Genetic Polymorphisms of SPRY4 are Associated with Adolescent Idiopathic Scoliosis in Chinese Han Population: A Single Center Retrospective Study
-
摘要:
目的 探究SPRY4基因多态性与中国汉族人群青少年特发性脊柱侧凸(adolescent idiopathic scoliosis,AIS)及PUMC分型的相关性,以期为该病的病因学研究提供思路。 方法 回顾性收集2017年12月—2021年12月北京协和医院诊治的中国北方地区汉族AIS患者及按年龄、性别与其进行1∶1匹配的健康受试者临床资料。比较二者SPRY4基因rs3797053、rs10040443位点等位基因频率及基因型分布差异,并分析上述位点基因型与AIS患者PUMC分型的关联性。 结果 共入选符合纳入与排除标准的AIS患者97例,健康受试者100名。AIS患者rs10040443位点等位基因C[17.5%(34/194)比8.0%(16/200),P=0.005]及CC基因型频率[10.3%(10/97)比1.0%(1/100),P=0.0014]均高于健康受试者,rs3797053位点等位基因频率及基因型分布与健康受试者均无显著差异(P均>0.05)。多因素Logistic回归分析校正性别的影响后,rs10040443位点多态性在共显性、隐性及加性遗传模式下与AIS均存在关联性,其CC基因型可增加AIS发生风险;在各种遗传模式下,rs3797053位点多态性与AIS均无明显关联性。AIS患者SPRY4基因rs10040443位点基因型分布与PUMC分型具有一定关联性,CT+TT基因型患者中PUMC Ⅱ型的比例显著高于CC基因型患者(66.67% 比0,P<0.001);rs3797053位点基因型分布与PUMC分型无明显关联性(P=0.315)。 结论 中国北方地区汉族人群SPRY4基因rs10040443位点多态性与AIS相关,该位点CC基因型可能是AIS的危险因素,CT+TT基因型与PUMC Ⅱ型具有一定关联。 -
关键词:
- 基因多态性 /
- 青少年特发性脊柱侧凸 /
- PUMC分型 /
- SPRY4基因
Abstract:Objective To explore the correlation between SPRY4 gene polymorphism and typing of adolescent idiopathic scoliosis (AIS) and PUMC in Han Chinese, in order to provide insights for etiological research of the disease. Methods Clinical data were retrospectively collected from Han nationality patients with AIS in northern China treated at Peking Union Medical College Hospital from December 2017 to December 2021, and healthy subjects were matched 1∶1 with them by age and sex. The allele frequency and genotype distribution of rs3797053 and rs10040443 of SPRY4 gene were compared, and the association between the above loci genotypes and PUMC typing of AIS patients was analyzed. Results A total of 97 patients with AIS and 100 healthy subjects who met inclusion and exclusion criteria were included in this study. The rs10040443 allele C[17.5%(34/194) vs. 8.0%(16/200), P=0.005] and the distribution frequency of CC genotype [10.3%(10/97) vs. 1.0%(1/100), P=0.0014] in AIS patients were higher than those in healthy subjects. There was no significant difference in allele frequency and genotype distribution of rs3797053 between AIS patients and healthy subjects (all P > 0.05). After adjusting for gender, multiple Logistic regression analysis showed that rs10040443 polymorphism was associated with AIS in codominant, recessive and additive genetic modes, and CC genotype could increase the risk of AIS. There was no significant association between rs3797053 polymorphism and AIS in all genetic models. The genotype distribution of rs10040443 of SPRY4 gene in AIS patients was associated with PUMC typing. The proportion of PUMC Ⅱ in CT+TT genotype patients was significantly higher than that in CC genotype patients (66.67% vs. 0, P < 0.001). Rs3797053 genotype distribution was not significantly associated with PUMC genotype distribution (P=0.315). Conclusions The polymorphism of rs10040443 of SPRY4 gene is associated with AIS in northern Chinese Han population. CC genotype of this locus may be a risk factor for AIS, and CT+TT genotype is associated with PUMCⅡ type. -
Key words:
- gene polymorphism /
- adolescent idiopathic scoliosis /
- PUMC type /
- SPRY4 gene
作者贡献:吴增玉负责研究设计、数据收集与整理、统计分析、论文撰写;张跃川负责文献检索;彭越负责伦理材料收集;吴南负责测序数据及伦理材料收集;邱贵兴、庄乾宇、仉建国负责研究设计、研究指导、论文修订。利益冲突:所有作者均声明不存在利益冲突 -
表 1 AIS患者与健康受试者SPRY4基因rs3797053、rs10040443位点基因型及等位基因分布比较[n(%)]
