帕金森病患者维生素D受体基因多态性及血清25-羟维生素D水平变化观察

Changes in vitamin D receptor gene polymorphism and serum 25-hydroxyvitamin D levels in patients with Parkinson's disease and their significance

目的 观察帕金森病(PD)患者维生素D受体(VDR)基因多态性和血清25-羟维生素D(25(OH)D)水平变化,分析二者与PD发病的相关性及对PD发病的预测效能,以明确VDR基因多态性及血清25(OH)D水平与PD发病的关系。方法 纳入178例PD患者(PD组)及同时期185例体检健康者(对照组)。采用PCR法和DNA测序法检测VDR基因FokⅠ(rs2228570)和BsmⅠ(rs1544410)位点的基因分型,采用酶联免疫吸附法检测外周血清25(OH)D,对两组上述指标进行比较。采用多因素Logistic回归分析PD发病独立危险因素;ROC分析维生素D受体基因多态性和血清25-羟维生素D水平对PD发病的预测效能。结果 PD组FokI位点T等位基因与TT基因型频率分别为48.6%、25.3%,对照组分别为37.7%、15.1%,两组比较,χ2分别为8.516、10.383,P分别为0.004、0.001。PD组BsmⅠ位点各等位基因及基因型与对照组比较差异均无统计学意义(P均>0.05)。PD组血清25(OH)D水平为(16.06±6.04)ng/mL,对照组为(19.22±6.32)ng/mL,两组比较,t=-4.873,P=0.000。PD组TC型、CC型患者血清25(OH)D水平均低于对照组(t分别为-3.093、3.329,P分别为0.002、0.001)。当血清25(OH)D水平一致时,基因型TT、TC分别是基因型CC患PD风险的2.527及1.888倍(P均<0.05)。当基因型一致时,血清25(OH)D水平缺乏是充足水平人群患PD风险的1.918倍(P<0.05)。当基因型为TT且伴25(OH)D缺乏、基因型为TC伴25(OH)D缺乏人群患PD的风险分别是基因型为CC伴25(OH)D充足人群的4.818、3.822倍(P均<0.05)。FokⅠ位点基因型TT预测PD发病的ROC下AUC为0.610,95%CI为0.532~0.687,诊断界值为0.502,灵敏度74.5%,特异度47.4%;血清25(OH)D水平缺乏预测PD发病的ROC下AUC为0.576,95%CI为0.517~0.635,诊断界值0.466,灵敏度72.5%,特异度42.7%;基因型TT联合血清25(OH)D缺乏预测PD发病ROC下AUC为0.693,95%CI为0.588~0.798,灵敏度64.2%,特异度74.5%。结论 VDR基因FokⅠ位点T等位基因与TT基因型频率高,血清25(OH)D水平低;FokⅠ位点T等位基因和维生素D缺乏单独及共同存在均可促进PD发生,二者对PD发病风险的预测效能欠佳。

Objective To observe the changes in vitamin D receptor(VDR) gene polymorphisms and serum 25-hydroxyvitamin D(25(OH)D) levels in patients with Parkinson's disease(PD),and to analyze their correlations with the onset of PD and their predictive efficiency on the onset of PD in order to clarify the significance of VDR gene polymorphisms and changes in serum 25(OH)D levels.Methods Totally 178 PD patients(PD group) and 185 healthy subjects(control group) during the same period were included.PCR and DNA sequencing methods were used to detect the genotyping of VDR gene FokI(rs2228570) and BsmI(rs1544410) sites,and enzyme-linked immunosorbent assay was used to detect peripheral serum 25(OH)D.The above indicators between the two groups were compared.Multivariate Logistic regression was used to analyze the independent risk factors for the onset of PD;ROC was used to analyze the predictive efficacy of vitamin D receptor gene polymorphisms and serum 25-hydroxyvitamin D levels for the onset of PD.Results The frequencies of T allele and TT genotype of FokI site in the PD group were 48.6% and 25.3% respectively,and 37.7% and 15.1% in the control group,respectively.Comparing the two groups,χ2 were 8.516 and 10.383,respectively,and P were 0.004 and 0.001,respectively.There were no statistically significant differences in the alleles or genotypes of the BsmI locus between the PD group and the control group(all P>0.05).The serum 25(OH)D level in the PD group was(16.06±6.04) ng/mL,and that in the control group was(19.22±6.32) ng/mL(t=–4.873,P=0.000).The serum 25(OH)D levels of patients with TC type and CC type in the PD group were lower than those in the control group(t=–3.093,3.329,respectively;P=0.002,0.001,respectively).When the serum 25(OH)D levels were consistent,patients with genotypes TT and TC were 2.527 and 1.888 times more likely to develop PD than patients with genotype CC,respectively(all P<0.05).When the genotypes were consistent,patients with deficient serum 25(OH)D level were 1.918 times more likely to develop PD than those with sufficient level(P<0.05).As for genotype TT patients with 25(OH)D deficiency,and genotype TC patients with 25(OH)D deficiency,their risks of developing PD were 4.818 and 3.822 times that of genotype CC patients with sufficient 25(OH)D,respectively(all P<0.05).The AUC under ROC of FokI locus genotype TT in predicting the onset of PD was 0.610,95%CI was 0.532–0.687,the diagnostic cut-off value was 0.502,the sensitivity was 74.5%,and the specificity was 47.4%;The AUC under the ROC of lack of serum 25(OH)D level in predicting the onset of PD was 0.576,the 95%CI was 0.517–0.635,the diagnostic cut-off value was 0.466,the sensitivity was 72.5%,and the specificity was 42.7%,respectively;the AUC under ROC of genotype TT combined with serum 25(OH)D deficiency in predicting the onset of PD was 0.693,95%CI was 0.588–0.798,the sensitivity was 64.2%,and the specificity was 74.5%,respectively.Conclusions The frequencies of the T allele and TT genotype at the FokI site of the VDR gene are high,and the serum 25(OH)D level is low;the T allele at the FokI site and vitamin D deficiency can promote the occurrence of PD individually or together,and both of them have poor predictive efficiency for the risk of PD onset.