Association of HIV-1 Infection and Antiretroviral Therapy With Type 2 Diabetes in the Hispanic Population of the Rio Grande Valley, Texas, USA.

The Rio Grande Valley (RGV) in South Texas has one of the highest prevalence of obesity and type 2 diabetes (T2D) in the United States (US). We report for the first time the T2D prevalence in persons with HIV (PWH) in the RGV and the interrelationship between T2D, cardiometabolic risk factors, HIV-related indices, and antiretroviral therapies (ART). The PWH in this study received medical care at Valley AIDS Council (VAC) clinic sites located in Harlingen and McAllen, Texas. Henceforth, this cohort will be referred to as Valley AIDS Council Cohort (VACC). Cross-sectional analyses were conducted using retrospective data obtained from 1,827 registries. It included demographic and anthropometric variables, cardiometabolic traits, and HIV-related virological and immunological indices. For descriptive statistics, we used mean values of the quantitative variables from unbalanced visits across 20 months. Robust regression methods were used to determine the associations. For comparisons, we used cardiometabolic trait data obtained from HIV-uninfected San Antonio Mexican American Family Studies (SAMAFS; N = 2,498), and the Mexican American population in the National Health and Nutrition Examination Survey (HHANES; N = 5,989). The prevalence of T2D in VACC was 51% compared to 27% in SAMAFS and 19% in HHANES, respectively. The PWH with T2D in VACC were younger (4.7 years) and had lower BMI (BMI 2.43 units less) when compared to SAMAFS individuals. In contrast, VACC individuals had increased blood pressure and dyslipidemia. The increased T2D prevalence in VACC was independent of BMI. Within the VACC, ART was associated with viral load and CD4+ T cell counts but not with metabolic dysfunction. Notably, we found that individuals with any INSTI combination had higher T2D risk: OR 2.08 (95%CI 1.67, 2.6; p < 0.001). In summary, our results suggest that VACC individuals may develop T2D at younger ages independent of obesity. The high burden of T2D in these individuals necessitates rigorously designed longitudinal studies to draw potential causal inferences and develop better treatment regimens.

Serum carotenoids and Pediatric Metabolic Index predict insulin sensitivity in Mexican American children.

High concentrations of carotenoids are protective against cardiometabolic risk traits (CMTs) in adults and children. We recently showed in non-diabetic Mexican American (MA) children that serum α-carotene and ß-carotene are inversely correlated with obesity measures and triglycerides and positively with HDL cholesterol and that they were under strong genetic influences. Additionally, we previously described a Pediatric Metabolic Index (PMI) that helps in the identification of children who are at risk for cardiometabolic diseases. Here, we quantified serum lycopene and ß-cryptoxanthin concentrations in approximately 580 children from MA families using an ultraperformance liquid chromatography-photodiode array and determined their heritabilities and correlations with CMTs. Using response surface methodology (RSM), we determined two-way interactions of carotenoids and PMI on Matsuda insulin sensitivity index (ISI). The concentrations of lycopene and ß-cryptoxanthin were highly heritable [h2 = 0.98, P = 7 × 10-18 and h2 = 0.58, P = 1 × 10-7]. We found significant (P ≤ 0.05) negative phenotypic correlations between ß-cryptoxanthin and five CMTs: body mass index (- 0.22), waist circumference (- 0.25), triglycerides (- 0.18), fat mass (- 0.23), fasting glucose (- 0.09), and positive correlations with HDL cholesterol (0.29). In contrast, lycopene only showed a significant negative correlation with fasting glucose (- 0.08) and a positive correlation with HDL cholesterol (0.18). Importantly, we found that common genetic influences significantly contributed to the observed phenotypic correlations. RSM showed that increased serum concentrations of α- and ß-carotenoids rather than that of ß-cryptoxanthin or lycopene had maximal effects on ISI. In summary, our findings suggest that the serum carotenoids are under strong additive genetic influences and may have differential effects on susceptibility to CMTs in children.

Further evidence supporting a potential role for ADH1B in obesity.

