Linkage of high-density lipoprotein-cholesterol concentrations to a locus on chromosome 9p in Mexican Americans.

High-density lipoproteins (HDLs) are anti-atherogenic lipoproteins that have a major role in transporting cholesterol from peripheral tissues to the liver, where it is removed. Epidemiologic studies have shown that low levels of high-density lipoprotein-cholesterol (HDL-C) are associated with an increased incidence of coronary heart disease and an increased mortality rate, indicating a protective role of high concentrations of HDL-C against atherogenesis and the development of coronary heart disease. HDL-C level is influenced by several genetic and nongenetic factors. Nongenetic factors include smoking, which has been shown to decrease the HDL-C level. Exercise and alcohol have been shown to increase HDL-C levels. Decreased HDL-C is often associated with other coronary heart disease risk factors such as obesity, hyperinsulinemia and insulin resistance, hypertriglyceridemia and hypertension. Although several genes have been identified for rare forms of dyslipidemia, the genes accounting for major variation in HDL-C levels have yet to be identified. Using a multipoint variance components linkage approach, we found strong evidence of linkage (lod score=3.4; P=0.00004) of a quantitative trait locus (QTL) for HDL-C level to a genetic location between markers D9S925 and D9S741 on chromosome 9p in Mexican Americans. A replication study in an independent set of Mexican American families confirmed the existence of a QTL on chromosome 9p.

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.

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.

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.

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.

The metabolic syndrome and the impact of diabetes on coronary heart disease mortality in women and men: the San Antonio Heart Study.

PURPOSE: An explanation for the differential impact of diabetes on coronary heart disease (CHD) mortality in men and women is that diabetes and cardiovascular disease (CVD) share a common antecedent that differentially affects men and women. In the San Antonio Heart Study we examined the relationship between gender, the metabolic syndrome defined by the National Cholesterol Education Program (NCEP-MetS) and diabetes and their ability to predict CHD mortality. METHODS: Over 15.5 years, 4996 men and women 25 to 64 years of age experienced 254 cardiovascular deaths, including 121 from CHD (International Classification of Diseases, Ninth Revision codes 410-414). RESULTS: At baseline, NCEP-MetS occurred more often in men than in women among those with normal glucose levels (12.3% vs. 9.7%, p < 0.05), but less often in men than in women among those with diabetes (65.7% vs. 74.4%, p < 0.05). Adjusted for age, ethnic group, and a history of CVD, relative to women with neither diabetes nor NCEP-MetS, women with both had a 14-fold (hazard ratio [HR] = 14.3 [95% confidence interval: 6.62, 30.7]) increased risk of CHD mortality, whereas men had only a 4-fold (HR = 4.21 (95% confidence interval: 2.32, 7.65]) increased risk, respectively. CONCLUSION: When diabetes occurred with NCEP-MetS, gender was a strong modifier of the joint effect of diabetes and NCEP-MetS on CHD mortality.

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.

Identification of individuals with insulin resistance using routine clinical measurements.

Insulin resistance is a treatable precursor of diabetes and potentially of cardiovascular disease as well. To identify insulin-resistant patients, we developed decision rules from measurements of obesity, fasting glucose, insulin, lipids, and blood pressure and family history in 2,321 (2,138 nondiabetic) individuals studied with the euglycemic insulin clamp technique at 17 European sites; San Antonio, Texas; and the Pima Indian reservation. The distribution of whole-body glucose disposal appeared to be bimodal, with an optimal insulin resistance cutoff of <28 micromol/min . kg lean body mass. Using recursive partitioning, we developed three types of classification tree models: the first, based on clinical measurements and all available laboratory determinations, had an area under the receiver operator characteristic curve (aROC) of 90.0% and generated a simple decision rule: diagnose insulin resistance if any of the following conditions are met: BMI >28.9 kg/m(2), homeostasis model assessment of insulin resistance (HOMA-IR) >4.65, or BMI >27.5 kg/m(2) and HOMA-IR >3.60. The fasting serum insulin concentrations corresponding to these HOMA-IR cut points were 20.7 and 16.3 microU/ml, respectively. This rule had a sensitivity and specificity of 84.9 and 78.7%, respectively. The second model, which included clinical measurements but no laboratory determinations, had an aROC of 85.0% and generated a decision rule that had a sensitivity and specificity of 78.7 and 79.6%, respectively. The third model, which included clinical measurements and lipid measurements but not insulin (and thus excluded HOMA-IR as well), had a similar aROC (85.1%), sensitivity (81.3%), and specificity (76.3%). Thus, insulin-resistant individuals can be identified using simple decision rules that can be tailored to specific needs.

