| Recombinant human GH (rhGH) replacement is standard therapy for children with short stature due to GH deficiency (GHD). Although rhGH replacement is generally safe and effective, these patients exhibit considerable interindividual variability regarding growth responses to rhGH. Some researchers developed prediction model for rhGH response, because of low power for prediction, other factors may be confirmed in future. From 2004, genetic influence on rhGH response gained more focus. To date, most studies aimed to assess the relationship between growth hormone receptor (GHR) exon-3 genotype with short and long-term response to rhGH therapy, but the results differed。Few researchers tried to explore the influence of a polymorphism in the IGF-binding protein-3 (IGFBP-3) promoter region (-202 A/C) on circulating IGFBP-3 levels and growth response to rhGH therapy in children with GH deficiency (GHD). There were no studies as to rhGH pharmacogenetics and prediction model development aimed at Chinese GHD patients. Based on that, we were to select genetic and non-genetic factors associated with rhGH response, and develop models for Chinese GHD patient, in order to individualize treatment therapy and evaluate response。GHR and IGFBP-3 were regarded as candidate genes, five polymorphisms were selected and determined by PCR, PCR-RFLP analysis or PCR-LDR. The validity was verified by direct sequencing. Among 100 healthy subjects and 85 GHD patients, the frequencies of GHR fl/fl, fl/d3, d3/d3 were 0.450,0.520,0.030 and 0.647,0.329,0.024. The frequencies of IGFBP-3 rs2854744 AA, AC and CC were 0.560,0.370,0.070and 0.553,0.400,0.047. The frequencies of rs3110697 GG, GA and AA were 0.510,0.400, 0.090 and 0.529,0.412. The frequencies of rs2132570 CC, CA and AA were 0.630, 0.310,0.060 and 0.612,0.365,0.024. The frequencies of rs2854746 GG,GC and CC were 0.550,0.380,0.070 and 0.565,0.400,0.035. There were no significant difference for the distribution feature in every gene sites between healthy subjects and GHD patients.Blood samples and clinical data were collected for 60 GHD patients treated by rhGH. Clinical data included general information, medical history, diagnosis, treatment, follow-up and other related information. Patient characteristics were analyzed and growth velocity were calculated. Clinical parameters were compared between different genotype groups in order to evaluate the influence of the genotypes on growth velociy. There were no significant difference for the age, bone age and hormone levels between different genotypes at the start of the treatment. Rs2132570 and rs2854746 were related with rhGH response for the first 3 months. GHR fl/d3 was related with rhGH response for the first 6 months. Rs2854744, rs2132570 and rs2854746 were related with rhGH response for 12 months. In conclusion, GHR fl/d3, IGFBP-3 rs2854744, rs2132570 (C/A) and rs2854746 (G/C) polymorphisms may be the genetic factors of the rhGH response.GHD patients were selected according to inclusion criteria and separated into two groups:there were complete clinical data and genotype records for patients in group A, and only complete clinical data in group B. We developed two prediction models of GV6 (model Al and A2) for group A, one included genetic factors, the other not. the third prediction model were developed in group B (model B) including non-genetic factors. After multiple regression analysis, Al was GV6(cm/y)=15.386-0.556×GH peak(μg/L)-0.284xinitial weight(kg)+1.703xrhGH dose(IU), which explained 58.9% variability(r2=0.589), with a SD of 1.81cm; A2 was GV6(cm/y)=13.312+1.324xfi/d3 polymorphism (fl/fl=1, fl/d2=2, d3/d3=3)-0.550xGHpeak(μg/l)-0.243×initial weight(kg)+1.419xrhGH dose(IU), which explained 63.4%variability(r2=0.634), with a SD of 1.79cm. Model A2 can explain variability better than Model Al. The two models both have high accuracy. When the two models were applied prospectively to the validation group, there were no significant differences between observed and predicted responses (P>0.05). In group B, GH peak, initial height and skeletal age. Model B is GV6(cm/y)=25.313-0.461 xGH peak(μg/L)-0.084×initial height(cm)-0.221 xinitial skeletal age(y), which explained 61.5% response variability(r2=0.615), with a SD of 2.64cm. When the models were applied prospectively to the validation group, there were no significant differences between observed and predicted responses (P>0.05). The three prediction model can explain 58.9%-63.4% response variability with high accuracy. The predictive indexes were available, so the model was applicable.To know cognition status on the rhGH treatment for the guardian or children with short staure, questionnaire were designed and developed in the Department of Endocrinology. The contents of the survey included the storage, usage and the recognition of the therapeutic effect and adverse drug reactions (ADR), the understanding of the purpose of Follow-up, the acquisition and attention of the label and other medical information, the observation and persuasion of the children's physical and mental pressure etc. A total of 67 questionnaires were collected. Most guardians can preserve and use the drugs correctly, have good compliance, and pay attention non-medication therapy. However, they felt hard to understand ADR and the purpose of on-time follow-up, the attention and persuasion of the children's physical and mental pressure etc. In addition, the guardian wish to know more relevant knowledge about the disease and the judgments of sexual development. The results of the questionnaire survey can provide evidence for doctors who develop pointed patient education for the dwarfishness and guardian.It can be concluded that1) There were 5 genetic polymorphisms of GHR and IGFBP-3 among Healthy Adults and GHD patients in China. There were no significant relationship between each gene sites and GHD.2) GHR fl/d3, IGFBP-3 rs2854744, rs2132570 (C/A) and rs2854746 (G/C) polymorphisms may be the genetic factors associated with rhGH response.3)3 prediction models were developedModel Al:GV6(cm/y)=15.386-0.556xGH peak(μg/L)-0.284×initial weight(kg)+1.703xrhGH dose(IU), (r2=0.589, SD=1.81cm)Model A2:GV6(cm/y)=13.312+1.324xfl/d3 polymorphism (fl/fl=1, fl/d2=2, d3/d3=3)-0.550xGH peak(μg/l)-0.243×initial weight(kg)+1.419xrhGH dose(IU), (r2=0.634,SD=1.79cm.Model A2 can explain variability better than Model Al. The two models both have high accuracy.Model B:GV6(cm/y)=25.313-0.461×GH peak(μg/L)-0.084×initial height(cm)-0.221xinitial skeletal age(y), (r2=0.615, SD=2.64cm).4) Children and their mothers should be major population for patient education The contents selected for patient education should combine what they care and the knowledge they do not know, for example, relevant knowledge about the disease and the judgement of sexual development. |
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