HMGA2基因多态性与血清IGF-1关系及对特发性矮小症患儿体格发育指标的影响

Relationship of HMGA2 gene polymorphism with serum IGF-1 and its effect on physical development indicators in children with idiopathic short stature

摘要

目的 分析高迁移率族蛋白A2(HMGA2)基因多态性与血清胰岛素样生长因子-1(IGF-1)关系及对特发性矮小症(ISS)患儿体格发育指标的影响。方法 选取2021年9月至2023年6月广西壮族自治区妇幼保健院收治的115例ISS患儿(ISS组)为研究对象,另选同期115例正常儿童作为对照组,比较两组基线资料、体格发育指标、HMGA2基因rs1042725及rs7968682位点多态性、血清IGF-1,并比较不同HMGA2基因分型患儿生长速率,以Spearman相关性分析HMGA2基因多态性与血清IGF-1、生长速率关系,使用交互作用系数γ和交互作用比值比(OR)分析交互作用是否存在。结果 ISS组身高、生长速率低于对照组,差异有统计学意义(t值分别为34.047、57.275,P<0.05);ISS组HMGA2基因rs1042725及rs7968682位点基因型分布频数与对照组差异无统计学意义(P>0.05);ISS组IGF-1低于对照组,差异有统计学意义(t=5.000,P<0.05);两组HMGA2基因rs1042725位点CC基因型患儿生长速率高于TT和CT基因型患儿,差异有统计学意义(F值分别为250.419、29.691,P<0.05);两组HMGA2基因rs7968682位点不同基因型患儿生长速率差异无统计学意义(P>0.05);HMGA2基因rs1042725位点多态性与血清IGF-1、生长速率正相关(r值分别为0.755、0.817,P<0.05);交互作用分析显示单独非CC基因型所致的OR值为4.312,单独血清IGF-1异常所致的OR值为2.095,两者交互作用的OR值为10.748,满足超相乘模型;由于两者交互作用的系数γ为1.626>1,提示血清IGF-1对HMGA2基因rs1042725位点多态性的效应具有正向交互作用(P<0.05)。结论 HMGA2基因rs1042725位点多态性与血清IGF-1及生长速率有关,rs1042725位点CC基因型患者生长速率更高,血清IGF-1对HMGA2基因rs1042725位点多态性的效应具有正向交互作用,并满足超相乘模型,这一发现可能为ISS的病因及个性化治疗提供一个新思路.

Abstract

Objective To analyze relationship of high mobility group A2 (HMGA2) gene polymorphism with serum insulin-like growth factor (IGF-1) and its effect on physical development indexes in children with idiopathic short stature (ISS). Methods A total of 115 children with ISS (ISS group) who admitted to Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region from September 2021 to June 2023 were selected as research subjects, and 115 normal children in the same period were selected as control group. Baseline data, physical development indicators, polymorphisms of HMGA2 gene rs1042725 and rs7968682 loci, and serum IGF-1 level were compared between the two groups. And growth rate of the children with different HMGA2 genotypes was compared between the two groups. Spearman correlation analysis was used to analyze relationship of HMGA2 gene polymorphism with serum IGF-1 level and growth rate. Interaction coefficient γ and interaction odds ratio (OR) were used to analyze presence of interaction. Results The height and growth rate of the children in the ISS group were lower than those in the control group, and the differences were statistically significant (t=34.047 and 57.275 respectively, both P<0.05). There was no significant difference in the genotype distribution frequency of rs1042725 and rs7968682 loci of the HMGA2 gene between the ISS group and the control group (P>0.05). The serum level of IGF-1 of the children in the ISS group was lower than that in the control group, and the difference was statistically significant (t=5.000, P<0.05). The growth rate of the children with CC genotype at the rs1042725 locus of the HMGA2 gene in both groups was higher than that of the children with TT and CT genotypes, and the differences were statistically significant (F=250.419 and 29.691 respectively, both P<0.05). There was no significant difference in growth rate of the children with different genotypes of the HMGA2 gene rs7968682 locus between the two groups (P>0.05). The polymorphism of HMGA2 gene rs1042725 locus was positively correlated with serum IGF-1 level and growth rate (r=0.755 and 0.817 respectively, both P<0.05). The interaction analysis showed that the OR value caused by non-CC genotype alone was 4.312, the OR value caused by abnormal serum IGF-1 level alone was 2.095, and the OR value of the interaction between the two was 10.748, which met the supermultiplication model. Because the interaction coefficient γ between the two was 1.626 (which was more than 1), it suggested that serum IGF-1 had a positive interaction effect on the polymorphism of the HMGA2 gene rs1042725 locus (P<0.05). Conclusion The polymorphism of the HMGA2 gene rs1042725 locus is associated with serum IGF-1 level and growth rate. The children with the CC genotype at the rs1042725 locus have a higher growth rate, and serum IGF-1 level has a positive interactive effect on polymorphism of the HMGA2 gene rs1042725 locus, which satisfies the super multiplication model. This finding may provide a new idea for etiology and personalized treatment of ISS.

关键词

儿童 / 特发性矮小症 / 体格发育 / 高迁移率族蛋白A2 / 基因多态性 / 胰岛素样生长因子-1 / 相关性

Key words

children / idiopathic short stature / physical development / high mobility group A2 / gene polymorphism / insulin-like growth factor-1 / relevance

参考文献

[1] 相媛媛, 杜维维, 高世全, 等. 特发性矮小症患儿rhGH治疗前后血清BMP-2、TAZ水平变化及其预后价值[J]. 标记免疫分析与临床, 2023, 30(5): 805-810.

