1395 participants, respectively). LDL-cholesterol was lower among those 25-30 at year 7 (5.9 to 10.2 mg/dL, depending on race-sex group; P < 0.001); weight was higher (8.3 to 12.5 lb; P < 0.001); Keys score was lower (-4.2 to -7.3 units; P < 0.001); and use of oral contraceptives was greater (white women only, P < 0.01). Among 4086 participants followed for 7 years, LDL-cholesterol changed little or decreased, despite substantial weight increases in all groups (11.6 to 19.0 lb; P < 0.001). Keys scores decreased by 6.1 to 8.0 units, and use of oral contraceptives decreased (P < 0.001). Declining secular trends in LDL-cholesterol occurred despite upward trends in weight; the decline was associated with lower dietary fat and cholesterol and offset expected age-related increases in LDL-cholesterol.

Relationship between changes in dietary sucrose and high density lipoprotein cholesterol: the CARDIA study. Coronary Artery Risk Development in Young Adults.

PURPOSE: Cross-sectional data from several observational studies have suggested that dietary sucrose may be inversely associated with high density lipoprotein cholesterol (HDL-C). This study examined associations between energy from dietary sucrose and HDL-C at baseline, year 7 and longitudinally (year 7 minus baseline) in a cohort of young black and white men and women from the Coronary Artery Risk Development in Young Adults (CARDIA) study. METHODS: The sample included 4734 black men, black women, white men and white women, ages 18-30 years, in 1985-86 (baseline); 3513 at year 7; and 3335 for longitudinal analyses. Multivariate analyses was used with adjustment for age, BMI, cigarettes smoked per day, physical activity score, and alcohol intake. RESULTS: Multivariate analyses indicated that energy intake from sucrose was inversely associated with HDL-C for each race-gender group at baseline, year 7, and longitudinally from baseline to year 7. This association was significant at baseline for black men, and white men and women (p < 0.01); at year 7 for white men and black women (p < 0.01), and longitudinally for white men, white women, and black women (p < 0.05). CONCLUSIONS: The consistent inverse associations between energy from dietary sucrose and HDL-C observed in both cross-sectional and longitudinal analyses, and in different race and gender groups in CARDIA suggest that lowering dietary sucrose intake may be beneficial for those who may have low HDL-C.

Validity of self-reported fat distribution in young adults: the CARDIA Study. Coronary Artery Risk Development in Young Adults.

To determine the validity of self-reported information on body fat distribution, relationships between reported location of weight gain and measured waist-to-hip ratio (WHR), high density lipoprotein cholesterol (HDL-C), and fasting insulin were analyzed in 5115 black and white men and women aged 18-30 years. In black men, WHR adjusted for age and body mass index (BMI) ranged from 0.833 among those reporting upper and central weight gain to 0.812 among those reporting lower body weight gain (trend across five reported fat distribution categories, P = 0.0004). Corresponding values were, for white men, 0.852 to 0.831; for black women, 0.777 to 0.721; and for white women, 0.772 to 0.701 (each P < 0.0001). Reported fat distribution was associated with HDL-C in women, but not in men, and with fasting insulin in all groups. While these associations were somewhat weaker than with measured WHR, self-reported fat distribution does provide valid information about body fat distribution in young adults, particularly women.

Correlates of fasting insulin levels in young adults: the CARDIA study.

Elevated fasting insulin is an independent risk factor for hyperlipidemia, hypertension, and cardiovascular disease, but determinants of insulin other than age and body mass remain poorly described. Potentially modifiable factors associated with insulin were identified by correlating anthropometric, dietary and physical activity data in the CARDIA cohort of 2643 black and 2472 white men and women aged 18-30 years. Insulin was positively correlated with serum glucose, body mass index (BMI), skinfold thickness, waist/hip ratio and sucrose intake, and negatively correlated with heavy physical activity score, treadmill exercise duration, and magnesium intake (each p less than 0.01). After adjustment for other covariates, the positive association of insulin with waist/hip ratio, skinfold thickness, and sucrose intake remained in the group as a whole, as did the negative associations with magnesium and treadmill duration. These relationships provide insight into potentially modifiable factors affecting insulin levels, and should be considered in interpreting associations between insulin levels and cardiovascular disease.

A comparison of two methods to ascertain dietary intake: the CARDIA Study.

