Diabetes is more lethal in Mexicans and Mexican-Americans compared to Non-Hispanic whites.

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.

The Ser(326)Cys polymorphism of 8-oxoguanine glycosylase 1 (OGG1) is associated with type 2 diabetes in Mexican Americans.

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.

Evaluation of gremlin 1 (GREM1) as a candidate susceptibility gene for albuminuria-related traits in Mexican Americans with type 2 diabetes mellitus.

Several novel genes that are up-regulated in the kidney in diabetes have been identified including GREM1, which encodes gremlin 1. GREM1 maps to human chromosome 15q12, a region previously found to be linked to albumin to creatinine ratio (ACR) in Mexican Americans. The objective of this study is to investigate whether genetic variants in GREM1, a positional candidate gene, contribute to variation in ACR. By sequencing 32 individuals for both exons and 2-kilobase putative promoter region of GREM1, we identified 19 genetic variants including 5 in the promoter region and 13 in the 3' untranslated region. Of 19 polymorphisms identified, 13 polymorphisms were genotyped in the entire cohort (N = 670, 39 large families) either by restriction fragment length polymorphism or by TaqMan (Applied Biosystems, Foster City, CA) assays. Association analyses between the genotypes and ACR, type 2 diabetes mellitus, and related phenotypes were carried out using a measured genotype approach as implemented in the variance component analytical tools (SOLAR). Of the variants examined for association, none exhibited statistically significant association with ACR after accounting for the effects of covariates such as age, sex, diabetes, duration of diabetes, systolic blood pressure, and antihypertensive medications. However, 2 novel variants at the 3' untranslated region showed significant association with estimated glomerular filtration rate (P = .010 and P = .049) and body mass index (P = .013 and P = .019) after accounting for trait-specific covariate influences. Furthermore, a novel variant located in the promoter exhibited a significant association with systolic (P = .038) and diastolic blood pressure (P = .005) after adjusting for the effects of age, sex, diabetes, and antihypertensive medications. In conclusion, the variants examined at GREM1 are not significant contributors to variation in ACR in Mexican Americans, although they appear to minimally influence risk factors related to ACR.

Endothelial nitric oxide synthase (eNOS) gene polymorphisms and their association with type 2 diabetes-related traits in Mexican Americans.

Genetic variants of the endothelial nitric oxide synthase (eNOS) gene such as T-786C, Glu298Asp and 27bp-VNTR have been examined for their association with type 2 diabetes (T2DM)-related traits in various populations but not in Mexican Americans. However, the results from such studies have been controversial. This study investigated whether these three polymorphisms are associated with T2DM and its related traits in Mexican Americans, a population at high risk for T2DM and its complications. The study participants (n=670; 39 families) were genotyped for the three polymorphisms using polymerase chain reaction followed by restriction fragment length polymorphism assay. Association analyses between these polymorphisms and T2DM and its related phenotypes were carried out using a measured genotype approach as implemented in the computer program SOLAR. Of the variants examined, only the 27bp-VNTR variant exhibited significant association with high-density lipoprotein cholesterol (HDL-C) (p=0.04) and diastolic blood pressure (DBP) levels (p=0.02) after accounting for trait-specific covariates. The carriers of the rare allele (27bp-VNTR-4a) were found to have decreased HDL-C and increased DBP levels. In conclusion, of the genetic polymorphisms examined at the eNOS locus, only 27bp-VNTR appears to be a minor contributor to the variation in T2DM-related traits in Mexican Americans.

Risk of progression to hypertension in a low-income Mexican population with prehypertension and normal blood pressure.

BACKGROUND: Blood pressure (BP) levels below the prehypertensive category may be associated with the risk of developing hypertension. We estimated the incidence rates of hypertension in a low-income Mexican population according to several subcategories of baseline BP within normal and prehypertensive categories. METHODS: In total, 1572 nonhypertensive men (n = 632) and nonpregnant women (n = 940), aged 35 to 64 years at baseline, were followed for a median of 5.8 years. Hypertension was defined as systolic blood pressure (SBP) >or=140 mm Hg, diastolic blood pressure (DBP) >or=90 mm Hg, or a self-reported physician's diagnosis with antihypertensive medications. RESULTS: During follow-up, 267 subjects developed hypertension, of whom 83 were men and 184 were women. The age-adjusted incidence rate was higher in women (37.1 per 1000 person-years) than in men (23.7 per 1000 person-years). There was a significant association between BP levels at baseline and incidence of hypertension, even within the normal category. For the upper levels of normal SBP (110 to 119 mm Hg), the hazards ratio (HR) was 2.43 (95% confidence interval [CI], 1.50 to 3.93) in women and 2.44 (95% CI, 1.05 to 5.69) in men, compared with SBP <110 mm Hg. For the upper levels of normal DBP (70 to 79 mm Hg), the HR was 2.33 (95% CI, 1.65 to 3.31) in women and 1.80 (95% CI, 0.92 to 3.52) in men, compared with DBP <70 mm Hg, after adjustment for recognized predictors. CONCLUSIONS: A high risk for the incidence of hypertension was associated with levels of BP, even within the normal category. This information could help define a population at high risk of progression to hypertension, to establish preventive measures.

