中国汉族人群NR3C1 MTHFR和IGFBP3基因多态性及DNA甲基化与激素性股骨头坏死风险的相关分析

目的 探究NR3C1、MTHFR和IGFBP3基因多态性及DNA甲基化状态与激素性股骨头坏死(SONFH)之间的关系。方法 本病例对照研究中,选自合肥及周边地区包括79例短期冲击或长期口服糖皮质激素治疗SONFH的患者为病例组,114例服用糖皮质激素但未发生SONFH的患者为对照组。评估两组NR3C1、MTHFR和IGFBP3基因中的5个单核苷酸多态性(SNPs),这些SNPs由iMLDR进行基因分型。采用MethylTarget技术检测阳性位点(CpG位点)的甲基化水平,利用e QTLD技术分析以上3个基因的SNPs与甲基化水平的相互作用。结果 病例组与对照组相比,rs3110697 A/G基因型携带者患病风险低;在隐性遗传模型下,rs3110697 A等位基因携带者患病风险低;CpG位点IGFBP3_ 2-143、MTHFR_1-36、MTHFR_1-77、MTHFR_1-139、MTHFR_2-42、NR3C1_2-163、NR3C1_4-47甲基化水平差异显著,差异有统计学意义(P<0.05);共有10对SNPs与甲基化位点线性回归检验差异有统计学意义(P<0.05)。结论 SONFH是一种多基因病,其3个关联基因NR3C1、MTHFR和IGFBP3中的SNPs与DNA甲基化水平均存在广泛交互作用,有助于进一步建立SONFH基因调控模型指导临床诊疗。

Association analysis of NR3C1, MTHFR, IGFBP3 gene polymorphisms and DNA methylation with SONFH risk in Chinese Han population

Objective To explore the relationship between gene polymorphisms of NR3C1,MTHFR,IGFBP3 and DNA methylation status with steroid-induced osteonecrosis of the femoral head (SONFH).Methods We selected 79 patients with SONFH and 114 patients who took glucocorticoids but no SONFH occurred from Hefei and surrounding areas in this case-control study. Five single nucleotide polymorphisms (SNPs) in NR3C1, MTHFR and IGFBP3 genes were evaluated in Chinese Han population. These SNPs were genotyped by iMLDR method. MethylTarget technique was used to detect the methylation level of positive sites(CpG sites), and eQTLD technique was used to analyze the interactions between SNPs of the above three genes and methylation level.Results The genotype frequency of rs3110697 A/G genotype carriers in the case group was lower than that in the control group. Under the recessive genetic model, the risk of rs3110697 A allele carriers was low.The methylation level of the screened CpG sites as IGFBP3_ 2-143,MTHFR_1-36,MTHFR_1-77,MTHFR_1-139,MTHFR_2-42,NR3C1_2-163,NR3C1_4-47 was significantly differentcompared with the control group,and the difference was statistically significant (P<0.05). There were 10 pairs of SNPs and methylation sites with statistical significance.Conclusions SONFH is a polygenic disease. The SNPs in NR3C1, MTHFR and IGFBP3 have extensive interaction with DNA methylation levels, which helps to further establish the model of SONFH gene regulatory network to dominate the disease process.