Relationship Between Collagen Type XI ?2 (COL11A2) Gene Polymorphisms And The Efficacy Of Recombinant Human Growth Hormone (rhGH) Treatment In Chinese Children With Growth Hormone Deficiency

Objective:We investigate the COL11A2 gene polymorphism to identify the correlation with growth hormone deficiency(GHD)firstly.And then to detect the relationship between COL11A2 gene polymorphism and the therapeutic effect of recombinant human growth hormone(rhGH)in children with GHD.To provide the clinical evidence for clinical individualized therapy and then introduce the precision medical model of short stature.Methods:A total of 229 children with GHD were selected as GHD group and 314 healthy children with normal stature were selected as the control group.Seven single nucleotide polymorphisms(SNPs)of COL11A2 gene that related to GHD were selected and genotyped by matrix-assisted laser desorption/ionization time of flight mass spectrometry(MALDI-TOF MS).106 GHD were treated with rhGH for one to fifteen months in 229 GHD,and 30 days treatment as the unit is analysed.The dose of treatment is 0.1-0.15U/Kg.d everyday.The growth velocity(GV),height standard deviation integral(HtSDS),body mass index(BMI)were measured by the same person with the same measuring instrument in every GHD follow-up visit after initiation of rhGH treatment.The blood biochemical parameters of the children such as Thyroid function,insulin-like growth factor-1(IGF-1)and insulin-like growth factor binding protein 3(IGFBP3)were measured by fasting blood samples.The aim of this study was to investigate whether there were differences between the efficacy of rhGH and genotypes in GHD with prolonged treatment time.Results:(1)The SNP rs9368758 of COL11A2 gene was more significantly frequent in GHD patients than controls(P =0.012),so it is associated with the occurrence of GHD.(2)The AGACCAT was a potential pathogenic haplotype of GHD through the analysis of linkage disequilibrium and haplotype.The risk of GHD was 41.3%higher than that of other haplotypes(P=0.005,OR=1.413,95%CI=1.113-1.823)(3)After analysis of relationship between therapeutic effect and genotypes,we found the curative effect of GHD patients in Tanner Stage I was different in different genotypes of rs9368758 under the premise after other factors adjustmented?In the GHD children with AA genotype,the HtSDS increased 0.081(P<0.001,-95%CI=0.061-0.103)and the height would increase 0.833cm(P<0.001,95%CI=0.756-0.910)with the 30 days treatment correspondingly.The HtSDS would increase 1.012(P<0.001,95%CI=0.783-1.241)and the height would increase 10.625cm/year(P<0.001,95%CI=9.635-11.615)with the 1 year treatment correspondingly.?On the GHD children with GA genotype,the HtSDS increased 0.068 after 30 days of treatment(P<0.001,95%CI=0.052-0.086)and the height will increase 0.773 cm correspondingly(P<0.001,95%CI=0.720-0.826).The HtSDS would increase 0.821(P<0.001,95%CI=0.641-1.001)and the height would increase 9.274cm/year(P<0.001,95%CI=8.709-9.838)with the 1 year treatment correspondingly.? Compared with the AA and GA genotype,the HtSDS of GG genotype increased 0.035(P<0.001,95%CI=0.018-0.051)and the height would increase 0.717cm correspondingly(P<0.001,95%CI=0.662-0.773).The HtSDS would increase 0.499(P<0.001,95%CI=0.274-0.724)and the height would increase 8.983cm/year(P<0.001,95%CI=8.125-9.841)with the 1 year treatment correspondingly.(4)As the extension of treatment time,the HtSDS of AA genotype is the best(#P=0.222,#P=0.003),then the GA genotype and GG genotype.(5)In the Tanner Stage II-V period of GHD patients,we have not found the differences between the genotypes and the treatment of rhGH in HtSDS(P=0.493,#P=0.128)and height with the treatment time prolongation.Conclusion:The COL11A2 gene is association with the GHD and the corresponding pathogenic haplotype AGACCAT,which increased the risk of 41.3%,also further confirmed the relationship between COL11A2 gene and GHD.With the prolongation of treatment time,there is difference between HtSDS,height and rs9368758 genotype.It can be seen that in GHD before puberty,AA genotype HtSDS increased most significantly with the duration of treatment(1.012/year),followed by GA(0.821/year)and GG genotypes(0.499/year),and the same as HT.In the same way,there is no difference between HtSDS and HT and genotype in adolescents who have already started to come in adolescence with GHD.