生长激素缺乏症患儿COL11A2基因多态性与重组人生长激素疗效相关性分析

发布时间：2018-05-21 08:54

本文选题：生长激素缺乏症 + 重组人生长激素　；参考：《山东大学》2017年硕士论文

【摘要】：目的:探讨COL11A2基因单核苷酸多态性与发生生长激素缺乏症(GHD)的相关性,以及GHD患儿应用重组人生长激素(rhGH)治疗后,COL11A2基因多态性不同基因型与疗效间的差异性,为开展临床个体化治疗提供临床证据,开启矮小症精准医疗模式。方法:选取229例GHD患儿作为GHD组,同期选取种族匹配的314例身高正常的健康儿童作为对照组。选择7个可能与GHD发生具有一定相关性的COL11A2基因单核苷酸多态性位点,利用基质辅助激光解吸电离飞行时间质谱(MALDI-TOF MS)的方法,对GHD组和正常对照组7个候选SNP位点进行基因型分型。GHD组229例患儿中有106例接受rhGH治疗,rhGH治疗时间范围1月到15月,治疗剂量为0.1～0.15U/Kg.d,以治疗30天为单位进行分析。GHD患儿开始rhGH治疗后定期门诊随访,均详细记录复诊日期,由专人用同一量具测量患儿的身高、体重,计算患儿生长速度(GV)、身高标准差积分(HtSDS)、体质指数(BM[);同时留取患儿空腹血标本检测甲状腺功能、生长因子、肝功等。旨在探讨不同COL11A2基因型的GHD患儿,随着治疗时间的延长,应用rhGH治疗后疗效之间是否存在差异性。结果:(1)COL11A2基因单核苷酸多态性位点rs9368758与GHD的发生具有一定的相关性,差异具有统计学意义(P=0.012);(2)经连锁不平衡评估和单体型分析后发现AGACCAT是发生GHD的潜在致病体型,发生GHD的风险较其他单倍体型增加了 41.3%(P=0.005,OR值=1.413,95%CI=1.113-1.823);(3)分析rs9368758位点不同基因型与疗效关系后发现应用rhGH治疗后的GHD患儿,在调整混杂因素后处于TannerⅠ期的GHD患儿,rs9368758位点不同基因型疗效不一:①AA基因型患儿治疗时间每增加30天,其HtSDS增加0.081个单位(P0.001,95%CI=0.061-0.103),相应身高治疗每增加30天可增长0.833cm(P0.001,95%CI=0.756-0.91);治疗 1 年后,其 HtSDS 约增加 1.012 个单位/年(P0.001,95%CI=0.783-1.241),相应身高约增加 10.625cm/年(P0.001,95%CI=9.635-11.615);②GA基因型患儿治疗每增加30天,其HtSDS增加0.068个单位(P0.001,95%CI=0.052-0.086),相应身高治疗 30 天后可增加 0.773cm(P0.001,95%CI=0.720-0.826);治疗 1 年后,其 HtSDS 约增加 0.821 个单位/年(P0.001,95%CI=0.641-1.001),相应身高约增加 9.274cm/年(P0.001,95%CI=8.709-9.838);③GG基因型患儿治疗30天后,其HtSDS增加0.035个单位(P0.001,95%CI=0.018-0.051),身高增加 0.717cm(P0.001,95%CI=0.662-0.773);治疗 1 年后,HtSDS 约增加 0.499 个单位/年(P0.001,95%CI=0.274-0.724),相应身高约增加 8.983cm/年(P0.001,95%CI=8.125-9.841);(4)随着治疗时间的延长,AA基因型HtSDS(#P=0.222,#P=0.003)和身高(#P=0.025,#P=0.010)增长最明显,其次是GA基因型和GG基因型。(5)在Tanner Ⅱ-Ⅴ期的GHD患者中,尚没有发现随着治疗时间的延长,不同基因型与 HtSDS(#P=0.493,#P=0.128)和身高(#P=0.0.629,#P=0.458)存在差异性。结论:COL11A2基因与GHD的发生具有一定的相关性,AGACCAT单倍体为发生GHD的潜在致病体型,其患病风险增加了 41.3%。应用rhGH治疗的GHD患儿随访发现随着治疗时间的延长,HtSDS及身高的变化与rs9368758位点基因型之间存在一定相关性,处于青春期启动之前的GHD患儿,随着治疗时间的延长,AA基因型HtSDS(1.012单位/年)及身高(10.625cm/年)增长最明显,其次是GA基因型(HtSDS=0.821单位/年,身高=9.274cm/年)和GG基因型(HtSDS=0.499单位/年,身高=8.983cm/年)。处于青春期启动后的GHD患儿,没有观察到HtSDS和身高与基因型之间的差异性。
[Abstract]:Objective: To investigate the correlation between single nucleotide polymorphisms of COL11A2 gene and growth hormone deficiency (GHD), and the difference between the different genotype of COL11A2 gene polymorphism and the curative effect after the treatment of recombinant human growth hormone (rhGH) in children with GHD, to provide clinical evidence for clinical individualized treatment and to open the precision medical model of dwarfism. Methods: 229 children with GHD were selected as group GHD, and 314 healthy children with normal height were selected as the control group at the same time. 7 single nucleotide polymorphic loci of COL11A2 gene, which might have a certain correlation with GHD, were selected, and the method of matrix assisted laser desorption ionization time mass spectrometry (MALDI-TOF MS) was used in GHD group. Of the 7 candidate SNP loci in the normal control group, 106 of the 229 children with genotyping.GHD were treated with rhGH, the duration of the rhGH treatment was from January to 15 months, the treatment dose was 0.1 to 0.15U/Kg.d, and the 30 days as the unit were analyzed for the regular follow-up after the rhGH treatment of the.GHD children. A measuring tool was used to measure the height and weight of the children, calculate the growth rate (GV), height standard deviation score (HtSDS), body mass index (BM[), and examine the thyroid function, growth