Data on dietary intake were collected in the Coronary Artery Risk Development in Young Adults (CARDIA) Study at the baseline examination in 1985-86 and again at the second examination 2 years later. At baseline, a diet history questionnaire developed for the CARDIA study was used; at the second exam the NCI (Block) food frequency questionnaire was used. The purpose of the present report is to compare the estimated nutrient intakes obtained with the two instruments; to compare correlations of nutrient intakes obtained at the two exams with those observed for other lifestyle and physiological variables also measured 2 years apart; and to assess ability to test hypotheses relating 2-year changes in risk factors to between-exam differences in reported nutrient intakes. Mean levels of reported intake were generally greater for both blacks and whites on the CARDIA diet history than on the Block food frequency. Rank order correlations of reported nutrient intakes between the two questionnaires indicated greater consistency between instruments for whites (r's ranging between 0.35 and 0.52) than for blacks (r's ranging between 0.29 and 0.45). Correlations over time for nutrients were smaller than those observed for body size measures and lipid levels but were similar in magnitude to those for blood pressure, physical activity, and life events. At both exams, total caloric intake was positively associated with physical activity (range of r's for CARDIA were 0.07 for white women to 0.23 for black men, the range of r's for Block were 0.06 for women to 0.11 for white men). Using data from the two examinations, 2-year changes in total plasma cholesterol were significantly related to 2 year changes in Keys scores. The results of this comparison are useful in that they show similarities and differences between two instruments developed to gather dietary intake data. The study also illustrates the need to monitor young adults during a time when rapid changes occur in many lifestyle and physiologic factors.

Seven-year tracking of dietary factors in young adults: the CARDIA study.

OBJECTIVES: This report determines the extent to which young adults in the highest and lowest intake quintiles of 13 nutrients remain in the same or adjacent quintiles (i.e., "tracked") relative to each other, over 7 years. METHODS: Data from baseline and year 7 of the CARDIA study were divided into race/gender-specific quintiles for each nutrient and cross-tabulated. RESULTS: For most nutrients, over 60% of those in the lowest absolute intake quintile at year 0 remained in the lowest or second-lowest quintile at year 7. A similar pattern was seen with highest absolute intake quintiles at years 0 and 7. Tracking was attenuated when nutrient density, rather than absolute intake, was examined. CONCLUSIONS: Ingrained dietary habits may cause high- or low-intake groups to retain relative ranking, even in the face of secular, age-, or lifestyle-related trends in dietary intake.

A study of the reliability and comparative validity of the cardia dietary history.

This study evaluated the reliability and comparative validity of the dietary history survey method developed for CARDIA, a longitudinal investigation of life-styles and the evolution of cardiovascular risk factors in young adults. The method was tested in a sample of 30 white men, 33 white women, 33 black men, and 32 black women, aged 18 to 35 years, in four regions reflecting the race, sex, age, and geographical distribution of CARDIA participants. For 64 of the participants, two dietary history interviews, 1 month apart, were conducted by trained nutritionists. These data were used to examine the reliability of the method. For all participants, seven telephone- assessed 24-hour dietary recalls were randomly scheduled during a 28-day period and were followed by a dietary history interview. These data were used to examine the comparative validity of the method. Calories, total fat, saturated fat, polyunsaturated fat, monounsaturated fat, dietary cholesterol, protein, carbohydrate, alcohol, potassium, calcium, and vitamin A were selected by the CARDIA Nutrition Working Group as the nutrients for comparison. Mean nutrient values from the first history tended to be higher than those obtained from the last history. However, for a majority of the nutrients, the differences were significant for blacks but not for whites. The correlations for the log-transformed nutrient values and calorie-adjusted nutrient values from the two histories were generally in the range of 0.50 to 0.80 for whites. For blacks, the correlations were lower, with a majority in the range of 0.30 to 0.70. The average nutrient values estimated from the histories were higher than those estimated from the average of the seven 24-hour recalls. The differences in blacks were larger than in whites. For both the log-transformed nutrient values and the calorie-adjusted nutrient values, the correlations between the two methods were generally larger than 0.50 for whites. However, for blacks, the correlations were lower, and for several macronutrients, the correlations were close to zero. These results suggest that the CARDIA dietary history is a reasonably reliable and valid dietary survey method for obtaining information about habitual intakes in whites. In blacks, the results are less consistent. The black-white differences remained when the analyses were stratified by education. These results raise a question about differences in reporting between blacks and whites.

Body image among men and women in a biracial cohort: the CARDIA Study.

