ABSTRACT
AIMS/HYPOTHESIS: Hyperinsulinaemia and insulin resistance usually precede clinical hyperglycaemia and Type 2 diabetes. Thus, plasma insulin concentrations and insulin resistance are important quantitative traits associated with risk of Type 2 diabetes, and represent key measures for genetic analysis of the syndrome. METHODS: We carried out a genome-wide search for loci related to plasma insulin concentrations and insulin resistance in 330 extended, community-based pedigrees from the Framingham Heart Study. Normalized deviates of the standardized residuals of plasma insulin concentrations in the fasting state, 2 h after oral glucose challenge and as a measure of insulin resistance were used in linkage analysis with the variance components model implemented in the computer program SOLAR. RESULTS: The results suggest susceptibility loci influencing plasma concentrations of fasting insulin and insulin resistance on chromosomes 11 (LOD 2.43 at 85 cM close to D11S2002) and 17 (LOD 1.8 at 60 cM, close to D17S784); and susceptibility loci influencing 2-h plasma insulin concentrations on chromosomes 9 (LOD 2.8 at 80 cM, close to D9S922) and 19 (LOD 1.8 at 66 cM, close to D19S245). The results of the analysis of 1000 simulations of the trait and an unlinked marker suggest that in a genome scan of 401 markers fewer than one LOD score over 1 would be due to Type 1 error, and be a false positive. CONCLUSION/INTERPRETATION: We conclude that these suggestive regions for quantitative pre-diabetic insulin traits could contain major loci in the pathogenesis of Type 2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2/genetics , Genome, Human , Insulin/blood , Insulin/genetics , Quantitative Trait Loci/genetics , Adolescent , Adult , Child , Female , Genetic Predisposition to Disease/genetics , Genetic Testing/methods , Humans , Insulin Resistance , Lod Score , Male , Middle AgedABSTRACT
BACKGROUND: Childhood asthma is generally believed to be a disorder with a good prognosis. However, some asthmatics develop irreversible airway obstruction, probably as a result of airway remodelling. METHODS: After 21-33 years, 228 adults (aged 13-44 years at baseline) with a history of asthma were re-examined to assess risk factors for the development of irreversible airway obstruction (IAO, forced expiratory volume in 1 second (FEV(1)) <80% predicted and reversibility <9% predicted) and a reduced postbronchodilator transfer coefficient (carbon monoxide transfer factor/alveolar volume, <80% predicted), both characteristics of COPD. RESULTS: At follow up, 41% did not have airway obstruction (NAO), 43% had reversible airway obstruction (RAO), and 16% had IAO; 23% had a reduced transfer coefficient. Patients with RAO had asthma-like characteristics (wheezing, asthma attacks, bronchial hyperresponsiveness (BHR)) while patients with IAO had COPD-like symptoms (cough, phlegm, dyspnoea) at follow up. The development of IAO is determined by a lower FEV(1), less reversibility of airway obstruction and, surprisingly, less severe BHR at initial screening. Eighty percent of the patients with asthma who used anti-inflammatory medication still had airway obstruction, but IAO developed less frequently. Smoking was associated with a reduced transfer coefficient but not with the development of IAO. Female sex was associated with a reduced transfer coefficient, whereas corticosteroid use was not. CONCLUSIONS: Although IAO and a low transfer coefficient are both characteristics of COPD, they represent distinct entities in adult asthmatics in terms of symptomatology, aetiology, and probably in therapeutic approaches and disease prevention.