factor, liver function, etc. in children with fasting blood samples. The purpose of the study was to explore the GHD children with different COL11A2 genotypes, with the prolongation of the treatment time and the effect of the curative effect after rhGH treatment. The results were as follows: (1) the single nucleotide polymorphic locus (rs9368758) of COL11A2 gene was correlated with the occurrence of GHD, and the difference was statistically significant (P=0.012). (2) after linkage disequilibrium assessment and haplotype analysis, AGACCAT was found to be a potential pathogeny of GHD, and the risk of GHD increased more than that of other haplotypes. 41.3% (P=0.005, OR value =1.413,95%CI=1.113-1.823); (3) after analyzing the relationship between the different genotypes of the rs9368758 locus and the effect of the curative effect, it was found that the GHD children with rhGH treatment after the rhGH treatment were in Tanner I stage GHD children, and the curative effect of the rs9368758 loci was different: (1) the treatment time of the AA gene type children was increased by 30 days, and the HtSDS was HtSDS. The increase of 0.081 units (P0.001,95%CI=0.061-0.103), the corresponding height treatment for each increase of 30 days can increase 0.833cm (P0.001,95%CI=0.756-0.91); after 1 years of treatment, its HtSDS increases about 1.012 units / years (P0.001,95%CI=0.783-1.241), the corresponding height increases 10.625cm/ years (P0.001,95%CI=9.635-11.615); secondly, the GA genotype children are treated with every increase. After 30 days, the HtSDS increased by 0.068 units (P0.001,95%CI=0.052-0.086), and the corresponding height treatment could increase 0.773cm (P0.001,95%CI=0.720-0.826) after 30 days. After 1 years of treatment, the HtSDS increased by 0.821 units / years (P0.001,95%CI=0.641-1.001), the corresponding height increased about 9.274cm/ years (P0.001,95%CI=8.709-9.838); 3. GG genotypes After 30 days of treatment, the HtSDS increased by 0.035 units (P0.001,95%CI=0.018-0.051) and the height increased by 0.717cm (P0.001,95%CI=0.662-0.773). After 1 years of treatment, HtSDS increased by 0.499 units / years (P0.001,95%CI=0.274-0.724), and the corresponding height increased by 8.983cm/ years (P0.001,95%CI=8.125-9.841); (4) AA genotype Ht. The growth of SDS (#P=0.222, #P=0.003) and height (#P=0.025, #P=0.010) was the most obvious, followed by GA genotypes and GG genotypes. (5) there was no difference between the different genotypes and HtSDS (#P=0.493, #P=0.128) and height in the GHD patients in the Tanner II - V period. The occurrence of the AGACCAT haploid is a potential pathogeny of the occurrence of GHD, and the risk of the disease is increased by the follow-up of the GHD children with the rhGH treatment by 41.3%.. There is a definite correlation between the changes of HtSDS and height and the genotype of the rs9368758 loci with the prolongation of the time of treatment and the GHD suffering before the initiation of puberty. The growth of AA genotype HtSDS (1.012 unit / year) and height (10.625cm/) was the most obvious, followed by GA genotype (HtSDS=0.821 unit / year, height =9.274cm/) and GG genotypes (HtSDS=0.499 unit / year, height =8.983cm/). Children in GHD after puberty did not observe HtSDS and height and genes. Differences between types.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R725.8

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