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.

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.

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.

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.

National Cholesterol Education Program versus World Health Organization metabolic syndrome in relation to all-cause and cardiovascular mortality in the San Antonio Heart Study.

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

Mode of onset of type 2 diabetes from normal or impaired glucose tolerance.

Fasting plasma glucose concentrations (FPG) predict development of type 2 diabetes. Whether hyperglycemia evolves from normoglycemia gradually over time or as a step increase is not known. We measured plasma glucose and insulin levels during oral glucose testing in 35- to 64-year-old men and nonpregnant women from a population-based survey (Mexico City Diabetes Study) at baseline (n = 2,279) and after 3.25 (n = 1,740) and 7 years (n = 1,711) of follow-up. In subjects with normal glucose tolerance (NGT) on all three occasions (nonconverters; n = 911), FPG increased only slightly (0.23 +/- 0.79 mmol/l, mean +/- SD; P < 0.0001) over 7 years. In contrast, conversion to diabetes among NGT subjects (n = 98) was marked by a large step-up in FPG regardless of time of conversion (3.06 +/- 2.57 and 2.94 +/- 3.11 mmol/l, respectively, at 3.25 and 7 years; P < 0.0001 vs. nonconverters). Likewise, in subjects who converted to diabetes from impaired glucose tolerance (n = 75), FPG rose by 3.14 +/- 3.83 and 3.12 +/- 3.61 mmol/l (P < 0.0001 vs. nonconverters). Three-quarters of converters had increments in FPG above the 90th percentile of the corresponding increments in nonconverters. Converters had higher baseline BMI (30.4 +/- 4.9 vs. 27.3 +/- 4.0 kg/m(2); P < 0.001) and fasting plasma insulin values (120 +/- 78 vs. 84 +/- 84 pmol/l; P < 0.02) than nonconverters; however, no consistent change in either parameter had occurred before conversion. In contrast, changes in 2-h postglucose insulin levels between time of conversion and preceding measurement were significantly (P < 0.0001) related to the corresponding changes in FPG in an inverse manner. We conclude that, within a 3-year time frame, the onset of diabetes is very often rapid rather than gradual and is in part explained by a fall in glucose-stimulated insulin response.

Prediction of type 2 diabetes using simple measures of insulin resistance: combined results from the San Antonio Heart Study, the Mexico City Diabetes Study, and the Insulin Resistance Atherosclerosis Study.

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.

Factors of insulin resistance syndrome--related phenotypes are linked to genetic locations on chromosomes 6 and 7 in nondiabetic mexican-americans.

Insulin resistance syndrome (IRS)-related phenotypes, such as hyperinsulinemia, obesity-related traits, impaired glucose tolerance, dyslipidemia, and hypertension, tend to cluster into factors. We attempted to identify loci influencing the factors of IRS-related phenotypes using phenotypic data from 261 nondiabetic subjects distributed across 27 low-income Mexican-American extended families. Principal component factor analyses were performed using eight IRS-related phenotypes: fasting glucose (FG), fasting specific insulin (FSI), BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), HDL cholesterol, ln triglycerides (ln TGs), and leptin (LEP). The factor analysis yielded three factors: factor 1 (BMI, LEP, and FSI), factor 2 (DBP and SBP), and factor 3 (HDL and ln TG). We conducted multipoint variance components linkage analyses on these factors with the program SOLAR using a 10--15 cM map. We found significant evidence for linkage of factor 1 to two regions on chromosome 6 near markers D6S403 (logarithm of odds [LOD] = 4.2) and D6S264 (LOD = 4.9). We also found strong evidence for linkage of factor 3 to a genetic location on chromosome 7 between markers D7S479 and D7S471 (LOD = 3.2). In conclusion, we found substantial evidence for susceptibility loci on chromosomes 6 and 7 that appear to influence the factors representing the IRS-related phenotypes in Mexican-Americans.

