尿苷二磷酸葡萄糖醛酸转移酶1A1、1A3、1A9基因多态性与非布司他疗效差异性的关系

Correlation between uridine diphosphate glucuronosyltransferase 1A1,1A3,1A9polymorphism and treatment response of febuxostat

目的探讨尿苷二磷酸葡萄糖醛酸转移酶(UGT)1A1(rs8330)、UGT1A3(rs6742078,rs887829)、UGT1A9(rs1105880,rs6759892)基因多态性对非布司他疗效的影响。方法收集102例接受非布司他(40 mg qd)治疗的高尿酸血症住院患者。用高通量测序分析相关基因多态性,收集给药前后血尿酸水平,用SPSS 17.0软件Shapiro-Wilk法对相关指标进行正态检验,用Kruskal-Wallis检验各基因多态性对非布司他调节尿酸疗效的影响。结果 UGT1A1(rs8330)突变率13.70%,治疗后野生型患者尿酸降低(232.64±107.17)μmol·L^(-1)、突变杂合型降低(267.10±135.14)μmol·L^(-1)、突变纯合型降低(398.70±160.65)μmol·L^(-1),各组间尿酸改变程度差异均无统计学意义(均P>0.05);但突变型患者治疗后的尿酸水平为(190.55±173.3)μmol·L^(-1)显著低于野生型的(324.08±98.15)μmol·L^(-1),差异有统计学意义(P<0.05)。UGT1A9(rs1105880,rs6759892)突变率为39.22%,治疗后野生型患者尿酸降低(251.37±112.10)μmol·L^(-1)、突变杂合型患者降低(225.08±114.53)μmol·L^(-1)、突变纯合型降296.50μmol·L^(-1),各组间尿酸改变程度差异均无统计学意义(均P>0.05)。UGT1A3(rs6742078,rs887829)突变率18.63%,突变纯合型患者经非布司他治疗,血尿酸改变433.90μmol·L^(-1)与突变杂合型(292.97±124.48)μmol·L^(-1)和野生纯合型(225.31±105.32)μmol·L^(-1)比较,差异均有统计学意义(均P<0.05)。结论 UGT1A3(rs6742078,rs887829)、UGT1A9(rs1105880,rs6759892)两基因的两位点分别呈连锁不平衡状态;UGT1A3(rs6742078,rs887829)突变基因携带的高尿酸血症患者以非布司他治疗时,疗效比野生型患者显著,其余研究位点单核苷酸多态性未显著影响其疗效。

Objective To investigate the influence of gene polymorphisms about uridine diphosphate glucuronosyltransferase(UGTs)1A1(rs8330),1A3(rs6742078,rs887829),1A9(rs1105880,rs6759892)locuses on the treatment response of febuxostat.Methods A total of 102 hyperuricemia patients receiving febuxostat 40 mg·d^(-1) were genotyped for UGT1A1(rs8330),UGT1A3(rs6742078,rs887829)and UGT1A9(rs1105880,rs6759892)polymorphisms.High throughput sequencing was used to analyze gene polymorphisms.The serum uric acid(SUA)concentration was measured before and after drug administration.A normal test was conducted on some relevant indexes using Shapiro-Wilk method and the differences among various genotypes was further tested.The genotypic influence on treatment response of febuxostat was explored through Kruskal-Wallis test by SPSS17.0.Results The mutation rate of UGT1 A1(rs8330)was 13.70%.After treatment,SUA of wild type patients decreased by(232.64±107.17)μmol·L^(-1),heterozygous patients decreased by(267.10±135.14)μmol·L^(-1),mutation homozygous patients decreased by(398.70±160.65)μmol·L^(-1),there were no significant differences in the reduction of SUA(ΔSUA)among different genotypic groups(all P>0.05).However,the SUA level(190.55±173.3)μmol·L^(-1) of UGT1 A1(rs8330)mutation carriers was obviously lower than that(324.08±98.15)μmol·L^(-1) of patients with wild type(P<0.05)after treatment.The mutation rate of UGT1 A9(rs1105880,rs6759892)was 39.22%.TheΔSUA of wild type patients was(251.37±112.10)μmol·L^(-1),it was(225.08±114.53)μmol·L^(-1) for heterozygous patients and 296.50μmol·L^(-1) for mutation homozygous patients,it showed no significant differences in theΔSUA among different genotypic groups(all P>0.05).The mutation rate of UGT1 A3(rs6742078,rs887829)was 18.63%.TheΔSUA for patients with homozygous mutation was 433.90μmol·L^(-1),which was more obvious than the patients of heterozygous(292.97±124.48)μmol·L^(-1) and wild type mutation(225.31±105.32)μmol·L^(-1)(P<0.05).Conclusion Two locuses of UGT1 A3(rs6742078,rs887829)and UGT1 A9(rs1105880,rs6759892)exposed significant linkage disequilibrium.Compared to hyperuricemia patients carrying wild type gene,the hyperuricemia patients with UGT1 A3(rs6742078,rs887829)displayed better treatment response.The single nucleotide polymorphism for UGT1 A1(rs8330)and UGT1 A9(rs1105880,rs6759892)had no effect on the treatment response of febuxostat significantly.