Search

Common and rare variants of the hepatocyte nuclear factor 4alpha (HNF4A) gene have been associated with type 2 diabetes and related traits in several populations suggesting the involvement of this transcription factor in diabetes pathogenesis. Single nucleotide polymorphisms (SNPs) within a large haplotype block surrounding the alternate P2 promoter, located approximately 45 kb upstream from the coding region, have been investigated in several populations of varying ethnicity with inconsistent results. Additionally, SNPs located within the P1 promoter and coding region have also been inconsistently associated with type 2 diabetes. Characterization of variation across this gene region in Mexican-American populations has not been reported. We therefore examined polymorphisms across the HNF4A gene in a cohort of Mexican-American pedigrees and assessed their association with type 2 diabetes. We observed evidence for association of SNPs in the P2 promoter region with type 2 diabetes (P = 0.003) and its age at diagnosis (P = 0.003). The risk allele frequency (53%) was intermediate to that reported in Caucasian populations (20-27%) and Pima Indians (83%). No other SNPs were associated with either trait. These results support the possibility that a variant in the P2 promoter region of HNF4A, or variants in linkage disequilibrium within this region, contributes to susceptibility to type 2 diabetes in many ethnic populations including Mexican Americans. [ABSTRACT FROM AUTHOR]

The San Antonio Family Diabetes/Gallbladder Study was initiated to identify susceptibility genes for type 2 diabetes. Evidence was previously reported of linkage to diabetes on 10q with suggestive evidence on 3p and 9p in a genome-wide scan of 440 individuals from 27 pedigrees ascertained through a single diabetic proband. Subsequently, the study was expanded to include 906 individuals from 39 extended Mexican-American pedigrees, two additional examination cycles approximately 5.3 and 7.6 years after baseline, and genotypes for a new set of genome-wide markers. Therefore, we completed a second genome-wide linkage scan. Using information from a participant's most recent exam, the prevalence of diabetes in nonprobands was 21.8%. We performed genome-wide variance components-based genetic analysis on the discrete trait diabetes using a liability model and on the quantitative Martingale residual obtained from modeling age of diabetes diagnosis using Cox proportional hazard models. Controlling for age and age(2), our strongest evidence for linkage to the trait diabetes and the quantitative Martingale residual was on chromosome 3p at marker D3S2406 with multipoint empirical logarithm of odds scores of 1.87 and 3.76, respectively. In summary, we report evidence for linkage to diabetes on chromosome 3p in a region previously identified in at least three independent populations. [ABSTRACT FROM AUTHOR]

Objective: To test the hypothesis that enzymes conventionally associated with liver dysfunction (aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase [GGT], and alkaline phosphatase) may predict diabetes.Research Design and Methods: From a population-based diabetes survey, we selected 1,441 men and women in whom serum enzyme levels were < or =3 SDs of the mean population value, alcohol intake was <250 g/week, and hepatitis B and C virus testing was negative. At follow-up (7 years), 94 subjects developed diabetes and 93 impaired glucose tolerance (IGT).Results: At baseline, all four enzymes were related to most of the features of the metabolic syndrome. After controlling for sex, age, adiposity/fat distribution, alcohol intake, serum lipids, and blood pressure, higher alanine aminotransferase and GGT values were significantly (P < 0.01) associated with both IGT and diabetes, whereas alkaline phosphatase was associated with diabetes only (P = 0.0004) and aspartate aminotransferase with IGT only (P = 0.0001). Raised GGT alone was associated with all the features of the metabolic syndrome. Raised GGT was a significant predictor of either IGT or diabetes (odds ratio 1.62 [95% CI 1.08-2.42] top quartile vs. lower quartiles, P < 0.02) after controlling for sex, age, adiposity/fat distribution, alcohol consumption, fasting plasma insulin and proinsulin levels, and 2-h postglucose plasma glucose concentrations.Conclusions: Although mild elevations in liver enzymes are associated with features of the metabolic syndrome, only raised GGT is an independent predictor of deterioration of glucose tolerance to IGT or diabetes. As GGT signals oxidative stress, the association with diabetes may reflect both hepatic steatosis and enhanced oxidative stress. [ABSTRACT FROM AUTHOR]