组别 rs3797053 rs3797053 rs10040443 rs10040443 A G AA GA GG C T CC CT TT 健康受试者(n=100) 126(63.0) 74(37.0) 40(40.0) 46(46.0) 14(14.0) 16(8.0) 184(92.0) 1(1.0) 14(14.0) 85(85.0) AIS患者(n=97) 133(68.5) 61(31.5) 45(46.3) 43(44.3) 9(9.4) 34(17.5) 160(82.5) 10(10.3) 14(14.4) 73(75.3) P值 0.245 0.499 0.005 0.014 AIS:青少年特发性脊柱侧凸 表 2 校正性别因素后,SPRY4基因rs3797053位点与AIS的关联性分析[n(%)]
遗传模式 健康受试者(n=100) AIS患者(n=97) OR(95% CI) P值 共显性 0.460 AA 40(40.0) 45(46.4) 1 GA 46(46.0) 43(44.3) 0.83(0.46~1.51) GG 14(14.0) 9(9.3) 0.57(0.22~1.46) 显性 0.340 AA 40(40.0) 45(46.4) 1 GA+GG 60(60.0) 52(53.6) 0.77(0.44~1.36) 隐性 0.280 AA+GA 86(86.0) 88(90.7) 1 GG 14(14.0) 9(9.3) 0.63(0.26~1.53) 超显性 0.800 AA+GG 54(54.0) 54(55.7) 1 GA 46(46.0) 43(44.3) 0.93(0.53~1.64) 加性 0.78(0.51~1.19) 0.230 AIS:同表 1 表 3 校正性别因素后,SPRY4基因rs10040443位点与AIS的关联性分析[n(%)]
遗传模式 健康受试者(n=100) AIS患者(n=97) OR(95% CI) P值 共显性 0.010 TT 85(85.0) 73(75.3) 1 CT 14(14.0) 14(14.4) 1.16(0.52~2.60) CC 1(1.0) 10(10.3) 11.64(1.46~93.10) 显性 0.093 TT 85(85.0) 73(75.3) 1 CT+CC 15(15.0) 24(24.7) 1.86(0.91~3.82) 隐性 0.0026 TT+CT 99(99.0) 87(89.7) 1 CC 1(1.0) 10(10.3) 11.38(1.43~90.66) 超显性 0.950 TT+CC 86(86.0) 83(85.6) 1 CT 14(14.0) 14(14.4) 1.04(0.47~2.31) 加性 1.96(1.12~3.43) 0.015 AIS: 同表 1 表 4 不同性别、PUMC分型AIS患者SPRY4基因rs3797053、rs10040443位点基因型分布比较[n(%)]
基因位点 性别 PUMC分型 男性 女性 Ⅰ型 Ⅱ型 Ⅲ型 rs3797053 AA 6(6.2) 39(40.2) 17(17.5) 24(24.8) 4(4.1) GA 6(6.2) 37(38.1) 9(9.3) 27(27.8) 7(7.2) GG 1(1.0) 8(8.2) 2(2.1) 7(7.2) 0(0) P值* >0.999 0.315 rs10040443 CC 1(1.0) 9(9.3) 6(6.2) 0(0) 4(4.1) CT 2(2.1) 12(12.4) 7(7.2) 5(5.2) 2(2.1) TT 10(10.3) 63(64.9) 15(15.4) 53(54.6) 5(5.2) P值* >0.999 <0.001 *采用Fisher精确概率法;AIS:同表 1 -
[1] Shere C, Clark EM. Systematic review of the association between isolated musculoskeletal hypermobility and adolescent idiopathic scoliosis[J]. Arch Orthop Trauma Surg, 2022. doi: 10.1007/s00402-022-04508-z. [2] Marya S, Tambe AD, Millner PA, et al. Adolescent idiopathic scoliosis: a review of aetiological theories of a multifactorial disease[J]. Bone Joint J, 2022, 104: 915-921. [3] Kruse LM, Buchan JG, Gurnett CA, et al. Polygenic threshold model with sex dimorphism in adolescent idiopathic scoliosis: the Carter effect[J]. J Bone Joint Surg Am, 2012, 94: 1485-1491. doi: 10.2106/JBJS.K.01450 [4] Li J, Li N, Chen Y, et al. SPRY4 is responsible for pathogenesis of adolescent idiopathic scoliosis by contributing to osteogenic differentiation and melatonin response of bone marrow-derived mesenchymal stem cells[J]. Cell Death Dis, 2019, 10: 805. doi: 10.1038/s41419-019-1949-7 [5] Hui S, Yang Y, Li J, et al. Differential miRNAs profile and bioinformatics analyses in bone marrow mesenchymal stem cells from adolescent idiopathic scoliosis patients[J]. Spine J, 2019, 19: 1584-1596. doi: 10.1016/j.spinee.2019.05.003 [6] Zhang R, Su B. Small but influential: the role of microRNAs on gene regulatory network and 3'UTR evolution[J]. J Genet Genomics, 2009, 36: 1-6. doi: 10.1016/S1673-8527(09)60001-1 [7] Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets[J]. Cell, 2005, 120: 15-20. doi: 10.1016/j.cell.2004.12.035 [8] Navarro E, Mallén A, Hueso M. Dynamic Variations of 3'UTR Length Reprogram the mRNA Regulatory Landscape[J]. Biomedicines, 2021, 46: 48-56. http://www.socolar.com/Article/Index?aid=100091223010&jid=100000036299 [9] Griesemer D, Xue JR, Reilly SK, et al. Genome-wide functional screen of 3'UTR variants uncovers causal variants for human disease and evolution[J]. Cell, 2021, 184: 5247-5260. doi: 10.1016/j.cell.2021.08.025 [10] Liu G, Liu S, Li X, et al. Genetic polymorphisms of PAX1 are functionally associated with different PUMC types of adolescent idiopathic