ESPE Yearbook of Paediatric Endocrinology

J Clin Endocrinol Metab. 2020;105:3203–3214. doi: 10.1210/clinem/dgaa443. PMID: 32652002

The authors performed a large genome-wide association study (GWAS) to assess the role of common genetic variants in the response to GH therapy. A total of 614 children treated with GH were included: 276 with idiopathic GHD, 297 with ISS, and 41 born SGA. The findings implicate some novel mechanisms that may contribute to the wide individual variation in GH response.

Recombinant human GH (rhGH) is used in children for treatment of short stature of various etiologies, including disorders of the growth hormone–insulin like growth factor-1 (GH/IGF-1) axis, genetic syndromes such as Turner and Noonan, and failure to catch-up growth in children born small for gestational age (SGA) (1). The response to treatment varies not only across different disorders but also between individuals with the same cause of short stature, suggesting that individual factors may contribute to GH responsiveness (2). Clinical parameters, such as age and severity of growth retardation at start of treatment, peak GH levels on stimulation tests, GH dose, birth size and mid-parental height, predict rhGH response only partially (3). Individual genetic factors could influence response to rhGH and explain part of this variability. Polymorphisms in genes within the GH/IGF-1 axis have been proposed as candidate determinants of rhGH response (4-7).

The aim of this study was to identify genetic variants that influence the height response to rhGH therapy, by evaluating the association between individual single nucleotide polymorphisms (SNPs) and the height gain in the first-year of rhGH. The primary analysis included all samples, regardless of diagnosis, and was adjusted for age, gender and principal components of genetic ancestry. The secondary analyses included all samples stratified by ancestry and diagnosis and was adjusted for the full set of clinical variables. Finally, a genetic polygene score was calculated in each individual using 697 known height-associated SNPs and the variance in GH response explained by this polygene score was evaluated by linear regression.

In the primary analysis, common variants near the B4GALT4 and TBCE genes showed the strongest suggestive signals. B4GALT4 is part of beta-1,4-galactosyltransferase (beta4GalT) gene family, composed by 7 genes. Despite mutations in B4GALT4 have not yet been reported to be associated with any specific disease, mutations in another gene family member, B4GALT7, cause abnormal skeletal growth. In secondary analyses, several loci reached significance including variants near ST3GAL6. ST3GAL6 encodes a sialyltransferase that acts in the same pathway as the beta4GalT family genes. The association of rhGH responses with SNPs related to glycosylation pathways is a novel finding and raises the hypothesis that variation in glycosylation may contribute to the individual variation in GH response.

Reference 1. Richmond E, Rogol AD. Current indications for growth hormone therapy for children and adolescents. Endocr Dev. 2010;18:92–108. 2. Ranke MB, Lindberg A, Mullis PE, Geffner ME, Tanaka T, Cutfield WS, et al. Towards optimal treatment with growth hormone in short children and adolescents: evidence and theses. Horm Res Paediatr. 2013;79(2):51–67. 3. Ranke MB, Lindberg A. Predicting growth in response to growth hormone treatment. Growth Horm IGF Res. 2009;19(1):1–11. 4. Binder G, Baur F, Schweizer R, Ranke MB. The d3-growth hormone (GH) receptor polymorphism is associated with increased responsiveness to GH in Turner syndrome and short small-for-gestational-age children. J Clin Endocrinol Metab. 2006;91(2):659–64. 5. 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(2):588–95. 6. Dos Santos C, Essioux L, Teinturier C, Tauber M, Goffin V, Bougneres P. A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone. Nat Genet. 2004;36(7):720–4. 7. Wassenaar MJ, Dekkers OM, Pereira AM, Wit JM, Smit JW, Biermasz NR, 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(10):3721–30.