Genotype by diabetes interaction effects on the detection of linkage of glomerular filtration rate to a region on chromosome 2q in Mexican Americans.

OBJECTIVE: Glomerular filtration rate (GFR) is used to assess the progression of renal disease. We performed linkage analysis to localize genes that influence GFR using estimated GFR data from the San Antonio Family Diabetes/Gallbladder Study. We also examined the effect of genotype by diabetes interaction (G x DM) on the detection of linkage to address whether genetic effects on GFR differ in diabetic and nondiabetic subjects. RESEARCH DESIGN AND METHODS: GFR (N = 453) was estimated using the recently recalculated Cockcroft-Gault (GFR-CGc) and the simplified Modification of Diet in Renal Disease (GFR-4VMDRD) formulae. Both estimates of GFR exhibited significant heritabilities, but only GFR-CGc showed significant G x DM interaction. We therefore performed multipoint linkage analyses on both GFR measures using models that did not include G x DM interaction effects (Model 1) and that included G x DM interaction effects (Model 2, in the case of GFR-CGc). RESULTS: The strongest evidence for linkage (Model 1) of both GFR-CGc (logarithm of odds [LOD] 2.9) and GFR-4VMDRD (LOD 2.6) occurred between markers D9S922 and D9S1120 on chromosome 9q. However, using Model 2, the strongest evidence for linkage of GFR-CGc on chromosome 2q was found near marker D2S427 (corrected LOD score [LOD(C)] 3.3) compared with the LOD score of 2.7 based on Model 1. Potential linkages (LOD or LOD(C) >or=1.2) were found only for GFR-CGc on chromosomes 3p, 3q, 4p, 8q, 11q, and 14q. CONCLUSIONS: We found a major locus on chromosome 2q that differentially influences GFR in diabetic and nondiabetic environments in the Mexican-American population.

Carotid intima-media thickness in confirmed prehypertensive subjects: predictors and progression.

OBJECTIVE: The purpose of this study was to test whether carotid intima-media thickness (IMT) is already increased in normotensive subjects who progress to hypertension (confirmed prehypertensives) independently of known determinants of vessel wall thickness. METHODS AND RESULTS: Common carotid artery (CCA) far-wall IMT was measured (B-mode ultrasound) in 1536 subjects from the population-based Mexico City Diabetes Study at baseline and 3.5 years later. In the 136 confirmed prehypertensives, CCA-IMT (720 [253] microm, median[interquartile range]) was intermediate between normotensives (615 [140] microm) and hypertensives (725 [215] microm). After multiadjusting for gender, age, BMI, blood pressure, total cholesterol, antihypertensive therapy, and diabetes, converter status was independently associated with a higher CCA-IMT (+93+/-14 microm). At follow-up, CCA-IMT increased by 35 [180] microm. Gender, age, blood pressure, and presence of diabetes, but not the converter status, were significant independent predictors of CCA-IMT progression. In a model adjusting for gender, age, blood pressure (level, status and treatment), diabetes status, total and HDL-cholesterol, the G variant of the 45T/G polymorphism of the adiponectin gene was associated with a hazard ratio of 1.45 (95% CI: 1.04 to 2.01) of a baseline CCA-IMT in the top quintile. CONCLUSIONS: In confirmed prehypertensives, CCA-IMT is increased independently of blood pressure and known determinants of wall thickness, but short-term CCA-IMT progression is not accelerated.

Association of neuropeptide Y receptor Y5 polymorphisms with dyslipidemia in Mexican Americans.

We examined the genetic association of neuropeptide Y receptor Y5 (NPY5R) single nucleotide polymorphisms (SNPs) with measures of the insulin resistance (metabolic) syndrome. We genotyped 10 NPY5R SNPs in 439 Mexican American individuals (age=43.3+/-17.3 years and BMI=30.0+/-6.7 kg/m2) distributed across 27 pedigrees from the San Antonio Family Diabetes Study and performed association analyses using the measured genotype approach as implemented in Sequential Oligogenic Linkage Analysis Routines (SOLAR). Minor alleles for five (rs11100493, rs12501691, P1, rs11100494, rs12512687) of the NPY5R SNPs were found to be significantly (p<0.05) associated with fasting plasma triglyceride concentrations and decreased high-density lipoprotein concentrations. In addition, the minor allele for SNP P2 was significantly associated (p=0.031) with a decreased homeostasis model assessment of beta-cell function (HOMA-%beta). Linkage disequilibrium between SNP pairs indicated one haplotype block of five SNPs (rs11100493, rs12501691, P1, rs11100494, rs12512687) that were highly correlated (r2>0.98). These preliminary results provide evidence for association of SNPs in the NPY5R gene with dyslipidemia (elevated triglyceride concentrations and reduced high-density lipoprotein levels) in our Mexican American 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 x 10(-5), relative risk [RR] 0.69; P = 6.7 x 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.