Insulin is an essential hormone that regulates glucose homeostasis and metabolism. Insulin resistance (IR) arises when tissues fail to respond to insulin, and it leads to serious health problems including Type 2 Diabetes (T2D). Obesity is a major contributor to the development of IR and T2D. We previously showed that gene expression of alcohol dehydrogenase 1B (ADH1B) was inversely correlated with obesity and IR in subcutaneous adipose tissue of Mexican Americans. In the current study, a meta-analysis of the relationship between ADH1B expression and BMI in Mexican Americans, African Americans, Europeans, and Pima Indians verified that BMI was increased with decreased ADH1B expression. Using established human subcutaneous pre-adipocyte cell lines derived from lean (BMI < 30 kg m-2) or obese (BMI ≥ 30 kg m-2) donors, we found that ADH1B protein expression increased substantially during differentiation, and overexpression of ADH1B inhibited fatty acid binding protein expression. Mature adipocytes from lean donors expressed ADH1B at higher levels than obese donors. Insulin further induced ADH1B protein expression as well as enzyme activity. Knockdown of ADH1B expression decreased insulin-stimulated glucose uptake. Our findings suggest that ADH1B is involved in the proper development and metabolic activity of adipose tissues and this function is suppressed by obesity.

Acanthosis nigricans as a composite marker of cardiometabolic risk and its complex association with obesity and insulin resistance in Mexican American children.

AIM: Acanthosis nigricans (AN) is a strong correlate of obesity and is considered a marker of insulin resistance (IR). AN is associated with various other cardiometabolic risk factors (CMRFs). However, the direct causal relationship of IR with AN in obesity has been debated. Therefore, we aimed to examine the complex causal relationships among the troika of AN, obesity, and IR in Mexican Americans (MAs). METHODS: We used data from 670 non-diabetic MA children, aged 6-17 years (49% girls). AN (prevalence 33%) severity scores (range 0-5) were used as a quasi-quantitative trait (AN-q) for analysis. We used the program SOLAR for determining phenotypic, genetic, and environmental correlations between AN-q and CMRFs (e.g., BMI, HOMA-IR, lipids, blood pressure, hs-C-reactive protein (CRP), and Harvard physical fitness score (PFS)). The genetic and environmental correlations were subsequently used in mediation analysis (AMOS program). Model comparisons were made using goodness-of-fit indexes. RESULTS: Heritability of AN-q was 0.75 (p<0.0001). It was positively/significantly (p<0.05) correlated with traits such as BMI, HOMA-IR, and CRP, and negatively with HDL-C and PFS. Of the models tested, indirect mediation analysis of BMI→HOMA-IR→AN-q yielded lower goodness-of-fit than a partial mediation model where BMI explained the relationship with both HOMA-IR and AN-q simultaneously. Using complex models, BMI was associated with AN-q and IR mediating most of the CMRFs; but no relationship between IR and AN-q. CONCLUSION: Our study suggests that obesity explains the association of IR with AN, but no causal relationship between IR and AN in Mexican American children.

Data on genetic associations of carotid atherosclerosis markers in Mexican American and European American rheumatoid arthritis subjects.

Carotid Intima-media thickness (CIMT) and plaque are well established markers of subclinical atherosclerosis and are widely used for identifying subclinical atherosclerotic disease. We performed association analyses using Metabochip array to identify genetic variants that influence variation in CIMT and plaque, measured using B-mode ultrasonography, in rheumatoid arthritis (RA) patients. Data on genetic associations of common variants associated with both CIMT and plaque in RA subjects involving Mexican Americans (MA) and European Americans (EA) populations are presented in this article. Strong associations were observed after adjusting for covariate effects including baseline clinical characteristics and statin use. Susceptibility loci and genes and/or nearest genes associated with CIMT in MAs and EAs with RA are presented. In addition, common susceptibility loci influencing CIMT and plaque in both MAs and EAs have been presented. Polygenic Risk Score (PRS) plots showing complementary evidence for the observed CIMT and plaque association signals are also shown in this article. For further interpretation and details, please see the research article titled "A Genetic Association Study of Carotid Intima-Media Thickness (CIMT) and Plaque in Mexican Americans and European Americans with Rheumatoid Arthritis" which is being published in Atherosclerosis (Arya et al., 2018) [1].(Arya et al., in press) Thus, common variants in several genes exhibited significant associations with CIMT and plaque in both MAs and EAs as presented in this article. These findings may help understand the genetic architecture of subclinical atherosclerosis in RA populations.

A genetic association study of carotid intima-media thickness (CIMT) and plaque in Mexican Americans and European Americans with rheumatoid arthritis.

