ESPE Abstracts (2014) 82 FC7.1

Genetic Markers of Insulin Resistance are Associated with GH Response in Short SGA Children: the North European SGA Study

Rikke Beck Jensena,b, Ajay Thankamonya, Felix Dayc, Jeremy Kirkd, Malcolm Donaldsone, Sten-A Ivarssonf, Olle Söderg, Edna Rocheh, Hilary Hoeyh, Anders Juulb, Ken Ongc & David Dungera

aDepartment of Pediatrics, Institute of Metabolic Science, University of Cambridge, Cambridge, UK; bDepartment of Growth and Reproduction, Rigshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; cMRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK; dDepartment of Endocrinology, Birmingham Children’s Hospital, Birmingham, UK; eDepartment of Endocrinology, Royal Hospital for Sick Children, Glasgow, UK; fDepartment of Clinical Sciences, Endocrine and Diabetes Unit, University of Lund, Lund, Sweden; gPediatric Endocrinology Unit, Department of Women’s and Children’s Health, Karolinska Institutet and University Hospital, Stockholm, Sweden; hDepartment of Pediatrics, The National Children’s Hospital, University of Dublin, Trinity College, Dublin, Ireland

Background: There is wide heterogeneity in responses to GH treatment in children born small for gestational age (SGA).

Objective and Hypotheses: The aim was to explore the impact of genetic markers on glucose metabolism and growth during first year high-dose GH treatment in SGA children.

Method: In North European Small for Gestational Age Study (NESGAS) patients received high-dose GH (67 μg/kg per day) the first year. 97 patients were genotyped using the ‘Metabochip’ a custom Illumina iSelect genotyping array enriched for single nucleotide polymorphisms (SNPs) associated with growth and metabolic traits. Combined multi-allele gene scores were generated comprising ten SNPs for insulin resistance (GS-IR) and 18 SNPs for insulin secretion (GS-IS).

Results: Higher GS-IR was associated with shorter height (B: −0.08 SDS/allele, 95% CI: −0.15 to 0, P=0.048) and lower weight (B: −0.10, 95% CI: −0.20 to −0.003, P=0.04) after 1 year of treatment (corrected for age, sex and mid-parental height). GS-IR was inversely associated with first year change in IGF1 (B: −0.16 SDS/allele, 95% CI: −0.29 to −0.02, P<0.03). GS-IR added significantly to the Ranke SGA growth prediction model, adding 8% to the variance explained in growth response (independent effect of GS-IR: B: −0.20, 95% CI: −0.38 to −0.02, P=0.03).

GS-IS was associated with increased insulin secretion (IVGTT) (corrected for age, sex, and BMI) at baseline (B: 0.03, 95% CI: 0.004–0.05, P=0.02) and 1 year (B: 0.03, 95% CI: 0.005–0.05, P=0.02). There was no association to HOMA-S, but GS-IS was positively associated with Disposition Index at baseline (B: 0.03, 95% CI: 0.004–0.05, P=0.02) and 1 year (B: 0.03, 95% CI: 0.01–0.05, P=0.002).

Conclusion: Increased genetic susceptibility to insulin resistance was associated with lower height and IGF1 responses to GH treatment in SGA children. Higher scores of insulin secretion alleles corresponded to increased insulin secretion and increased disposition index. These novel results highlight the potential role of genetic factors in defining the response of treatment in SGA patients.