P2 promoter variants of the hepatocyte nuclear factor 4alpha gene are associated with type 2 diabetes in Mexican Americans.

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.

A novel missense mutation in ADRB3 increases risk for type 2 diabetes in a Mexican American family.

BACKGROUND: The human beta3-adrenergic receptor gene (ADRB3) has been investigated as a candidate gene for diabetes-related traits in many studies. However, the results have been inconsistent so it is unclear whether variation in ADRB3 is a risk factor for type 2 diabetes. We have identified a novel missense mutation of ADRB3 in a single large pedigree of the San Antonio Family Diabetes/Gallbladder Study (SAFDGS) that is located in the first transmembrane domain at amino acid 62 (Ile62Met). The aim of this study was to investigate the association of this mutation in the SAFDGS with risk for diabetes. METHODS: Variance components-based statistical methods were used to determine association of this mutation with diabetes traits in the SAFDGS. The ADRB3 gene was also resequenced to identify all variants present in this pedigree. RESULTS: Significant association was observed for the Ile62Met mutation and type 2 diabetes (p = 0.01, relative risk 2.3), an earlier age of onset (p = 0.01) and 2-h glucose measures (p = 0.006) in the single pedigree. Average age and body mass index do not differ between the two genotypic groups. In a recent genome-wide linkage analysis of SAFDGS, we observed suggestive linkage of diabetes to this region at marker D8S1477 (2pt LOD of 2.55). The variance attributed to Ile62Met accounted for nearly all of the family-specific LOD score. CONCLUSIONS: These results suggest that this variant in ADRB3 is influencing diabetes risk in this Mexican American family and supports a role for alterations of the beta3-adrenergic receptor in the pathogenesis of type 2 diabetes.

A genomewide search finds major susceptibility loci for gallbladder disease on chromosome 1 in Mexican Americans.

Gallbladder disease (GBD) is one of the major digestive diseases. Its risk factors include age, sex, obesity, type 2 diabetes, and metabolic syndrome (MS). The prevalence of GBD is high in minority populations, such as Native and Mexican Americans. Ethnic differences, familial aggregation of GBD, and the identification of susceptibility loci for gallstone disease by use of animal models suggest genetic influences on GBD. However, the major susceptibility loci for GBD in human populations have not been identified. Using ultrasound-based information on GBD occurrence and a 10-cM gene map, we performed multipoint variance-components analysis to localize susceptibility loci for GBD. Phenotypic and genotypic data from 715 individuals in 39 low-income Mexican American families participating in the San Antonio Family Diabetes/Gallbladder Study were used. Two GBD phenotypes were defined for the analyses: (1) clinical or symptomatic GBD, the cases of cholecystectomies due to stones confirmed by ultrasound, and (2) total GBD, the clinical GBD cases plus the stone carriers newly diagnosed by ultrasound. With use of the National Cholesterol Education Program/Adult Treatment Panel III criteria, five MS risk factors were defined: increased waist circumference, hypertriglyceredemia, low high-density lipoprotein cholesterol, hypertension, and high fasting glucose. The MS risk-factor score (range 0-5) for a given individual was used as a single, composite covariate in the genetic analyses. After accounting for the effects of age, sex, and MS risk-factor score, we found stronger linkage signals for the symptomatic GBD phenotype. The highest LOD scores (3.7 and 3.5) occurred on chromosome 1p between markers D1S1597 and D1S407 (1p36.21) and near marker D1S255 (1p34.3), respectively. Other genetic locations (chromosomes 2p, 3q, 4p, 8p, 9p, 10p, and 16q) across the genome exhibited some evidence of linkage (LOD >or=1.2) to symptomatic GBD. Some of these chromosomal regions corresponded with the genetic locations of Lith loci, which influence gallstone formation in mouse models. In conclusion, we found significant evidence of major genetic determinants of symptomatic GBD on chromosome 1p in Mexican Americans.

Bivariate linkage analysis of the insulin resistance syndrome phenotypes on chromosome 7q.