BACKGROUND AND AIMS: Little is known about specific genetic determinants of carotid-intima-media thickness (CIMT) and carotid plaque in subjects with rheumatoid arthritis (RA). We have used the Metabochip array to fine map and replicate loci that influence variation in these phenotypes in Mexican Americans (MAs) and European Americans (EAs). METHODS: CIMT and plaque were measured using ultrasound from 700 MA and 415 EA patients with RA and we conducted association analyses with the Metabochip single nucleotide polymorphism (SNP) data using PLINK. RESULTS: In MAs, 12 SNPs from 11 chromosomes and 6 SNPs from 6 chromosomes showed suggestive associations (p < 1 × 10-4) with CIMT and plaque, respectively. The strongest association was observed between CIMT and rs17526722 (SLC17A2 gene) (ß ± SE = -0.84 ± 0.18, p = 3.80 × 10-6). In EAs, 9 SNPs from 7 chromosomes and 7 SNPs from 7 chromosomes showed suggestive associations with CIMT and plaque, respectively. The top association for CIMT was observed with rs1867148 (PPCDC gene, ß ± SE = -0.28 ± 0.06, p = 5.11 × 10-6). We also observed strong association between plaque and two novel loci: rs496916 from COL4A1 gene (OR = 0.51, p = 3.15 × 10-6) in MAs and rs515291 from SLCA13 gene (OR = 0.50, p = 3.09 × 10-5) in EAs. CONCLUSIONS: We identified novel associations between CIMT and variants in SLC17A2 and PPCDC genes, and between plaque and variants from COL4A1 and SLCA13 that may pinpoint new candidate risk loci for subclinical atherosclerosis associated with RA.

Genetic and environmental (physical fitness and sedentary activity) interaction effects on cardiometabolic risk factors in Mexican American children and adolescents.

Knowledge on genetic and environmental (G × E) interaction effects on cardiometabolic risk factors (CMRFs) in children is limited.  The purpose of this study was to examine the impact of G × E interaction effects on CMRFs in Mexican American (MA) children (n = 617, ages 6-17 years). The environments examined were sedentary activity (SA), assessed by recalls from "yesterday" (SAy) and "usually" (SAu) and physical fitness (PF) assessed by Harvard PF scores (HPFS). CMRF data included body mass index (BMI), waist circumference (WC), fat mass (FM), fasting insulin (FI), homeostasis model of assessment-insulin resistance (HOMA-IR), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), systolic (SBP) and diastolic (DBP) blood pressure, and number of metabolic syndrome components (MSC). We examined potential G × E interaction in the phenotypic expression of CMRFs using variance component models and likelihood-based statistical inference. Significant G × SA interactions were identified for six CMRFs: BMI, WC, FI, HOMA-IR, MSC, and HDL, and significant G × HPFS interactions were observed for four CMRFs: BMI, WC, FM, and HOMA-IR. However, after correcting for multiple hypothesis testing, only WC × SAy, FM × SAy, and FI × SAu interactions became marginally significant. After correcting for multiple testing, most of CMRFs exhibited significant G × E interactions (Reduced G × E model vs. Constrained model). These findings provide evidence that genetic factors interact with SA and PF to influence variation in CMRFs, and underscore the need for better understanding of these relationships to develop strategies and interventions to effectively reduce or prevent cardiometabolic risk in children.

The Diabetes Gene and Wnt Pathway Effector TCF7L2 Regulates Adipocyte Development and Function.

The gene encoding for transcription factor 7-like 2 (TCF7L2) is the strongest type 2 diabetes mellitus (T2DM) candidate gene discovered to date. The TCF7L2 protein is a key transcriptional effector of the Wnt/ß-catenin signaling pathway, which is an important developmental pathway that negatively regulates adipogenesis. However, the precise role that TCF7L2 plays in the development and function of adipocytes remains largely unknown. Using a combination of in vitro approaches, we first show that TCF7L2 protein is increased during adipogenesis in 3T3-L1 cells and primary adipocyte stem cells and that TCF7L2 expression is required for the regulation of Wnt signaling during adipogenesis. Inactivation of TCF7L2 protein by removing the high-mobility group (HMG)-box DNA binding domain in mature adipocytes in vivo leads to whole-body glucose intolerance and hepatic insulin resistance. This phenotype is associated with increased subcutaneous adipose tissue mass, adipocyte hypertrophy, and inflammation. Finally, we demonstrate that TCF7L2 mRNA expression is downregulated in humans with impaired glucose tolerance and adipocyte insulin resistance, highlighting the translational potential of these findings. In summary, our data indicate that TCF7L2 has key roles in adipose tissue development and function that may reveal, at least in part, how TCF7L2 contributes to the pathophysiology of T2DM.

