María Eugenia Garay-Sevilla

Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 10 -3 ) and candidate genes from knockout mice (P = 5.2 10 -3 ). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.

OBJECTIVE: To examine the association between thyroid function and the components of the metabolic syndrome and insulin resistance in an Hispanic population. DESIGN: Cross-sectional study. METHODS: Subjects with no history of thyroid disease or diabetes were included. Thyroid function was stratified as euthyroid or subclinical hypothyroidism (SCH) status and subsequently by free thyroxine (FT(4)) and TSH tertiles. The association of the metabolic syndrome components (defined by 2004 Adult Treatment Panel III criteria) and insulin resistance with thyroid status, TSH, and FT(4) were examined. RESULTS: A total of 3148 subjects were analyzed. The prevalence of SCH was 8.3%. The prevalence of the metabolic syndrome was similar in euthyroid and SCH patients (31.6 vs 32.06%, P=0.89). Total cholesterol was higher in patients with SCH (5.51+/-1.19 vs 5.34+/-1.05 mmol/l, P<0.032). Serum TSH values showed a positive correlation (adjusted for age and sex) with total cholesterol, triglycerides, and waist circumference. In contrast, FT(4) showed a positive correlation with high-density lipoprotein cholesterol, and an inverse correlation with waist circumference, insulin, and HOMA-IR. CONCLUSION: SCH is not associated with an increased risk for the metabolic syndrome (as conceived as a diagnostic category defined by the National Cholesterol, Education Program, Adult Treatment Panel III criteria). Despite this, low thyroid function (even in the euthyroid state) predisposes to higher cholesterol, glucose, insulin, and HOMA-IR levels. The combined use of TSH and FT(4), compared with the assessment based on only FT(4), is a more convenient approach to evaluate the association between thyroid function and metabolic variables.

OBJECTIVE: Several cutoff points of the homeostasis model assessment of insulin resistance (HOMA-IR; varying from 2.5 to 4.0) have been suggested for diagnosing IR in youth. In this study, we determined the distribution of the HOMA-IR in Mexican children and adolescents. DESIGN AND METHODS: A total of 6132 children and adolescents from San Luis Potosi, León, Queretaro, and Durango, which are cities in central and northern Mexico, were enrolled in a population-based cross-sectional study. Eligible participants were apparently healthy children and adolescents aged 6-18 years. Pregnancy and the presence of chronic illnesses were exclusion criteria. RESULTS: A total of 3701 (60.3%) girls and 2431 (39.7%) boys were included in this study. In the overall population, the mean body mass index, insulin levels, and fasting glucose levels were 21.8±1.3 kg/m(2), 7.1±3.2 μU/ml, and 86.2±10.0 mg/dl respectively. The concentrations of insulin and fasting glucose gradually increased from 6 to 12 years of age, whereas the concentrations tended to plateau in the 13- to 18-year-old population. The absolute mean of the HOMA-IR was 2.89±0.7. The HOMA-IR gradually increased with age and reached a plateau at 13 years of age. CONCLUSIONS: Because the insulin concentrations, glucose levels, and HOMA-IR exhibited a gradual increase with age that was not related to obesity, our results suggested that the evaluation of IR in children should be based on percentiles of the HOMA-IR rather than a dichotomous value derived from a single cutoff point.

Type 2 diabetes mellitus (T2D) is a leading cause of morbidity and mortality in Mexico. Here, we aimed to report incidence rates (IR) of type 2 diabetes in middle-aged apparently-healthy Mexican adults, identify risk factors associated to ID and develop a predictive model for ID in a high-risk population. Prospective 3-year observational cohort, comprised of apparently-healthy adults from urban settings of central Mexico in whom demographic, anthropometric and biochemical data was collected. We evaluated risk factors for ID using Cox proportional hazard regression and developed predictive models for ID. We included 7636 participants of whom 6144 completed follow-up. We observed 331 ID cases (IR: 21.9 per 1000 person-years, 95%CI 21.37–22.47). Risk factors for ID included family history of diabetes, age, abdominal obesity, waist-height ratio, impaired fasting glucose (IFG), HOMA2-IR and metabolic syndrome. Early-onset ID was also high (IR 14.77 per 1000 person-years, 95%CI 14.21–15.35), and risk factors included HOMA-IR and IFG. Our ID predictive model included age, hypertriglyceridemia, IFG, hypertension and abdominal obesity as predictors (Dxy = 0.487, c-statistic = 0.741) and had higher predictive accuracy compared to FINDRISC and Cambridge risk scores. ID in apparently healthy middle-aged Mexican adults is currently at an alarming rate. The constructed models can be implemented to predict diabetes risk and represent the largest prospective effort for the study metabolic diseases in Latin-American population.