scoliosis in a northern Chinese Han population[J]. Gene, 2019, 688: 215-220. doi: 10.1016/j.gene.2018.12.013 [11] Nguyen-Chi ME, Bryson-Richardson R, Sonntag C, et al. Morphogenesis and cell fate determination within the adaxial cell equivalence group of the zebrafish myotome[J]. PLoS Genet, 2012, 8: e1003014. doi: 10.1371/journal.pgen.1003014 [12] Sutherland D, Samakovlis C, Krasnow MA. Branchless encodes a Drosophila FGF homolog that controls tracheal cell migration and the pattern of branching[J]. Cell, 1996, 87: 1091-1101. doi: 10.1016/S0092-8674(00)81803-6 [13] Wells KL, Gaete M, Matalova E, et al. Dynamic relationship of the epithelium and mesenchyme during salivary gland initiation: the role of Fgf10[J]. Biol Open, 2014, 3: 677. doi: 10.1242/bio.20149084 [14] Kuracha MR, Burgess D, Siefker E, et al. Spry1 and Spry2 are necessary for lens vesicle separation and corneal differentiation[J]. Invest Ophthalmol Vis Sci, 2011, 52: 6887-6897. doi: 10.1167/iovs.11-7531 [15] Casci T, Vinós J, Freeman M. Sprouty, an intracellular inhibitor of Ras signaling[J]. Cell, 1999, 96: 655-665. doi: 10.1016/S0092-8674(00)80576-0 [16] Plotnik JP, Budka JA, Ferris MW, et al. ETS1 is a genome-wide effector of RAS/ERK signaling in epithelial cells[J]. Nucleic Acids Res, 2014, 42: 11928-11940. doi: 10.1093/nar/gku929 [17] Yang X, Gong Y, Tang Y, et al. Spry1 and Spry4 differentially regulate human aortic smooth muscle cell phenotype via Akt/FoxO/myocardin signaling[J]. PLoS One, 2013, 8: e58746. doi: 10.1371/journal.pone.0058746 [18] Felfly H, Klein OD. Sprouty genes regulate proliferation and survival of human embryonic stem cells[J]. Sci Rep, 2013, 3: 2277. doi: 10.1038/srep02277 [19] Sasaki A, Taketomi T, Wakioka T, et al. Identification of a dominant negative mutant of Sprouty that potentiates fibroblast growth factor- but not epidermal growth factor-induced ERK activation[J]. J Biol Chem, 2001, 276: 36804-36808. doi: 10.1074/jbc.C100386200 [20] Li N, Chen Y, Wang H, et al. SPRY4 promotes adipogenic differentiation of human mesenchymal stem cells through the MEK-ERK1/2 signaling pathway[J]. Adipocyte, 2022, 11: 588-600. doi: 10.1080/21623945.2022.2123097 [21] Tian L, Xiao H, Li M, et al. A novel Sprouty4-ERK1/2-Wnt/β-catenin regulatory loop in marrow stromal progenitor cells controls osteogenic and adipogenic differentiation[J]. Metabolism, 2020, 105: 154-189. doi: 10.3760/cma.j.cn121383-20190905-09007 [22] Wang Y, Li M, Chan CO, et al. Biological effect of dysregulated LBX1 on adolescent idiopathic scoliosis through modulating muscle carbohydrate metabolism[J]. Spine J, 2022, 22: 1551-1565. doi: 10.1016/j.spinee.2022.04.005 [23] Yang Y, Yang M, Shi D, et al. Single-cell RNA Seq reveals cellular landscape-specific characteristics and potential etiologies for adolescent idiopathic scoliosis[J]. JOR Spine, 2021, 4: e1184. http://doc.paperpass.com/foreign/rgArti2021295348444.html [24] Song YQ, Karasugi T, Cheung KM, et al. Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant[J]. J Clin Invest, 2013, 123: 4909-4917. doi: 10.1172/JCI69277 [25] Zhu DL, Guo Y, Zhang Y, et al. A functional SNP regulated by miR-196a-3p in the 3'UTR of FGF2 is associated with bone mineral density in the Chinese population[J]. Hum Mutat, 2017, 38: 725-735. doi: 10.1002/humu.23216 [26] 邱勇, 朱泽章, 朱锋, 等. 青少年特发性脊柱侧凸King、Lenke和PUMC(协和)分型的可信度和可重复性比较及意义[J]. 中华骨科杂志, 2007, 10: 748-752. doi: 10.3760/j.issn:0253-2352.2007.10.007
计量
- 文章访问数: 232
- HTML全文浏览量: 27
- PDF下载量: 27
- 被引次数: 0