Previously Implicated Variants in the Growth Hormone Receptor (GHR) and IGFBP-3 Do Not Have Substantial Effects On Growth Hormone Responsiveness

Program: Late-Breaking Abstracts
Session: SUN-LB-Late-Breaking Poster Session 2
Bench to Bedside
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-LB-05
Andrew Dauber*1, Yan Meng2, Laura Audí3, Antonio Carrascosa4, Michael B Ranke5, Michael Paul Wajnrajch6, Anders Lindberg7, Cecilia Camacho-Hubner8 and Joel N Hirschhorn9
1Division of Endocrinology, Boston Children's Hospital and Program in Medical and Population Genetics, Broad Institute, Boston, MA, 2Boston Children's Hospital and Program in Medical and Population Genetics, Broad Institute, Boston, MA, 3Hospital Universitari Vall d'Hebrón, Barcelona, Spain, 4Hospital Vall d’Hebron, Centre for Biomedical Research on Rare Diseases (CIBERER), Autonomous University Barcelona, Spain, 5Univ Klinikum Tubingen, Tubingen, Germany, 6Pfizer Inc., New York, NY, 7Pfizer Endocrine Care, Sollentuna, Sweden, 8Pfizer Inc., New York, 9Division of Endocrinology, Boston Children's Hospital and Program in Medical and Population Genetics, Broad Institute, Harvard Medical School, Boston, MA
Introduction: Significant variability exists in individuals’ responsiveness to growth hormone (GH) treatment. Prediction models have been created using demographic and clinical variables which partially explain this variability (1), but these do not include genetic factors. Prior studies have implicated a common deletion of exon 3 in the GHR (GHRd3) (2, 3) and a SNP (rs2854744) in the IGFBP3 promoter region (4, 5) as genetic variants that influence GH responsiveness.  However, these associations have not been consistent or conclusive. Methods: As part of a larger genomewide association study of GH responsiveness, we genotyped these 2 variants in a total of 620 individuals receiving GH from 4 distinct short stature cohorts. After removing samples that failed quality control filters (including genotyping success rate, outliers for heterozygosity or ancestry, and other filters in the PLINK software package), 581 prepubertal subjects remained: 270 with idiopathic short stature, 251 with isolated GH deficiency, and 60 who were born small for gestational age.  Association with GH responsiveness was performed using linear regression, adjusting for diagnosis and for ancestry estimated from the genetic data. The IGFBP3 SNP was imputed and the GHRd3 was assessed using a SNP that is highly correlated with the deletion in European-ancestry samples (rs6873545). Two primary analyses were performed: the first one used an outcome measure of change in height SDS over the 1st year of treatment without adjustment for further clinical variables and the second used an index of responsiveness (IOR) defined as the standardized residual of the individual subject’s response compared to the response predicted by GH responsiveness prediction algorithms (1). This second analysis adjusts for clinical variables known to affect GH responsiveness. Results: There was no significant association between either the GHRd3 or IGFBP3 polymorphism with 1st year change in height SDS (p = 0.35 and 0.98 respectively) or with the IOR (p = 0.18 and 0.57). Subgroup analyses were performed for each clinical diagnosis and no significant associations were observed. Conclusions: We have performed the largest pharmacogenetic study to date of GH responsiveness. We did not find any significant associations between the GHRd3 or the previously reported IGFBP3 variant with GH responsiveness. Analysis of the genomewide data is ongoing searching for novel genetic predictors of GH responsiveness.

(1) Ranke MB, Lindberg A. Predicting growth in response to growth hormone treatment. Growth Horm IGF Res 2009;19:1-11. (2) Wassenaar MJ, Dekkers OM, Pereira AM, et al. Impact of the exon 3-deleted growth hormone (GH) receptor polymorphism on baseline height and the growth response to recombinant human GH therapy in GH-deficient (GHD) and non-GHD children with short stature: a systematic review and meta-analysis. J Clin Endocrinol Metab 2009;94:3721-30. (3) Carrascosa A, Esteban C, Espadero R, Fernandez-Cancio M, Andaluz P, Clemente M, Audi L, Wollmann H, Fryklund L, Parodi L, Spanish SGA Study Group The d3/fl-growth hormone (GH) receptor polymorphism does not influence the effect of GH treatment (66 microg/kg per day) or the spontaneous growth in short non-GH-deficient small-for-gestational-age children: results from a two-year controlled prospective study in 170 Spanish patients.J Clin Endocrinol Metab 2006;  91:3281-3286. (4) Costalonga EF, Antonini SR, Guerra-Junior G, Mendonca BB, Arnhold IJ, Jorge AA. The -202 A allele of insulin-like growth factor binding protein-3 (IGFBP3) promoter polymorphism is associated with higher IGFBP-3 serum levels and better growth response to growth hormone treatment in patients with severe growth hormone deficiency. J Clin Endocrinol Metab 2009;94:588-95. (5) van der Kaay DC, Hendriks AE, Ester WA, et al. Genetic and epigenetic variability in the gene for IGFBP-3 (IGFBP3): correlation with serum IGFBP-3 levels and growth in short children born small for gestational age. Growth Horm IGF Res 2009;19:198-205.

Disclosure: MBR: Medical Advisory Board Member, Pfizer, Inc., Speaker, Novo Nordisk, Speaker, Eli Lilly & Company, Speaker, Ipsen. MPW: Employee, Pfizer, Inc.. AL: Employee, Pfizer, Inc.. CC: Employee, Pfizer, Inc.. JNH: Investigator, Pfizer, Inc.. Nothing to Disclose: AD, YM, LA, AC

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This study was sponsored by a research grant from Pfizer Inc. to J. N. H.