Growth Hormone (GH) Receptor C.1319 G>T Polymorphism, But Not Exon 3 Retention or Deletion Is Associated With Better First-Year Growth Response to GH Therapy in Patients With GH Deficiency

Abstract

ABSTRACT:We investigated possible influences of single nucleotide polymorphisms (SNPs) on first-year growth velocity in response to growth hormone (GH) therapy in GH-deficient (GHD) children. We recruited a total of 154 GHD prepubertal children who had undergone GH therapy for 1 y. To exclude the possibility that the genotype/allele variants influenced the height of GHD patients, we studied the same gene polymorphisms in 208 familial short stature (FSS) patients and 100 normal control individuals. In the present study, the first-year growth velocities of GHD patients treated with GH were measured and then compared with the allelic frequencies of various SNP of genes involved in the GH-insulinlike growth factor-I (IGF-I) axis. Only c.1319 GϾT of the GH receptor (GHR) gene showed significant correlation with first-year growth velocity (p ϭ 0.02). However, the genetic frequency of the c.1319 GϾT polymorphism of GHD did not correlate with FSS and normal controls. Therefore, the c.1319 GϾT polymorphism does not influence the height of individuals but can affect the therapeutic efficacy of GH in GHD patients. Moreover, the GHR c.1319 T allele showed higher transcriptional activity and stronger signal transducers and activators of transcription (STAT)-5 Tyr694 phosphorylation. Based on these findings, we conclude that the GHRc.1319 T allele is associated with the therapeutic efficacy of GH replacement therapy.

The Exon 3-Deleted/Full-Length Growth Hormone Receptor Polymorphism and Response to Growth Hormone Therapy in Growth Hormone Deficiency and Turner Syndrome: A Multicenter Study

“…In most previous studies on the effect of the GHR exon 3 polymorphism on growth response in GHD patients, no association was reported, which is in agreement with our results [17,18,33,34,35]. However in a number of studies, including the study by Dos Santos et al [9], response to GH therapy was found to be more marked in patients carrying d3 homozygously or heterozygously.…”

“…The distribution of GHR exon 3 isoforms in GHD in our study (28.4% fl/fl, 46.8% fl/d3 and 24.8% d3/d3) showed that the frequency of d3/d3 is higher and that of fl/fl is slightly lower than the distribution in most of the European studies which report a frequency of 43–55% in fl/fl, 36–47% in fl/d3 and 3–11% in d3/d3 [16,17,18,33,34,35,36]. …”

The d3/fl-GH receptor gene polymorphism does not influence quality of life and body composition in GH-deficient adults receiving GH replacement therapy

“…However, the c.1319 GOT polymorphism was found to be associated with therapeutic efficacy in GHD children (22). Additionally, other genes within the GH pathway may also be important, and this relative importance may differ between adults and children.…”

Predicting Response to Growth Hormone Treatment

“…Wan and coworkers examined the frequencies of 13 known SNPs of genes in this axis among 154 prepubertal children with GHD, 208 with familial short stature and 100 healthy children of normal stature [35]. SNPs of the following genes were evaluated: GHR, JAK2, STAT5a, STAT5b, IGF-I, IGFBP-3, ALS and SOCS-2.…”