Genetics of serum carotenoid concentrations and their correlation with obesity-related traits in Mexican American children.

Background: Dietary intake of phytonutrients present in fruits and vegetables, such as carotenoids, is associated with a lower risk of obesity and related traits, but the impact of genetic variation on these associations is poorly understood, especially in children.Objective: We estimated common genetic influences on serum carotenoid concentrations and obesity-related traits in Mexican American (MA) children.Design: Obesity-related data were obtained from 670 nondiabetic MA children, aged 6-17 y. Serum α- and ß-carotenoid concentrations were measured in ∼570 (α-carotene in 565 and ß-carotene in 572) of these children with the use of an ultraperformance liquid chromatography-photodiode array. We determined heritabilities for both carotenoids and examined their genetic relation with 10 obesity-related traits [body mass index (BMI), waist circumference (WC), high-density lipoprotein (HDL) cholesterol, triglycerides, fat mass (FM), systolic and diastolic blood pressure, fasting insulin and glucose, and homeostasis model assessment of insulin resistance] by using family data and a variance components approach. For these analyses, carotenoid values were inverse normalized, and all traits were adjusted for significant covariate effects of age and sex.Results: Carotenoid concentrations were highly heritable and significant [α-carotene: heritability (h2) = 0.81, P = 6.7 × 10-11; ß-carotene: h2 = 0.90, P = 3.5 × 10-15]. After adjusting for multiple comparisons, we found significant (P ≤ 0.05) negative phenotypic correlations between carotenoid concentrations and the following traits: BMI, WC, FM, and triglycerides (range: α-carotene = -0.19 to -0.12; ß-carotene = -0.24 to -0.13) and positive correlations with HDL cholesterol (α-carotene = 0.17; ß-carotene = 0.24). However, when the phenotypic correlations were partitioned into genetic and environmental correlations, we found marginally significant (P = 0.051) genetic correlations only between ß-carotene and BMI (-0.27), WC (-0.30), and HDL cholesterol (0.31) after accounting for multiple comparisons. None of the environmental correlations were significant.Conclusions: The findings from this study suggest that the serum carotenoid concentrations were under strong additive genetic influences based on variance components analyses, and that the common genetic factors may influence ß-carotene and obesity and lipid traits in MA children.

Sympathetic nervous system activity and anti-lipolytic response to iv-glucose load in subcutaneous adipose tissue of obese and obese type 2 diabetic subjects.

The study aim was to investigate the effect of endogenous insulin release on lipolysis in subcutaneous adipose tissue after adrenergic stimulation in obese subjects diagnosed with type 2 diabetes (T2D). In 14 obese female T2D subjects, or 14 obese non-T2D controls, glycerol concentration was measured in response to the α1,2,ß-agonist norepinephrine, the α1-agonist norfenefrine and the ß2-agonist terbutaline (each 10-4 M), using the microdialysis technique. After 60 minutes of stimulation, an intravenous glucose load (0.5 g/kg lean body mass) was given. Local blood flow was monitored by means of the ethanol technique. Norepinephrine and norfenefrine induced a four and three fold rise in glycerol dialysate concentration (p<0.001, each), with a similar pattern in adipose tissue. Following agonist stimulation and glucose infusion, endogenous insulin release inhibited lipolysis in the presence of norepinephrine, which was more rapid and pronounced in healthy obese controls than in T2D subjects (p = 0.024 obese vs T2D subjects). Insulin-induced inhibition of lipolysis in the presence of norfenefrine was similar in all study participants. In the presence of terbutaline the lipolysis rate increased two fold until the effect of endogenous insulin (p<0.001). A similar insulin-induced decrease in lipolysis was observed for each of the norfenefrine groups and the terbutaline groups, respectively. Adipose tissue blood flow remained unchanged after the iv-glucose load. Both norepinephrine and norfenefrine diminished blood flow slightly, but insulin reversed this response (p<0.001 over the entire time). Terbutaline alone and terbutaline plus increased endogenous insulin augmented local blood flow (p<0.001 over the entire time). In conclusion, a difference in insulin-induced inhibition of lipolysis was observed in obese T2D subjects compared to obese healthy controls following modulation of sympathetic nervous system activity and is assumed to be due to ß1-adrenoceptor mediated stimulation by norepinephrine.