The observation that Hispanics have lower all-cause and cardiovascular mortality rates despite increased rates of diabetes and obesity and lower socioeconomic status has been termed the 'Hispanic paradox.' The authors therefore examined the relation between ethnicity and mortality in 1,438 Mexican-American and 921 non-Hispanic White San Antonio Heart Study participants, aged 45-64 years when they enrolled between 1979 and 1988. Over an average of 14.5 years, 466 deaths occurred: 238 attributed to cardiovascular disease (death certificate International Classification of Diseases, Ninth Revision, codes 401-414 or codes 420-447 with the exception of code 427.5) and 117 attributed to coronary heart disease (codes 410-414). Age- and gender-adjusted hazard ratios for all-cause, cardiovascular, and coronary heart disease mortality comparing Mexican Americans with non-Hispanic Whites were 1.50 (95% confidence interval (CI): 1.23, 1.81), 1.70 (95% CI: 1.30, 2.24), and 1.60 (95% CI: 1.09, 2.36), respectively. After adjusting for possible confounders, among diabetic individuals not using insulin, the authors found excess risk of all-cause, cardiovascular, and coronary heart disease mortality associated with being Mexican American; however, in nondiabetic individuals and insulin-using diabetic individuals, Mexican Americans and non-Hispanic Whites appeared to be at similar risk of mortality. Contrary to the prediction of the 'Hispanic paradox,' in the San Antonio Heart Study, Mexican Americans were at greater risk of all-cause, cardiovascular, and coronary heart disease mortality than were non-Hispanic Whites. [ABSTRACT FROM AUTHOR]

Objective: The oral glucose tolerance test identifies high-risk subjects for diabetes, but it is costly and inconvenient. To find better predictors of type 2 diabetes, we evaluated two different definitions of the metabolic syndrome because insulin resistance, which is commonly associated with this clustering of metabolic factors, frequently precedes the onset of type 2 diabetes.Research Design and Methods: We compared the ability of the National Cholesterol Education Program (NCEP) definition, a modified version of the 1999 World Health Organization (WHO) definition that excludes the 2-h glucose requirement, and impaired glucose tolerance (IGT) to predict incident type 2 diabetes. In the San Antonio Heart Study, 1734 participants completed a 7- to 8-year follow-up examination.Results: IGT and the NCEP definition had higher sensitivity than the modified WHO definition (51.9, 52.8, and 42.8%, respectively). IGT had a higher positive predictive value than the NCEP and modified WHO definitions (43.0, 30.8, and 30.4%, respectively). The combination of the IGT and NCEP definitions increased the sensitivity to 70.8% with an acceptable positive predictive value of 29.7%. Risk for incidence of type 2 diabetes using the NCEP definition was independent of other risk factors, including IGT and fasting insulin (odds ratio 3.30, 95% CI 2.27-4.80). The NCEP definition performed better with fasting glucose >or=5.4 mmol/l (sensitivity 62.0% and positive predictive value 30.9%).Conclusions: The metabolic syndrome predicts diabetes independently of other factors. However, the NCEP definition performs better than the modified 1999 WHO definition. Lowering the fasting glucose cutoff to 5.4 mmol/l improves the prediction of diabetes by the metabolic syndrome. [ABSTRACT FROM AUTHOR]

Objective: To examine the influence of obesity and prevention of weight gain on the incidence of type 2 diabetes.Research Design and Methods: We examined participants in the San Antonio Heart Study, a prospective population-based study of Mexican Americans and non-Hispanic whites residing in San Antonio, Texas. BMI was stratified into four categories: normal (<25 kg/m(2)), overweight (> or =25 kg/m(2) and <30 kg/m(2)), obese (> or =30 kg/m(2) and <35 kg/m(2)), and very obese (> or =35 kg/m(2)). The number and proportion of incident cases prevented by targeting each BMI category were estimated. In addition, we calculated the decrease in risk of developing type 2 diabetes associated with weight gain prevention across both the BMI and age spectra.Results: Preventing normal individuals from becoming overweight would result in the greatest reduction in incidence of type 2 diabetes. This would result in a 62 and 74% reduction in the incidence of type 2 diabetes in Mexican Americans and non-Hispanic whites, respectively. Preventing the entire population from gaining, on average, 1 BMI unit would result in a reduction in incidence of type 2 diabetes of 12.4 and 13.0% in Mexican Americans and non-Hispanic whites, respectively.Conclusions: The majority of cases of type 2 diabetes were in individuals who were overweight or mildly obese with a family history of type 2 diabetes. Public health resources should be directed toward the prevention of weight gain among normal and overweight individuals in order to prevent the maximum number of cases of type 2 diabetes. [ABSTRACT FROM AUTHOR]