[2] Zhang H, Wu X, Sui Z, et al. High-mobility group AT-hook2 promotes growth and metastasis and is regulated by miR-204-5p in oesophageal squamous cell carcinoma[J]. Eur J Clin Invest, 2021, 51(8): e13563.

[3] 陈雅楠, 谭鑫, 邓德明, 等. 重组人生长激素治疗骨及软骨相关矮小症的疗效及其影响因素[J]. 临床药物治疗杂志, 2022, 20(9): 67-71.

[4] Zhong K, Zhu G, Jing X, et al. Genome-wide compound heterozygote analysis highlights alleles associated with adult height in Europeans[J]. Hum Genet, 2017, 136(11-12): 1407-1417.

[5] Vignali R, Marracci S. HMGA Genes and Proteins in Development and Evolution[J]. Int J Mol Sci, 2020, 21(2): 654.

[6] Srikanth K, Kim N Y, Park W, et al. Comprehensive genome and transcriptome analyses reveal genetic relationship,selection signature,and transcriptome landscape of small-sized Korean native Jeju horse[J]. Sci Rep, 2019, 9(1): 16672.

[7] Fusco I, Babu D, Mellone S, et al. Variations in the high-mobility group-A2 gene (HMGA2) are associated with idiopathic short stature[J]. Pediatr Res, 2016, 79(2): 258-261.

[8] 古佳露, 孙思媛, 高雪婷, 等. 生长激素联合营养治疗对特发性矮小症患儿身体机能指标的影响[J]. 中国妇幼健康研究, 2024, 35(2): 59-63.

[9] 李堂. 生长激素激发试验和胰岛素样生长因子1水平检测对生长激素缺乏症的诊断意义和思考[J]. 中国当代儿科杂志, 2023, 25(12): 1193-1197.

[10] 中华医学会儿科学分会内分泌遗传代谢学组, 《中华儿科杂志》编辑委员会, 梁雁. 基因重组人生长激素儿科临床规范应用的建议[J]. 中华儿科杂志, 2013, 51(6): 426-432.

[11] 陈婷婷, 郑晨果, 张佳舒, 等. 六君子汤合六味地黄汤联合生长激素治疗特发性矮小的疗效及对血清IGF-1、IGFBP-3的影响[J]. 中国卫生检验杂志, 2023, 33(19): 2319-2322.

[12] 叶芳兵, 朱宝菊. MMP2、IGF2BP2及HMGA2在侵入性胎盘组织中的表达[J]. 中国医药导报, 2022, 19(33): 92-95.

[13] 李鹏, 刘咏梅, 刘振华. 敲减HMGA2基因抑制TGF-β1诱导的人胚肺成纤维细胞生长及胶原合成[J]. 中国病理生理杂志, 2019, 35(9): 1648-1653.

[14] 肖雅. HMGA2基因多态性与青春期前特发性矮小患儿及重组人生长激素疗效的相关性研究分析[D]. 郑州: 郑州大学, 2020: 6-12.

[15] Bai H, Lu H, Wang L, et al. SNPs analysis of height traits in Ningqiang pony[J]. Anim Biotechnol, 2021, 32(5): 566-572.

[16] Takeshita H, Fujihara J, Soejima M, et al. Confirmation that SNPs in the high mobility group-A2 gene (HMGA2) are associated with adult height in the Japanese population;wide-ranging population survey of height-related SNPs in HMGA2[J]. Electrophoresis, 2011, 32(14): 1844-1851.

[17] Weedon M N, Lettre G, Freathy R M, et al. A common variant of HMGA2 is associated with adult and childhood height in the general population[J]. Nat Genet, 2007, 39(10): 1245-1250.

[18] 王伟, 肖雅, 罗向阳, 等. 高迁移率蛋白A2基因多态性与青春期前特发性矮小患儿及重组人生长激素疗效的相关性研究[J]. 中华实用儿科临床杂志, 2020, 35(17): 1351-1354.

[19] 余蓉蓉, 张小燕. 矮小症患儿血清维生素D、相关元素及其与患儿体格、生长激素、胰岛素样生长因子-1的相关性[J]. 中国现代医学杂志, 2022, 32(9): 78-83.

[20] 宋晓龙, 李玉芳, 周建平. 儿童身材发育缓慢与OC、β-CTX、IGF-1、IGFBP-3的相关性[J]. 检验医学与临床, 2023, 20(14): 2058-2061, 2065.

[21] 王潇敏, 洪开听, 杨晓岚. 矮小症儿童血尿酸与体格发育指标、胰岛素样生长因子1及丙氨酸转氨酶水平的关系[J]. 中国医药导报, 2024, 21(6): 98-101.

[22] 沈琳娜, 宋月娟, 夏欢. 血清Ghrelin、Omentin-1及IGF-1在特发性矮小症患儿中的表达变化及其与生长发育的相关性分析[J]. 临床和实验医学杂志, 2023, 22(20): 2208-2211.

[23] 邓茜, 陈雨青, 王娟娟, 等. 特发性矮小症患儿治疗前后血清IGF-1、IGFBP-3、25(OH)D、皮质醇水平变化及其与体格发育和骨龄的相关性分析[J]. 现代生物医学进展, 2022, 22(18): 3524-3527, 3595.

[24] Toni L, Plachy L, Dusatkova P, et al. The Genetic Landscape of Children Born Small for Gestational Age with Persistent Short Stature[J]. Horm Res Paediatr, 2024, 97(1): 40-52.

基金资助

广西壮族自治区卫生和计划生育委员会自筹经费科研项目(Z20210597)