Metabolic abnormalities of the insulin resistance syndrome (IRS) have been shown to aggregate in families and to exhibit trait-pair correlations, suggesting a common genetic component. A broad region on chromosome 7q has been implicated in several studies to contain loci that cosegregate with IRS-related traits. However, it is not clear whether such loci have any common genetic (pleiotropic) influences on the correlated traits. Also, it is not clear whether the chromosomal regions contain more than one locus influencing the IRS-related phenotypes. In this study we present evidence for linkage of five IRS-related traits [body mass index (BMI), waist circumference (WC), In split proinsulin (LSPI), In triglycerides (LTG), and high-density lipoprotein cholesterol (HDLC)] to a region at 7q11.23. Subsequently, to gain further insight into the genetic component(s) mapping to this region, we explored whether linkage of these traits is due to pleiotropic effects using a bivariate linkage analytical technique, which has been shown to localize susceptibility regions with precision. Four hundred forty individuals from 27 Mexican American families living in Texas were genotyped for 19 highly polymorphic markers on chromosome 7. Multipoint variance component linkage analysis was used to identify genetic location(s) influencing IRS-related traits of obesity (BMI and WC), dyslipidemia (LTG and HDLC), and insulin levels (LSPI); the analysis identified a broad chromosomal region spanning approximately 24 cM. To gain more precision in localization, we used a bivariate linkage approach for each trait pair. These analyses suggest localization of most of these bivariate traits to an approximately 6-cM region near marker D7S653 [7q11.23, 103-109 cM; a maximum bivariate LOD of 4.51 was found for the trait pair HDLC and LSPI (the LODeq score is 3.94)]. We observed evidence of pleiotropic effects in this region on obesity and insulin-related trait pairs.

Genome-wide linkage analyses of type 2 diabetes in Mexican Americans: the San Antonio Family Diabetes/Gallbladder Study.

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.

Family history of type 2 diabetes is associated with increased carotid artery intimal-medial thickness in Mexican Americans.

OBJECTIVE: To evaluate whether the joint risk of diabetes and atherosclerosis tracked within families, we assessed the correlation between a family history of diabetes and intimal-medial thickness (IMT) of the common carotid artery (CCA). RESEARCH DESIGN AND METHODS: Study subjects included 620 nondiabetic individuals from 24 families enrolled in the San Antonio Family Heart Study. The thickness of the far walls of the CCA was measured by B-mode ultrasonography. Statistical analyses included familial correlations to account for the nonindependence of family data. RESULTS: After adjusting for sex, age, and IMT reader effects, the heritability of IMT in this population was 16% (P = 0.009). Using a more comprehensive family history score that accounted for diabetes status of the individual's parents and older siblings, we observed a significant correlation between family history score and increased CCA IMT (0.006 mm increase in CCA IMT for every point increase of diabetes family history score, P = 0.016). This association remained even after further adjustment for BMI, smoking, and fasting insulin and glucose levels. After adjusting for several cardiovascular risk factors, the mean CCA IMT in those with high family history scores for diabetes was still 0.037 mm thicker than those with low family history scores for diabetes (P = 0.040). CONCLUSIONS: These results suggest that the genetic contribution to CCA IMT variability is modest. Also, the small increase in subclinical atherosclerosis observed even among nondiabetic Mexican Americans with a positive family history of diabetes is probably transmitted along with the risk of diabetes through shared etiologic risk factors between diabetes and cardiovascular disease.

Liver enzymes, the metabolic syndrome, and incident diabetes: the Mexico City diabetes study.

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.

A single nucleotide polymorphism in MGEA5 encoding O-GlcNAc-selective N-acetyl-beta-D glucosaminidase is associated with type 2 diabetes in Mexican Americans.

Excess O-glycosylation of proteins by O-linked beta-N-acetylglucosamine (O-GlcNAc) may be involved in the pathogenesis of type 2 diabetes. The enzyme O-GlcNAc-selective N-acetyl-beta-d glucosaminidase (O-GlcNAcase) encoded by MGEA5 on 10q24.1-q24.3 reverses this modification by catalyzing the removal of O-GlcNAc. We have previously reported the linkage of type 2 diabetes and age at diabetes onset to an overlapping region on chromosome 10q in the San Antonio Family Diabetes Study (SAFADS). In this study, we investigated menangioma-expressed antigen-5 (MGEA5) as a positional candidate gene. Twenty-four single nucleotide polymorphisms (SNPs), identified by sequencing 44 SAFADS subjects, were genotyped in 436 individuals from 27 families whose data were used in the original linkage report. Association tests indicated significant association of a novel SNP with the traits diabetes (P = 0.0128, relative risk = 2.77) and age at diabetes onset (P = 0.0017). The associated SNP is located in intron 10, which contains an alternate stop codon and may lead to decreased expression of the 130-kDa isoform, the isoform predicted to contain the O-GlcNAcase activity. We investigated whether this variant was responsible for the original linkage signal. The variance attributed to this SNP accounted for approximately 25% of the logarithm of odds. These results suggest that this variant within the MGEA5 gene may increase diabetes risk in Mexican Americans.