To determine and formally compare the ability of simple indexes of insulin resistance (IR) to predict type 2 diabetes, we used combined prospective data from the San Antonio Heart Study, the Mexico City Diabetes Study, and the Insulin Resistance Atherosclerosis Study, which include well-characterized cohorts of non-Hispanic white, African-American, Hispanic American, and Mexican subjects with 5-8 years of follow-up. Poisson regression was used to assess the ability of each candidate index to predict incident diabetes at the follow-up examination (343 of 3,574 subjects developed diabetes). The areas under the receiver operator characteristic (AROC) curves for each index were calculated and statistically compared. In pooled analysis, Gutt et al.'s insulin sensitivity index at 0 and 120 min (ISI(0,120)) displayed the largest AROC (78.5%). This index was significantly more predictive (P < 0.0001) than a large group of indexes (including those by Belfiore, Avignon, Katz, and Stumvoll) that had AROC curves between 66 and 74%. These findings were essentially similar both after adjustment for covariates and when analyses were conducted separately by glucose tolerance status and ethnicity/study subgroups. In conclusion, we found substantial differences between published IR indexes in the prediction of diabetes, with ISI(0,120) consistently showing the strongest prediction. This index may reflect other aspects of diabetes pathogenesis in addition to IR, which might explain its strong predictive abilities despite its moderate correlation with direct measures of IR. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the extent to which levels of physical activity and nutrient intake aggregate in families, and secondarily, to assess the repeatability of these behavioral measures over a 5-year period.Methods: Measurements were obtained in a population-based sample consisting of 1364 members of 42 large Mexican American families. Nutrient intake was assessed by a food frequency questionnaire validated for use in this population. Usual level of physical activity was estimated using a 7-day recall questionnaire.Results: Correlations between baseline (obtained 1992-1995) and follow-up (obtained 1996 to 2000) measures of all behaviors were highly significant (p < 0.001), ranging from 0.24 for % of calories derived from fat to 0.44 for % of calories derived from alcohol. Familial effects, estimated using variance component methods, were stronger when modeled as a genetic heritability than as a shared household effect; as a heritability they accounted for a significant portion of the total variation of all traits (9% for physical activity levels, p < 0.05; and 13-26% for nutrient intake, p < 0.001 for all).Conclusions: Measurements of physical activity and dietary behaviors in this population tracked over 5 years, and there was a significant degree of aggregation of these behaviors within families. Understanding the sources of these family effects may facilitate efforts to improve cardiovascular health. [ABSTRACT FROM AUTHOR]

Purpose: To examine the mortality risk associated with diabetes in the Mexico City Diabetes Study (MCDS) and the San Antonio Heart Study (SAHS)., Methods: Prospective cohorts conducted 1990-2007 in MCDS and 1979-2000 in SAHS. Mortality risk was examined using Cox proportional hazard models in 1402 non-Hispanic whites (NHW), 1907 U.S.-born Mexican-Americans (MA), 444 Mexican-born MA, and 2281 Mexico City residents (MCR) between the ages of 35-64., Results: Age- and sex-adjusted mortality hazard ratios (HR) comparing U.S.-born MA, Mexican-born MA, and MCR to NHW were 1.09 (95% confidence interval [CI]: 0.86, 1.37), 1.23 (95% CI: 0.86, 1.76), and 0.97 (95% CI: 0.77, 1.23), respectively, in nondiabetic individuals; in contrast, mortality risk varied in diabetic individuals with respective HRs of 1.77 (95% CI: 1.20, 2.61), 1.08 (95% CI: 0.59, 1.97), and 2.27 (95% CI: 1.53, 3.35) (interaction p = .0003). Excluding Mexican-born MA and nondiabetic individuals, controlling for medication use, insulin use, fasting glucose levels, and duration of diabetes explained a significant proportion of the mortality differential (HRs relative to NHW were 1.31 [95% CI: 0.87, 1.98] in U.S.-born MA and 1.38 [95% CI: 0.89, 2.12] in MCR)., Conclusions: This study provides evidence that diabetes is more lethal in U.S.-born MA and MCR than in NHW., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To develop a model for the prediction of type 2 diabetes mellitus (T2DM) risk on the basis of a multivariate logistic model and 1-h plasma glucose concentration (1-h PG)., Research Design and Methods: The model was developed in a cohort of 1,562 nondiabetic subjects from the San Antonio Heart Study (SAHS) and validated in 2,395 nondiabetic subjects in the Botnia Study. A risk score on the basis of anthropometric parameters, plasma glucose and lipid profile, and blood pressure was computed for each subject. Subjects with a risk score above a certain cut point were considered to represent high-risk individuals, and their 1-h PG concentration during the oral glucose tolerance test was used to further refine their future T2DM risk., Results: We used the San Antonio Diabetes Prediction Model (SADPM) to generate the initial risk score. A risk-score value of 0.065 was found to be an optimal cut point for initial screening and selection of high-risk individuals. A 1-h PG concentration >140 mg/dL in high-risk individuals (whose risk score was >0.065) was the optimal cut point for identification of subjects at increased risk. The two cut points had 77.8, 77.4, and 44.8% (for the SAHS) and 75.8, 71.6, and 11.9% (for the Botnia Study) sensitivity, specificity, and positive predictive value, respectively, in the SAHS and Botnia Study., Conclusions: A two-step model, based on the combination of the SADPM and 1-h PG, is a useful tool for the identification of high-risk Mexican-American and Caucasian individuals.

