Genetic variations at the human growth hormone receptor (GHR) gene locus are associated with idiopathic short stature |
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| Authors: | Christel Dias Mara Giordano Rosalie Frechette Simonetta Bellone Constantin Polychronakos Laurent Legault Cheri L Deal Cynthia Gates Goodyer |
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| Affiliation: | 1. Department of Experimental Medicine, McGill University, Montreal, QC, Canada;2. Laboratory of Human Genetics, Department of Health Science, University of Eastern Piedmont, Novara, Italy;3. Genotyping Platform, Genome‐Québec, Montreal, QC, Canada;4. Division of Pediatrics, Department of Health Science, University of Eastern Piedmont, Novara, Italy;5. Departments of Experimental Medicine, Human Genetics and Pediatrics, McGill University, Montreal, QC, Canada;6. Department of Pediatrics, McGill University, Montreal, QC, Canada;7. CHU Ste‐Justine Research Centre and Department of Pediatrics, Université de Montréal, Montreal, QC, Canada;8. Departments of Experimental Medicine and Pediatrics, McGill University, Montreal, QC, Canada |
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| Abstract: | GH plays an essential role in the growing child by binding to the growth hormone receptor (GHR) on target cells and regulating multiple growth promoting and metabolic effects. Mutations in the GHR gene coding regions result in GH insensitivity (dwarfism) due to a dysfunctional receptor protein. However, children with idiopathic short stature (ISS) show growth impairment without GH or GHR defects. We hypothesized that decreased expression of the GHR gene may be involved. To test this, we investigated whether common genetic variants (microsatellites, SNPs) in regulatory regions of the GHR gene region were associated with the ISS phenotype. Genotyping of a GT‐repeat microsatellite in the GHR 5′UTR in a Montreal ISS cohort (n = 37 ISS, n = 105 controls) revealed that the incidence of the long/short (L/S) genotype was 3.3× higher in ISS children than controls (P = 0.04, OR = 3.85). In an Italian replication cohort (n = 143 ISS, n = 282 controls), the medium/short (M/S) genotype was 1.9× more frequent in the male ISS than controls (P = 0.017, OR = 2.26). In both ISS cohorts, logistic regression analysis of 27 SNPs showed an association of ISS with rs4292454, while haplotype analysis revealed specific risk haplotypes in the 3′ haploblocks. In contrast, there were no differences in GT genotype frequencies in a cohort of short stature (SS) adults versus controls (CARTaGENE: n = 168 SS, n = 207 controls) and the risk haplotype in the SS cohort was located in the most 5′ haploblock. These data suggest that the variants identified are potentially genetic markers specifically associated with the ISS phenotype. |
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| Keywords: | growth hormone receptor idiopathic short stature short stature GT microsatellite SNPs haplotype |
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