Rikke Beck Jensen1, Ajay Thankamony, Felix Day, Robert A Scott, Claudia Langenberg, Jeremy Kirk, Malcolm Donaldson, Sten-A Ivarsson, Olle Söder, Edna Roche, Hilary Hoey, Anders Juul, Ken K Ong, David B Dunger. 1. Department of Growth and Reproduction (R.B.J., A.J.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; Department of Pediatrics (R.B.J., A.T., D.B.D.), Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Medical Research Council, Epidemiology Unit (F.D., R.A.S., C.L., K.K.O.), Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom; Department of Endocrinology (M.D.), Royal Hospital for Sick Children, Glasgow G3 8SJ, United Kingdom; Department of Clinical Sciences (S.I.), Endocrine and Diabetes Unit, University of Lund, SE-205 02 Malmö, Sweden; Pediatric Endocrinology Unit (O.S.), Department of Women's and Children's Health, Karolinska Institutet and University Hospital, 171 76 Stockholm, Sweden; and Department of Pediatrics (E.R., H.H.), The National Children's Hospital, University of Dublin, Trinity College, Dublin, Ireland.
Abstract
PURPOSE: The wide heterogeneity in the early growth and metabolism of children born small for gestational age (SGA), both before and during GH therapy, may reflect common genetic variations related to insulin secretion or sensitivity. METHOD: Combined multiallele single nucleotide polymorphism scores with known associations with insulin sensitivity or insulin secretion were analyzed for their relationships with spontaneous postnatal growth and first-year responses to GH therapy in 96 short SGA children. RESULTS: The insulin sensitivity allele score (GS-InSens) was positively associated with spontaneous postnatal weight gain (regression coefficient [B]: 0.12 SD scores per allele; 95% confidence interval [CI], 0.01-0.23; P = .03) and also in response to GH therapy with first-year height velocity (B: 0.18 cm/y per allele; 95% CI, 0.02-0.35; P = .03) and change in IGF-1 (B: 0.17 SD scores per allele; 95% CI, 0.00-0.32; P = .03). The association with first-year height velocity was independent of reported predictors of response to GH therapy (adjusted P = .04). The insulin secretion allele score (GS-InSec) was positively associated with spontaneous postnatal height gain (B: 0.15; 95% CI, 0.01-0.30; P = .03) and disposition index both before (B: 0.02; 95% CI, 0.00-0.04; P = .04) and after 1 year of GH therapy (B: 0.03; 95% CI, 0.01-0.05; P = .002), but not with growth and IGF-1 responses to GH therapy. Neither of the allele scores was associated with size at birth. CONCLUSION: Genetic allele scores indicative of insulin sensitivity and insulin secretion were associated with spontaneous postnatal growth and responses to GH therapy in short SGA children. Further pharmacogenetic studies may support the rationale for adjuvant therapies by informing the mechanisms of treatment response.
PURPOSE: The wide heterogeneity in the early growth and metabolism of children born small for gestational age (SGA), both before and during GH therapy, may reflect common genetic variations related to insulin secretion or sensitivity. METHOD: Combined multiallele single nucleotide polymorphism scores with known associations with insulin sensitivity or insulin secretion were analyzed for their relationships with spontaneous postnatal growth and first-year responses to GH therapy in 96 short SGA children. RESULTS: The insulin sensitivity allele score (GS-InSens) was positively associated with spontaneous postnatal weight gain (regression coefficient [B]: 0.12 SD scores per allele; 95% confidence interval [CI], 0.01-0.23; P = .03) and also in response to GH therapy with first-year height velocity (B: 0.18 cm/y per allele; 95% CI, 0.02-0.35; P = .03) and change in IGF-1 (B: 0.17 SD scores per allele; 95% CI, 0.00-0.32; P = .03). The association with first-year height velocity was independent of reported predictors of response to GH therapy (adjusted P = .04). The insulin secretion allele score (GS-InSec) was positively associated with spontaneous postnatal height gain (B: 0.15; 95% CI, 0.01-0.30; P = .03) and disposition index both before (B: 0.02; 95% CI, 0.00-0.04; P = .04) and after 1 year of GH therapy (B: 0.03; 95% CI, 0.01-0.05; P = .002), but not with growth and IGF-1 responses to GH therapy. Neither of the allele scores was associated with size at birth. CONCLUSION: Genetic allele scores indicative of insulin sensitivity and insulin secretion were associated with spontaneous postnatal growth and responses to GH therapy in short SGA children. Further pharmacogenetic studies may support the rationale for adjuvant therapies by informing the mechanisms of treatment response.
Authors: Ajay Thankamony; Rikke Beck Jensen; Susan M O'Connell; Felix Day; Jeremy Kirk; Malcolm Donaldson; Sten A Ivarsson; Olle Söder; Edna Roche; Hilary Hoey; Ken K Ong; David B Dunger; Anders Juul Journal: J Clin Endocrinol Metab Date: 2015-11-20 Impact factor: 5.958