Omics-squared: human genomic, transcriptomic and phenotypic data for genetic analysis workshop 19.

BACKGROUND: The Genetic Analysis Workshops (GAW) are a forum for development, testing, and comparison of statistical genetic methods and software. Each contribution to the workshop includes an application to a specified data set. Here we describe the data distributed for GAW19, which focused on analysis of human genomic and transcriptomic data. METHODS: GAW19 data were donated by the T2D-GENES Consortium and the San Antonio Family Heart Study and included whole genome and exome sequences for odd-numbered autosomes, measures of gene expression, systolic and diastolic blood pressures, and related covariates in two Mexican American samples. These two samples were a collection of 20 large families with whole genome sequence and transcriptomic data and a set of 1943 unrelated individuals with exome sequence. For each sample, simulated phenotypes were constructed based on the real sequence data. 'Functional' genes and variants for the simulations were chosen based on observed correlations between gene expression and blood pressure. The simulations focused primarily on additive genetic models but also included a genotype-by-medication interaction. A total of 245 genes were designated as 'functional' in the simulations with a few genes of large effect and most genes explaining < 1 % of the trait variation. An additional phenotype, Q1, was simulated to be correlated among related individuals, based on theoretical or empirical kinship matrices, but was not associated with any sequence variants. Two hundred replicates of the phenotypes were simulated. The GAW19 data are an expansion of the data used at GAW18, which included the family-based whole genome sequence, blood pressure, and simulated phenotypes, but not the gene expression data or the set of 1943 unrelated individuals with exome sequence.

Transcriptomics in type 2 diabetes: Bridging the gap between genotype and phenotype.

Type 2 diabetes (T2D) is a common, multifactorial disease that is influenced by genetic and environmental factors and their interactions. However, common variants identified by genome wide association studies (GWAS) explain only about 10% of the total trait variance for T2D and less than 5% of the variance for obesity, indicating that a large proportion of heritability is still unexplained. The transcriptomic approach described here uses quantitative gene expression and disease-related physiological data (deep phenotyping) to measure the direct correlation between the expression of specific genes and physiological traits. Transcriptomic analysis bridges the gulf between GWAS and physiological studies. Recent GWAS studies have utilized very large population samples, numbering in the tens of thousands (or even hundreds of thousands) of individuals, yet establishing causal functional relationships between strongly associated genetic variants and disease remains elusive. In light of the findings described below, it is appropriate to consider how and why transcriptomic approaches in small samples might be capable of identifying complex disease-related genes which are not apparent using GWAS in large samples.

Genetic Variants Influencing Joint Damage in Mexican Americans and European Americans With Rheumatoid Arthritis.

Joint destruction in rheumatoid arthritis (RA) is heritable, but knowledge on specific genetic determinants of joint damage in RA is limited. We have used the Immunochip array to examine whether genetic variants influence variation in joint damage in a cohort of Mexican Americans (MA) and European Americans (EA) with RA. We studied 720 MA and 424 EA patients with RA. Joint damage was quantified using a radiograph of both hands and wrists, scored using Sharp's technique. We conducted association analyses with the transformed Sharp score and the Immunochip single nucleotide polymorphism (SNP) data using PLINK. In MAs, 15 SNPs from chromosomes 1, 5, 9, 17 and 22 associated with joint damage yielded strong p-values (p < 1 × 10(-4) ). The strongest association with joint damage was observed with rs7216796, an intronic SNP located in the MAP3K14 gene, on chromosome 17 (ß ± SE = -0.25 ± 0.05, p = 6.23 × 10(-6) ). In EAs, 28 SNPs from chromosomes 1, 4, 6, 9, and 21 showed associations with joint damage (p-value < 1 × 10(-4) ). The best association was observed on chromosome 9 with rs59902911 (ß ± SE = 0.86 ± 0.17, p = 1.01 × 10(-6) ), a synonymous SNP within the CARD9 gene. We also observed suggestive evidence for some loci influencing joint damage in MAs and EAs. We identified two novel independent loci (MAP3K14 and CARD9) strongly associated with joint damage in MAs and EAs and a few shared loci showing suggestive evidence for association.