Impact of diabetes/metabolic syndrome in patients with established cardiovascular disease.

The significance of the metabolic syndrome (MetS) resides either in its ability to identify individuals at high risk of future disease and disability or in its ability to identify individuals in need of a specific treatment. We have previously shown that in the general population the ability of the MetS to identify individuals at increased risk of diabetes or cardiovascular disease (CVD) is inferior to the ability of established predicting models for these conditions. Although it may someday become routine to recommend treatment with insulin-sensitising agents for non-diabetic individuals with the MetS, most of whom are insulin resistant, there are no clinical trial data to support such a recommendation at the present time. Currently, the treatment of the MetS is based on treatment of its component parts. In the present paper, we examine the role of the MetS as defined by the National Cholesterol Education Program (NCEP) criteria in predicting all-cause and CVD mortality in patients with prevalent CVD from the San Antonio Heart Study (SAHS). This population contains a high proportion of Mexican Americans, who are at high risk of developing type 2 diabetes. After adjusting for age and gender, the MetS is moderately predictive of all-cause and CVD mortality. After further adjustment for diabetes, however, the effect of the MetS becomes non-significant in this population. Moreover, among non-diabetics with prevalent CVD, the MetS was not associated with either all-cause or CVD mortality. Thus, this study indicates that the effect of the MetS on these endpoints is primarily driven by the inclusion in the NCEP definition of diabetes, itself a well-established, potent CVD risk factor. In fact, the prevalence of diabetes in SAHS patients with CVD and the MetS was 42% compared with only 9% in patients with CVD, but without the MetS. This excess prevalence of diabetes appears to account for the enhanced all-cause and CVD mortality in subjects with the MetS. However, these results will need to be confirmed in other populations.

Lower hypertension risk in Mexico City than in San Antonio.

BACKGROUND: We examined the effects of blood pressure (BP), weight, and weight gain on hypertension risk in two similar ethnic origin populations, subjects in Mexico City and Mexican Americans in San Antonio. METHODS: The Mexico City Diabetes Study and San Antonio Heart Study are population-based, epidemiologic studies with identical survey protocols. Incident hypertension (BP > or = 140/90 mm Hg or current antihypertensive treatment) was analyzed in subjects aged 35 to 64 years of Mexican ethnicity living in low-income neighborhoods (n = 1467 in Mexico City, n = 628 in San Antonio). RESULTS: In Mexico City, 10.6% of men and 13.1% of women developed hypertension in a 6.5-year period; in San Antonio, 28.6% and 28.7% in a 7.5-year period, respectively. Poisson regression analysis demonstrated a greater hypertension risk in San Antonio for both men (risk ratio [RR] = 1.75, 95% confidence interval [CI]: 1.19-2.56) and women (RR = 1.40, 95% CI: 1.05-1.86). In a multiple linear regression analysis, systolic BP change was associated with weight gain in Mexico City (P < .001 in men and women) and San Antonio (P = .045 in men, and P = .027 in women) independently of age, BP, obesity, alcohol consumption, cigarette smoking, diabetes, and antihypertensive treatment. These covariates did not fully explain greater increments of systolic BP in San Antonio than in Mexico City (P < .001 in men and women). CONCLUSIONS: Hypertension risk is lower in Mexico City than in San Antonio. Systolic BP increases with weight gain, independently of other determinants of hypertension.

Elevated carotid artery intima-media thickness levels in individuals who subsequently develop type 2 diabetes.

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