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Background: There is growing interest in the hypertriglyceridemic waist (HTGW) phenotype, defined as high waist circumference (≥95 cm in males and ≥80 cm in females) combined with high serum triglyceride concentration (≥2.0 mmol/L in males and ≥1.5 mmol/L in females) as a marker of type 2 diabetes (T2D) and cardiovascular disease. However, the prevalence of this phenotype in high-risk populations, its association with T2D, and the genetic or epigenetic influences on HTGW are not well explored. Using data from large, extended families of Mexican Americans (a high-risk minority population in the USA) we aimed to: (1) estimate the prevalence of this phenotype, (2) test its association with T2D and related traits, and (3) dissect out the genetic and epigenetic associations with this phenotype using genome-wide and epigenome-wide studies, respectively., Results: Data for this study was from 850 Mexican American participants (representing 39 families) recruited under the ongoing San Antonio Family Heart Study, 26 % of these individuals had HTGW. This phenotype was significantly heritable (h (2) r = 0.52, p = 1.1 × 10(-5)) and independently associated with T2D as well as fasting glucose levels and insulin resistance. We conducted genome-wide association analyses using 759,809 single nucleotide polymorphisms (SNPs) and epigenome-wide association analyses using 457,331 CpG sites. There was no evidence of any SNP associated with HTGW at the genome-wide level but two CpG sites (cg00574958 and cg17058475) in CPT1A and one CpG site (cg06500161) in ABCG1 were significantly associated with HTGW and remained significant after adjusting for the closely related components of metabolic syndrome. CPT1A holds a cardinal position in the metabolism of long-chain fatty acids while ABCG1 plays a role in triglyceride metabolism., Conclusions: Our results reemphasize the value of HTGW as a marker of T2D. This phenotype shows association with DNA methylation within CPT1A and ABCG1, genes involved in fatty acid and triglyceride metabolism. Our results underscore the importance of epigenetics in a clinically informative phenotype.

Background: Mexican Americans are at an increased risk of both thyroid dysfunction and metabolic syndrome (MS). Thus it is conceivable that some components of the MS may be associated with the risk of thyroid dysfunction in these individuals. Our objective was to investigate and replicate the potential association of MS traits with thyroid dysfunction in Mexican Americans., Methods: We conducted association testing for 18 MS traits in two large studies on Mexican Americans - the San Antonio Family Heart Study (SAFHS) and the National Health and Nutrition Examination Survey (NHANES) 2007-10. A total of 907 participants from 42 families in SAFHS and 1633 unrelated participants from NHANES 2007-10 were included in this study. The outcome measures were prevalence of clinical and subclinical hypothyroidism and thyroid function index (TFI) - a measure of thyroid function. For the SAFHS, we used polygenic regression analyses with multiple covariates to test associations in setting of family studies. For the NHANES 2007-10, we corrected for the survey design variables as needed for association analyses in survey data. In both datasets, we corrected for age, sex and their linear and quadratic interactions., Results: TFI was an accurate indicator of clinical thyroid status (area under the receiver-operating-characteristic curve to detect clinical hypothyroidism, 0.98) in both SAFHS and NHANES 2007-10. Of the 18 MS traits, waist circumference (WC) showed the most consistent association with TFI in both studies independently of age, sex and body mass index (BMI). In the SAFHS and NHANES 2007-10 datasets, each standard deviation increase in WC was associated with 0.13 (p < 0.001) and 0.11 (p < 0.001) unit increase in the TFI, respectively. In a series of polygenic and linear regression models, central obesity (defined as WC ≥ 102 cm in men and ≥88 cm in women) was associated with clinical and subclinical hypothyroidism independent of age, sex, BMI and type 2 diabetes in both datasets. Estimated prevalence of hypothyroidism was consistently high in those with central obesity, especially below 45y of age., Conclusions: WC independently associates with increased risk of thyroid dysfunction. Use of WC to identify Mexican American subjects at high risk of thyroid dysfunction should be investigated in future studies.

Objective: Waist circumference (WC), the clinical marker of central obesity, is gaining popularity as a screening tool for type 2 diabetes (T2D). While there is epidemiologic evidence favoring the WC-T2D association, its biological substantiation is generally weak. Our objective was to determine the independent association of plasma lipid repertoire with WC., Methods: Samples and data from the San Antonio Family Heart Study of 1208 Mexican Americans from 42 extended families were used. Association of plasma lipidomic profiles with the cross-sectionally assessed WC was determined. Plasma lipidomic profiling entailed liquid chromatography with mass spectrometry. Statistical analyses included multivariable polygenic regression models and bivariate trait analyses using the SOLAR software., Results: After adjusting for age and sex interactions, body mass index, homeostasis model of assessment-insulin resistance, total cholesterol, triglycerides, high density lipoproteins and use of lipid lowering drugs, dihydroceramides as a class were associated with WC. Dihydroceramide species 18:0, 20:0, 22:0, and 24:1 were significantly associated and genetically correlated with WC. Two sphingomyelin species (31:1 and 41:1) were also associated with WC., Conclusions: Plasma dihydroceramide levels independently associate with WC. Thus, high resolution plasma lipidomic studies can provide further credence to the biological underpinnings of the association of WC with T2D., (Copyright © 2013 The Obesity Society.)