Transcriptomic identification of ADH1B as a novel candidate gene for obesity and insulin resistance in human adipose tissue in Mexican Americans from the Veterans Administration Genetic Epidemiology Study (VAGES).

Type 2 diabetes (T2D) is a complex metabolic disease that is more prevalent in ethnic groups such as Mexican Americans, and is strongly associated with the risk factors obesity and insulin resistance. The goal of this study was to perform whole genome gene expression profiling in adipose tissue to detect common patterns of gene regulation associated with obesity and insulin resistance. We used phenotypic and genotypic data from 308 Mexican American participants from the Veterans Administration Genetic Epidemiology Study (VAGES). Basal fasting RNA was extracted from adipose tissue biopsies from a subset of 75 unrelated individuals, and gene expression data generated on the Illumina BeadArray platform. The number of gene probes with significant expression above baseline was approximately 31,000. We performed multiple regression analysis of all probes with 15 metabolic traits. Adipose tissue had 3,012 genes significantly associated with the traits of interest (false discovery rate, FDR ≤ 0.05). The significance of gene expression changes was used to select 52 genes with significant (FDR ≤ 10(-4)) gene expression changes across multiple traits. Gene sets/Pathways analysis identified one gene, alcohol dehydrogenase 1B (ADH1B) that was significantly enriched (P < 10(-60)) as a prime candidate for involvement in multiple relevant metabolic pathways. Illumina BeadChip derived ADH1B expression data was consistent with quantitative real time PCR data. We observed significant inverse correlations with waist circumference (2.8 x 10(-9)), BMI (5.4 x 10(-6)), and fasting plasma insulin (P < 0.001). These findings are consistent with a central role for ADH1B in obesity and insulin resistance and provide evidence for a novel genetic regulatory mechanism for human metabolic diseases related to these traits.

Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population.

IMPORTANCE: Latino populations have one of the highest prevalences of type 2 diabetes worldwide. OBJECTIVES: To investigate the association between rare protein-coding genetic variants and prevalence of type 2 diabetes in a large Latino population and to explore potential molecular and physiological mechanisms for the observed relationships. DESIGN, SETTING, AND PARTICIPANTS: Whole-exome sequencing was performed on DNA samples from 3756 Mexican and US Latino individuals (1794 with type 2 diabetes and 1962 without diabetes) recruited from 1993 to 2013. One variant was further tested for allele frequency and association with type 2 diabetes in large multiethnic data sets of 14,276 participants and characterized in experimental assays. MAIN OUTCOME AND MEASURES: Prevalence of type 2 diabetes. Secondary outcomes included age of onset, body mass index, and effect on protein function. RESULTS: A single rare missense variant (c.1522G>A [p.E508K]) was associated with type 2 diabetes prevalence (odds ratio [OR], 5.48; 95% CI, 2.83-10.61; P = 4.4 × 10(-7)) in hepatocyte nuclear factor 1-α (HNF1A), the gene responsible for maturity onset diabetes of the young type 3 (MODY3). This variant was observed in 0.36% of participants without type 2 diabetes and 2.1% of participants with it. In multiethnic replication data sets, the p.E508K variant was seen only in Latino patients (n = 1443 with type 2 diabetes and 1673 without it) and was associated with type 2 diabetes (OR, 4.16; 95% CI, 1.75-9.92; P = .0013). In experimental assays, HNF-1A protein encoding the p.E508K mutant demonstrated reduced transactivation activity of its target promoter compared with a wild-type protein. In our data, carriers and noncarriers of the p.E508K mutation with type 2 diabetes had no significant differences in compared clinical characteristics, including age at onset. The mean (SD) age for carriers was 45.3 years (11.2) vs 47.5 years (11.5) for noncarriers (P = .49) and the mean (SD) BMI for carriers was 28.2 (5.5) vs 29.3 (5.3) for noncarriers (P = .19). CONCLUSIONS AND RELEVANCE: Using whole-exome sequencing, we identified a single low-frequency variant in the MODY3-causing gene HNF1A that is associated with type 2 diabetes in Latino populations and may affect protein function. This finding may have implications for screening and therapeutic modification in this population, but additional studies are required.

