Insulin clearance: confirmation as a highly heritable trait, and genome-wide linkage analysis

• Published in: Diabetologia 2012-08, Vol.55 (8), p.2183-2192
• Main Authors: Guo, X., Cui, J., Jones, M. R., Haritunians, T., Xiang, A. H., Chen, Y.-D. I., Taylor, K. D., Buchanan, T. A., Davis, R. C., Hsueh, W. A., Raffel, L. J., Rotter, J. I., Goodarzi, M. O.
• Format: Article
• Language: English
• Subjects: Adult; Biological and medical sciences; Cardiovascular disease; Chromosomes; Chromosomes, Human, Pair 15 - genetics; Chromosomes, Human, Pair 20 - genetics; Cohort Studies; Coronary vessels; Diabetes; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Gene loci; Genetic Linkage; Genome-Wide Association Study; Genomes; Glucose Clamp Technique; Hispanic Americans; Hispanic or Latino - genetics; Human Physiology; Humans; Insulin - metabolism; Insulin resistance; Insulin Resistance - genetics; Internal Medicine; Lod Score; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolic Syndrome - genetics; Minority & ethnic groups; Pathophysiology; Phenotype; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Vein & artery diseases
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-012-2577-2

Aims/hypothesis We have previously documented a high heritability of insulin clearance in a Hispanic cohort. Here, our goal was to confirm the high heritability in a second cohort and search for genetic loci contributing to insulin clearance. Methods Hyperinsulinaemic–euglycaemic clamps were performed in 513 participants from 140 Hispanic families. Heritability was estimated for clamp-derived insulin clearance and a two-phase genome-wide linkage scan was conducted using a variance components approach. Linkage peaks were further investigated by candidate gene association analysis in two cohorts. Results The covariate-adjusted heritability of insulin clearance was 73%, indicating that the majority of the phenotypic variance is due to genetic factors. In the Phase 1 linkage scan, no signals with a logarithm of odds (LOD) score >2 were detected. In the Phase 2 scan, two linkage peaks with an LOD >2 for insulin clearance were identified on chromosomes 15 (LOD 3.62) and 20 (LOD 2.43). These loci harbour several promising candidate genes for insulin clearance, with 12 single nucleotide polymorphisms (SNPs) on chromosome 15 and six SNPs on chromosome 20 being associated with insulin clearance in both Hispanic cohorts. Conclusions/interpretation In a second Hispanic cohort, we confirmed that insulin clearance is a highly heritable trait and identified chromosomal loci that harbour genes regulating insulin clearance. The identification of such genes may improve our understanding of how the body clears insulin, thus leading to improved risk assessment, diagnosis, prevention and therapy of diabetes, as well as of other hyperinsulinaemic disorders, such as the metabolic syndrome and polycystic ovary syndrome.