OBJECTIVE: To examine body image in a population-based, biracial cohort. METHOD: Body image measures were obtained on 1,837 men (45% Black) and 1,895 women (51% Black) in the CARDIA study. Subscales of the Multidimensional Body Self-Relations Questionnaire (Appearance Evaluation and Appearance Orientation) and a measure of body size dissatisfaction were obtained. RESULTS: Blacks were more invested in appearance than Whites and women were more invested than men. Women were more dissatisfied with size and overall appearance than men, and White men were more dissatisfied with appearance than Black men. Black and White women were similarly dissatisfied with size and appearance. However, after adjustment for age, body mass index, and education, Black women were more satisfied with both dimensions than White women. Obesity was strongly associated with body dissatisfaction across all gender-ethnicity groups. DISCUSSION: Significant differences in body image were apparent by gender and ethnicity, and different patterns were evident depending on the dimension considered.

Dietary antioxidants and plasma lipids: the CARDIA Study.

OBJECTIVE: To determine if dietary antioxidants play a role in preventing coronary heart disease (CHD) by having an impact on lipid levels. METHODS: Data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study were used to assess the associations of reported intake of vitamins A, C, E and beta carotene, and their use in supplements, with lipid levels in a black and white, healthy adult (18 to 30 years of age at the baseline examination) population. RESULTS: After adjusting for age, education level, physical activity, body size, alcohol consumption and caloric intake, vitamin A, beta carotene, and vitamin C (white women) intake were directly associated with HDL-cholesterol levels among women who smoked cigarettes, with the strongest associations being observed for white women. Black men who took supplements of vitamins A and C and did not smoke cigarettes had significantly higher HDL-cholesterol levels compared to those in the lowest levels of dietary intake. Although vitamin E was associated with higher levels of HDL-cholesterol, the association was only of borderline significance among white men who smoked cigarettes (p = 0.06). We did not observe any consistent associations between antioxidants and other plasma lipids, including total cholesterol, LDL-cholesterol, or triglycerides. CONCLUSIONS: We conclude that dietary antioxidants are associated with HDL-cholesterol levels in some subsets of the population, although these associations may be operating in conjunction with other lifestyle behaviors.

Regional disparities in the incidence of elevated blood pressure among young adults: the CARDIA study.

BACKGROUND: Within the United States, little is known about regional disparities in blood pressure (BP), their changes over time, or explanations for their existence. METHODS AND RESULTS: A population-based cohort of 5115 black and white men and women, 18 to 30 years old in 1985-1986 (balanced on age, race, sex, and education), was followed up for 7 years in four centers: Birmingham, Ala; Chicago, Ill; Minneapolis, Minn; and Oakland, Calif. Differences in elevated BP (EBP) prevalence among centers at years 0, 2, 5, and 7 and in 7-year incidence of EBP were assessed. Sociodemographic and dietary variables, physical activity, weight, smoking, and alcohol were considered. At year 0, no regional differences were seen. Seven years later, there was marked variability in prevalence of EBP overall and for both black and white men, from a low in Chicago (9% for black men and 5% for white men) to a high in Birmingham (25% for black men and 14% for white men). Birmingham also had the highest 7-year incidence (11%) and overall prevalence at year 7 (14%). The adjusted odds ratios, with Birmingham as referent (95% CIs), for 7-year incidence of EBP overall were 0.38 (0.24, 0.60) for Chicago, 0.37 (0.24, 0.57) for Minneapolis, and 0.74 (0.52, 1.07) for Oakland. CONCLUSIONS: Regional disparities are absent at baseline but become apparent as the cohort ages. These differences are not fully explained by the available behavioral and sociodemographic characteristics.

Serum leptin and weight gain over 8 years in African American and Caucasian young adults.