Strong association between insulin-mediated glucose uptake and the 2-hour, not the fasting plasma glucose concentration, in the normal glucose tolerance range.

AIM: The aim of this study was to examine the relationship between whole-body insulin-mediated glucose disposal and the fasting plasma glucose concentration in nondiabetic individuals. RESEARCH DESIGN AND METHODS: Two hundred fifty-three nondiabetic subjects with normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance, and combined glucose intolerance received a 75-g oral glucose tolerance test and euglycemic hyperinsulinemic clamp. Total glucose disposal (TGD) during the insulin clamp was compared in IFG and NGT individuals and was related to fasting and 2-hour plasma glucose concentrations in each group. RESULTS: TGD varied considerably between NGT and IFG individuals and displayed a strong inverse relationship with the 2-hour plasma glucose (PG; r = 0.40, P < .0001) but not with the fasting PG. When IFG and NGT individuals were stratified based on their 2-hour PG concentration, the increase in 2-hour PG was associated with a progressive decrease in TGD in both groups, and the TGD was comparable among NGT and IFG individuals. CONCLUSION: The present results indicate the following: 1) as in NGT, insulin-stimulated TGD varies considerably in IFG individuals; 2) the large variability in TGD in IFG and NGT individuals is related to the 2-hour PG concentration; and 3) after adjustment for the 2-hour proglucagon concentration, IFG subjects have comparable TGD with NGT individuals.

Linkage of type 2 diabetes on chromosome 9p24 in Mexican Americans: additional evidence from the Veterans Administration Genetic Epidemiology Study (VAGES).

OBJECTIVE: Type 2 diabetes (T2DM) is a complex metabolic disease and is more prevalent in certain ethnic groups such as the Mexican Americans. The goal of our study was to perform a genome-wide linkage (GWL) analysis to localize T2DM susceptibility loci in Mexican Americans. METHODS: We used the phenotypic and genotypic data from 1,122 Mexican-American individuals (307 families) who participated in the Veterans Administration Genetic Epidemiology Study (VAGES). GWL analysis was performed using the variance components approach. Data from 2 additional Mexican-American family studies, the San Antonio Family Heart Study (SAFHS) and the San Antonio Family Diabetes/Gallbladder Study (SAFDGS), were combined with the VAGES data to test for improved linkage evidence. RESULTS: After adjusting for covariate effects, T2DM was found to be under significant genetic influences (h2 = 0.62, p = 2.7 × 10(-6)). The strongest evidence for linkage of T2DM occurred between markers D9S1871 and D9S2169 on chromosome 9p24.2-p24.1 (LOD = 1.8). Given that we previously reported suggestive evidence for linkage of T2DM at this region also in SAFDGS, we found the significant and increased linkage evidence (LOD = 4.3, empirical p = 1.0 × 10(-5), genome-wide p = 1.6 × 10(-3)) for T2DM at the same chromosomal region, when we performed a GWL analysis of the VAGES data combined with the SAFHS and SAFDGS data. CONCLUSION: Significant T2DM linkage evidence was found on chromosome 9p24 in Mexican Americans. Importantly, the chromosomal region of interest in this study overlaps with several recent genome-wide association studies involving T2DM-related traits. Given its overlap with such findings and our own initial T2DM association findings in the 9p24 chromosomal region, high throughput sequencing of the linked chromosomal region could identify the potential causal T2DM genes.

Genetic epidemiology of cardiometabolic risk factors and their clustering patterns in Mexican American children and adolescents: the SAFARI Study.

Pediatric metabolic syndrome (MS) and its cardiometabolic components (MSCs) have become increasingly prevalent, yet little is known about the genetics underlying MS risk in children. We examined the prevalence and genetics of MS-related traits among 670 non-diabetic Mexican American (MA) children and adolescents, aged 6-17 years (49 % female), who were participants in the San Antonio Family Assessment of Metabolic Risk Indicators in Youth study. These children are offspring or biological relatives of adult participants from three well-established Mexican American family studies in San Antonio, TX, at increased risk of type 2 diabetes. MS was defined as ≥3 abnormalities among 6 MSC measures: waist circumference, systolic and/or diastolic blood pressure, fasting insulin, triglycerides, HDL-cholesterol, and fasting and/or 2-h OGTT glucose. Genetic analyses of MS, number of MSCs (MSC-N), MS factors, and bivariate MS traits were performed. Overweight/obesity (53 %), pre-diabetes (13 %), acanthosis nigricans (33 %), and MS (19 %) were strikingly prevalent, as were MS components, including abdominal adiposity (32 %) and low HDL-cholesterol (32 %). Factor analysis of MS traits yielded three constructs: adipo-insulin-lipid, blood pressure, and glucose factors, and their factor scores were highly heritable. MS itself exhibited 68 % heritability. MSC-N showed strong positive genetic correlations with obesity, insulin resistance, inflammation, and acanthosis nigricans, and negative genetic correlation with physical fitness. MS trait pairs exhibited strong genetic and/or environmental correlations. These findings highlight the complex genetic architecture of MS/MSCs in MA children, and underscore the need for early screening and intervention to prevent chronic sequelae in this vulnerable pediatric population.