Objective: In spite of the growing recognition of the specific association of waist circumference (WC) with type 2 diabetes (T2D) and insulin resistance (IR), current guidelines still use body mass index (BMI) as a tool of choice. Our objective was to determine whether WC is a better T2D predictor than BMI in family-based settings., Research Design and Methods: Using prospectively collected data on 808 individuals from 42 extended Mexican American families representing 7617.92 person-years follow-up, we examined the performance of WC and BMI as predictors of cumulative and incident risk of T2D. We used robust statistical methods that accounted for the kinships and included polygenic models, discrete trait modeling, Akaike information criterion, odds ratio (OR), relative risk (RR) and Kullback-Leibler R(2). SOLAR software was used to conduct all the data analyses., Results: We found that in multivariate polygenic models, WC was an independent predictor of cumulative (OR = 2.76, p = 0.0002) and future risk of T2D (RR = 2.15, p = 3.56×10(-9)) and outperformed BMI when compared in a head-to-head fashion. High WC (≥94.65 cm after adjusting for age and sex) was also associated with high fasting glucose, insulin and triglyceride levels and low high-density lipoprotein levels indicating a potential association with IR. Moreover, WC was specifically and significantly associated with insulin resistant T2D (OR = 4.83, p = 1.01×10(-13))., Conclusions: Our results demonstrate the value of using WC as a screening tool of choice for future risk of T2D in Mexican American families. Also, WC is specifically associated with insulin resistant T2D.

Background: Ethnically endogamous populations can shed light on the genetics of type 2 diabetes. Such studies are lacking in India. We conducted this study to determine the genetic and environmental contributions of anthropometric traits to type 2 diabetes risk in the Sindhi families in central India. Methods: We conducted a family study in Indian Sindhi families with at least one case of type 2 diabetes. Variance components methods were used to quantify the genetic association of 18 anthropometric traits with eight type 2 diabetes related traits. Univariate and bivariate polygenic models were used to determine the heritability, genetic and environmental correlation of anthropometric traits with type 2 diabetes related traits. Results: We included 1,152 individuals from 112 phenotyped families. The ascertainment-bias corrected prevalence of type 2 diabetes was 35%. Waist circumference, hip circumference and the biceps, triceps, subscapular and medial calf skinfold thicknesses were polygenically and significantly associated with type 2 diabetes. The range of heritability of the anthropometric traits and type 2 diabetes related traits was 0.27–0.73 and 0.00–0.39, respectively. Heritability of type 2 diabetes as a discrete trait was 0.35. Heritability curves demonstrated a substantial local influence of type 2 diabetes related traits. Bivariate trait analyses showed that biceps and abdominal skinfold thickness and all waist-containing indexes were strongly genetically correlated with type 2 diabetes. Conclusions: In this first study of Sindhi families, we found evidence for genetic and environmental concordance of anthropometric traits with type 2 diabetes. Future studies need to probe into the genetics of type 2 diabetes in this population. [ABSTRACT FROM AUTHOR]

Background: In spite of several available anthropometric indexes, the relative merit of these indexes for the prediction of type 2 diabetes remains unknown. Considering that obesity and diabetes commonly coexist as co-morbidities, our objective was to directly compare the performance of measures of central and general obesity to predict the risk of type 2 diabetes. Methods: We conducted a case-control study of type 2 diabetes on 150 cases and 150 age- and gender-matched controls. We directly compared the predictive performance of five anthropometric indexes: four related to central obesity—waist circumference (WC), waist/hip ratio (WHR), abdominal volume index (AVI) and conicity index (CI); and one related to general obesity—body mass index (BMI). We used various statistical approaches like area under (AUC) receiver-operating characteristic (ROC) curves, likelihood ratios, logistic regression and Shannon''s entropy to compare the performance of the indexes in the study sample as well as bootstrapped samples. Results: WC had the highest overall predictive accuracy that was gender insensitive (AUC=0.77 in males and 0.74 in females); a comparable information content as that of AVI (Shannon''s entropy=1.81 for WC and 1.84 for AVI) and was a better predictor of the risk of type 2 diabetes than all the remaining indexes. WC also correlated strongly with the biochemical markers of diabetes like blood sugar and lipid profile. Conclusions: WC is a simple, non-invasive and accurate predictor of the risk of type 2 diabetes that can potentially be used in screening programs in developing countries. [Copyright &y& Elsevier]