OBJECTIVE To assess the relative contribution of increased fasting and postload plasma glucose concentrations to the incidence of type 2 diabetes in subjects with a normal 2-h plasma glucose concentration. RESEARCH DESIGN AND METHODS A total of 3,450 subjects with 2-h plasma glucose concentration <140 mg/dl at baseline were followed up in the San Antonio Heart Study (SAHS) and the Botnia Study for 7-8 years. The incidence of type 2 diabetes at follow-up was related to the fasting, 1-h, and 2-h plasma glucose concentrations. RESULTS In subjects with 2-h plasma glucose <140 mg/dl, the incidence of type 2 diabetes increased with increasing fasting plasma glucose (FPG) and 1-h and 2-h plasma glucose concentrations. In a multivariate logistic analysis, after adjustment for all diabetes risk factors, the FPG concentration was a strong predictor of type 2 diabetes in both the SAHS and the Botnia Study (P < 0.0001). However, when the 1-h plasma glucose, but not 2-h plasma glucose, concentration was added to the model, FPG concentration was no longer a significant predictor of type 2 diabetes in both studies (NS). When subjects were matched for the level of 1-h plasma glucose concentration, the incidence of type 2 diabetes markedly increased with the increase in 1-h plasma glucose, but the increase in FPG was not associated with a significant increase in the incidence of type 2 diabetes. CONCLUSIONS An increase in postload glycemia in the normal range is associated with an increase in the incidence of type 2 diabetes. After controlling for 1-h plasma glucose concentration, the increase in FPG concentration is not associated with an increase in the incidence of type 2 diabetes.

Objective: Human 8-oxoguanine glycosylase 1 (OGG1) excises oxidatively damaged promutagenic base 8-oxoguanine, a lesion previously observed in a rat model of type 2 diabetes (T2DM). The objective of the present study is to determine whether genetic variation in OGG1 is associated with type 2 diabetes (T2DM) in a Mexican American cohort., Methods: Ten SNPs including two tagging SNPs (rs1052133, rs2072668) across the OGG1 gene region were selected from the Hapmap database and genotyped in the entire cohort (n = 670; 29% diabetes; 39 families) by TaqMan assay. Association analyses between the SNPs and T2DM were performed using the measured genotype approach as implemented in the program SOLAR., Results: Of the ten SNPs genotyped, only five were polymorphic. The minor allele frequencies of these 5 SNPs ranged from 1-38%. Of the SNPs examined for association, the Ser(326)Cys (rs1052133) exhibited significant association with T2DM (p = 0.016) after accounting for age and sex effects. Another intronic variant (rs2072668), which was in strong linkage disequilibrium (r(2) = 0.96) with Ser(326)Cys also exhibited significant association with T2DM (p = 0.031)., Conclusions: These results suggest for the first time that the variants in OGG1 could influence diabetes risk in these Mexican American families and support a role for alterations of OGG1 in the pathogenesis of T2DM., (Copyright © 2010 S. Karger AG, Basel.)

Background. D-dimer is associated with increasing severity of atherosclerosis and with increased risk of a cardiovascular disease (CVD). Methods and Results. To better understand this risk factor, we performed a genome scan on 803 (301 males and 502 females) Mexican Americans in the San Antonio Family Heart Study (SAFHS). The SAFHS is ideal for the discovery of quantitative trait loci (QTLs) influencing CVD because CVD risk factors are prevalent in Mexican Americans of San Antonio and because the study design involves large families, which is optimal for QTL discovery. D-dimer levels were normalized in our study. We found that D-dimer levels were heritable, at about 23% heritability (P ≈ .00001). In a linkage analysis employing 432 microsatellite markers, we found strong evidence of a QTL on chromosome 5p with a lod score of 3.32 at 21 centiMorgans (cM). We also found suggestive evidence of a QTL on chromosome 2q with a lod score of 2.33 at 207 cM. Conclusions. To our knowledge, the putative QTL on chromosome 5p is novel. The possible QTL on chromosome 2q is discussed in relation to a recent report of linkage of a related hemostatic factor to the same location. These results warrant further investigation.