Metabolic syndrome is linked to chromosome 7q21 and associated with genetic variants in CD36 and GNAT3 in Mexican Americans.

The prevalence of metabolic syndrome (MS) has been rising alarmingly worldwide, including in the United States, but knowledge on specific genetic determinants of MS is very limited. Therefore, we planned to identify the genetic determinants of MS as defined by National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATPIII) criteria. We performed linkage screen for MS using data from 692 Mexican Americans, who participated in the San Antonio Family Diabetes/Gallbladder Study (SAFDGS). We found strong evidence for linkage of MS on chromosome 7q (LOD = 3.6, empirical P = 6.0 × 10(-5)), between markers D7S2212 and D7S821. In addition, six chromosomal regions exhibited potential evidence for linkage (LOD ≥1.2) with MS. Furthermore, we examined 29 single-nucleotide polymorphisms (SNPs) from the fatty acid translocase (FAT or CD36, 18 SNPs) gene and guanine nucleotide binding protein, α transducing 3 (GNAT3, 11 SNPs) gene, located within the 1-LOD support interval region for their association with MS and its related traits. Several SNPs were associated with MS and its related traits. Remarkably, rs11760281 in GNAT3 and rs1194197 near CD36 exhibited the strongest associations with MS (P = 0.0003, relative risk (RR) = 1.6 and P = 0.004, RR = 1.7, respectively) and several other related traits. These two variants explained ~18% of the MS linkage evidence on chromosome 7q21, and together conferred approximately threefold increase in MS risk (RR = 2.7). In conclusion, our linkage and subsequent association studies implicate a region on chromosome 7q21 to influence MS in Mexican Americans.

Genome-wide linkage screen for systolic blood pressure in the Veterans Administration Genetic Epidemiology Study (VAGES) of Mexican-Americans and confirmation of a major susceptibility locus on chromosome 6q14.1.

OBJECTIVE: Hypertension or high blood pressure is a strong correlate of diseases such as obesity and type 2 diabetes. We conducted a genome-wide linkage screen to identify susceptibility genes influencing systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Mexican-Americans from the Veterans Administration Genetic Epidemiology Study (VAGES). METHODS: Using data from 1,089 individuals distributed across 266 families, we performed a multipoint linkage analysis to localize susceptibility loci for SBP and DBP by applying two models. In model 1, we added a sensible constant to the observed BP values in treated subjects [Tobin et al.; Stat Med 2005;24:2911-2935] to account for antihypertensive use (i.e. 15 and 10 mm Hg to SBP and DBP values, respectively). In model 2, we fixed values of 140 mm Hg for SBP and 90 mm Hg for DBP, if the treated values were less than the standard referenced treatment thresholds of 140/ 90 mm Hg for hypertensive status. However, if the observed treated BP values were found to be above these standard treatment thresholds, the actual observed treated BP values were retained in order not to reduce them by substitution of the treatment threshold values. RESULTS: The multipoint linkage analysis revealed strong linkage signals for SBP compared with DBP. The strongest evidence for linkage of SBP (model 1, LOD = 5.0; model 2, LOD = 3.6) was found on chromosome 6q14.1 near the marker D6S1031 (89 cM) in both models. In addition, some evidence for SBP linkage occurred on chromosomes 1q, 4p, and 16p. Most importantly, our major SBP linkage finding on chromosome 6q near marker D6S1031 was independently confirmed in a Caucasian population (LOD = 3.3). In summary, our study found evidence for a major locus on chromosome 6q influencing SBP levels in Mexican-Americans.