OBJECTIVE: There is considerable interest in how to prevent weight gain in adulthood. Leptin, a peptide hormone expressed in adipose tissue, is believed to signal the central nervous system about the level of body fat stores, and thereby may control appetite. Little information exists on whether the serum leptin concentration influences long-term weight changes in the free-living population. RESEARCH METHODS AND PROCEDURES: From an ongoing cohort study of young African American and white adults, we selected a sample of participants (n=492), stratified on sex, race, and weight changes over 8 years. Serum leptin was measured on stored specimens using a radioimmunoassay. Weight change was modeled in relation to baseline leptin concentrations. RESULTS: Cross-sectionally, leptin concentration was associated positively with body mass index, negatively with physical activity level, and was higher in women than men. These variables explained 72% of the variance in serum leptin. Over the 8 years, the sample gained an average of 7.8 kg (standard deviation = 10.8). There was no evidence that 8-year weight change was associated with initial leptin concentration: 8-year weight change was only 0.5 kg less (95% confidence interval =-1.8 to 0.8, p = 0.47) per each 10 ng/ mL increment (approximately one standard deviation) of baseline leptin. In contrast, leptin change correlated highly (r=0.62) with weight change. DISCUSSION: Our data corroborate evidence that adiposity determines leptin levels but do not support the hypothesis that leptin deficiency plays an important role in obesity in the general population.

Differences in weight gain in relation to race, gender, age and education in young adults: the CARDIA Study. Coronary Artery Risk Development in Young Adults.

OBJECTIVE: To assess ethnic differences in weight gain in young adults. DESIGN: Five-year weight change was assessed in 4207 young adults initially aged 18-30 years at the CARDIA Study baseline examination (1985-1986). RESULTS: Weight gain was significantly (p < 0.0001) greater in black versus white men (13.2 versus 9.1 lb) and in black versus white women (13.2 versus 7.4 lb). Baseline weight and year-five weight in all race and gender groups were strongly associated, suggesting a high degree of tracking of adiposity during young adulthood. Greater weight gain was noted in participants reporting baseline education of high school or less versus college graduates in black women (14.4 versus 10.0 lb, p < 0.05), white women (10.2 versus 5.2 lb, p < 0.0001) and white men (10.2 versus 7.8 lb, p < 0.001). Significantly greater weight gain was observed in younger (18-24 years) versus older (25-30 years) men, but no age-related difference was seen in women. The racial differences in weight gain remained after adjustment for age and level of education. The above trends were confirmed for other measures of body size, i.e. body mass index and skinfold thickness. CONCLUSION: These data indicate that young adults are at high risk of weight gain, and that weight gain was greatest among African Americans and among less educated participants. These high-risk groups can be identified and targeted for primary prevention of adult obesity in addition to population wide efforts that will be required to counteract the secular trend of increased obesity observed in US adults.

Changes in measurements of body fat distribution accompanying weight change.

The waist-to-hip circumference ratio (WHR), as an indicator of body fat distribution is related to several clinical diseases. Whether one can reduce this ratio with weight loss is still unconfirmed and may differ between sexes. The degree to which WHR changes with weight gain is also unclear. Changes in waist and hip circumferences and WHR accompanying changes in weight over 5 years were examined in 3,753 black and white men and women initially ages 18-30. Those who gained weight increased their WHR and in most cases those whose weight remained stable increased their WHR. Those who gained the most weight had the greatest increases in WHR. Men had greater increases in WHR per kg weight gain than women. In general, weight loss was accompanied by a decrease in the WHR. However, in those whose initial WHR was below the median, weight loss was associated with an increase in WHR. Smokers and black males also had increases in WHR with weight losses up to 4.9 kg.

Plasma fibrinogen: levels and correlates in young adults. The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Sufficient evidence exists that plasma fibrinogen is a risk factor for cardiovascular disease to prompt a search for fibrinogen determinants. The authors measured fibrinogen in 4,193 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) Study with three objectives: to describe fibrinogen levels in young adults, to determine if correlates of fibrinogen in older adults apply to younger adults, and to examine several additional hypothesized correlates. Fibrinogen (overall mean +/- standard deviation = 263 +/- 57 mg/dl) was greater in women than in men and in blacks than in whites; it was associated positively with cigarette smoking, body mass index, low density lipoprotein cholesterol, triglycerides, and blood pressure, and negatively with physical activity, high density lipoprotein cholesterol, and ethanol intake. Socioeconomic stress indicators and negative personality traits hypothesized as being associated with fibrinogen, possibly through adrenergic mechanisms, proved weak correlates. Parental history of diabetes was correlated positively with fibrinogen, in part because those with a positive parental history had greater body mass. Diabetes mellitus, lipoprotein(a), left ventricular mass, and oral contraceptive use were also positively correlated with fibrinogen concentration. Thus, even in young adults, fibrinogen is associated positively with most risk factors for atherosclerotic cardiovascular disease. This has implications for the role of fibrinogen as a risk factor and, potentially, for cardiovascular disease prevention.