诱骗受体和护骨素基因多态性与克罗恩病易感性和疾病表型的相关性

Association of decoy receptors and osteoprotegerin gene polymorphisms with susceptibility and clinical phenotypes of Crohn′s disease

目的探讨浙江籍汉族人群中诱骗受体1、诱骗受体2和护骨素基因多态性与CD易感性的关系。方法纳入2008年4月至2017年7月于温州医科大学附属第二医院、温州医科大学附属第一医院、温州市中心医院和温州市人民医院消化内科确诊为CD的285例患者,另外纳入同期在温州医科大学附属第二医院进行体检的572名健康对照者。采用SNaPshot技术检测研究对象诱骗受体1 (rs12549481)、诱骗受体2 (rs1133782)和护骨素(rs3102735) 3种单核苷酸多态性(SNP)。在CD组和健康对照组之间,采用非条件logistic回归分析各SNP的突变等位基因和基因型频率差异,评价其与CD临床病理特征、糖皮质激素和英夫利西单克隆抗体疗效的关系。结果 CD组诱骗受体2 (rs1133782)的突变等位基因A和基因型GA+AA频率分别为11.93%(68/570)和22.81%(65/285),分别高于健康对照组的8.22%(94/1 144)和15.91%(91/572),差异均有统计学意义(OR=1.513,95%CI 1.088~2.104,P=0.013;OR=1.562,95%CI 1.094~2.230,P=0.014);两组间诱骗受体1 (rs12549481)和护骨素(rs3102735)突变等位基因和基因型频率差异均无统计学意义(P均>0.05)。狭窄型CD患者诱骗受体1 (rs12549481)的突变等位基因C和基因型TC+CC频率分别为13.89%(25/180)和27.78%(25/90),分别低于非狭窄非穿透型CD患者的27.68%(62/224)和48.21%(54/112),差异均有统计学意义(OR=0.421,95%CI 0.252~0.705,P=0.001;OR=0.413,95%CI 0.229~0.747,P=0.003);穿透型CD患者诱骗受体2 (rs1133782)的突变等位基因A和基因型GA+AA频率分别为7.23%(12/166)和13.25%(11/83),分别低于非狭窄非穿透型CD患者的15.62%(35/224)和30.36%(34/112),差异均有统计学意义(OR=0.407,95%CI 0.205~0.809,P=0.009;OR=0.350,95%CI 0.165~0.743,P=0.005);CD不同疾病行为亚组之间,护骨素(rs3102735)的突变等位基因和基因型频率差异均无统计学意义(P均>0.012 5)。诱骗受体1 (rs12549481)、诱骗受体2 (rs1133782)和护骨素(rs3102735)基因多态性与糖皮质激素和英夫利西单克隆抗体疗效均无关联(P均>0.05)。结论诱骗受体1 (rs12549481)基因突变可能与狭窄型CD相关。诱骗受体2 (rs1133782)基因突变可能与CD尤其是穿透型CD相关。护骨素(rs3102735)基因多态性与CD发病风险无关。上述基因SNP可能与糖皮质激素和英夫利西单克隆抗体疗效均无关。

Objective To investigate the correlation between decoy receptor (DcR)1, DcR2, osteoprotegerin (OPG) gene polymorphisms and susceptibility of Crohn′s disease (CD) in Han population in Zhejiang province. Methods From April 2008 to July 2017, at the Department of Gastroenterology of The Second Affiliated Hospital of Wenzhou Medical University, The First Affiliated Hospital of Wenzhou Medical University, Central Hospital of Wenzhou and Renmin Hospital of Wenzhou, 285 patients diagnosed as having CD were enrolled, and during the same period 572 healthy individuals who received health checkup at the Second Affiliated Hospital of Wenzhou Medical University were collected as healthy control. The single nucleotide polymorphism (SNP) of DcR1 (rs12549481), DcR2 (rs1133782) and OPG (rs3102735) were examined by SNaPshot technique. An unconditional logistic regression analysis was performed to analyze the differences in each SNP mutation alleles and genotype frequencies between CD group and control group. Furthermore, their correlation with clinicopathological features of CD and the efficacy of corticosteroid and infliximab was also evaluated. Results The frequencies of mutant allele A and genotype GA+ AA of DcR2 (rs1133782) of CD group were 11.93%(68/570) and 22.81%(65/285), respectively, which were higher than those of healthy control group (8.22%, 94/1 144;and 15.91%, 91/572;odds ratio (OR)=1.513, 95% confidence interval (CI) 1.088 to 2.104, P=0.013;OR=1.562, 95%CI 1.094 to 2.230, P=0.014). However there was no statistically significant difference in the mutant allele and genotype frequencies of DcR1 (rs12549481) and OPG (rs3102735) between two groups (all P>0.05). The frequencies of mutant allele C and genotype TC+ CC of DcR1 (rs12549481) in patients with stricturing CD were 13.89%(25/180) and 27.78%(25/90), respectively, which were lower than those of patients with non-stricturing, non-penetrating CD (27.68%, 62/224 and 48.21%, 54/112), and the differences were statistically significant (OR=0.421, 95%CI 0.252 to 0.705, P=0.001;OR=0.413, 95%CI 0.229 to 0.747, P=0.003). Besides, the frequencies of mutant allele A and genotypes GA+ AA of DcR2 in patients with penetrating CD were 7.23%(12/166) and 13.25%(11/83), which were lower than those of patients with non-stricturing, non-penetrating CD (15.62%, 35/224 and 30.36%, 34/112), and the differences were statistically significant (OR=0.407, 95%CI 0.205 to 0.809, P=0.009;OR=0.350, 95%CI 0.165 to 0.743, P=0.005). In addition, there was no statistically significant difference in the frequencies of mutant allele and genotypes of OPG (rs3102735) among subtypes of CD with different features (all P>0.012 5). Moreover, the DcR1 (rs12549481), DcR2 (rs1133782) and OPG (rs3102735) polymorphisms were not correlated with the efficacy of corticosteroid and infliximab (all P>0.05). Conclusions DcR1 (rs12549481) mutation may be correlated with stricturing CD. DcR2 (rs1133782) mutation may be correlated with CD, especially with penetrating CD. However, the gene polymorphism of OPG (rs3102735) is not correlated with the risk of CD susceptibility. And the above gene SNP may be independent of the efficacy of corticosteroid and infliximab.