HLA基因多态性与非典型抗精神病药物性肝损伤关联性研究

Correlation between HLA-B and drug induced liver injury caused by atypical antipsychotics

目的研究HLA相关基因(HLA-B)多态性与非典型抗精神病药物性肝损伤的关联性。方法选取单一使用非典型抗精神病药的194例精神分裂症患者,符合药物性肝损伤(DILI)诊断的95例患者为DILI组,不符合DILI诊断的99例患者为非DILI组。采用Sanger法对DILI组和非DILI组间的HLA-B基因上的SNP位点rs3819299、rs2523608、rs3819284、rs2523605进行测序,对DILI组和非DILI组间的4个SNPs等位基因和基因型分布频率、单体型进行统计学分析。结果两组间的4个SNPs等位基因和基因型分布频率差异无统计学意义(P>0.05)。HLA-B基因单体型(rs3819299-rs2523608-rs3819284-rs2523605)分析发现A-C-C-A在DILI组和非DILI组间比较差异有统计学意义(P<0.05),经Bonferroni方法校正后差异仍有统计学意义(P<0.05)。结论 HLA-B基因单体型中的A-C-C-A可能会增加非典型抗精神病药物性肝损伤的风险,HLA-B基因可能是DILI的易感基因。

Objective To analyze the correlation between HLA-B and drug induced liver injury（ DILI） caused by atypical antipsychotics in patients with schizophrenia. Methods A total of 95 schizophrenia patients diagnosed as DILI（ DILI group）,99 schizophrenia patients without DILI（ non-DILI group） were selected and treated with single atypical antipsychotics. Sanger method was used for sequencing the genes of HLA in both groups and genotype frequencies of rs3819299,rs2523608,rs3819284 and rs2523605 in both groups were compared. The group differences between DILI group and non-DILI group in allele frequency,genotype distribution and haplotype of the above four SNPs were also compared. Results The four SNPs alleles and genotype frequency distributions showed no differences between DILI group and non-DILI group（ P〉0. 05）. HLA-B gene haplotype analysis（ rs3819299-rs2523608-rs3819284-rs2523605） showed a difference of A-C-C-A between DILI group and non-DILI group（ P〈0. 05） and the difference remained after Bonferroni correction（ P〈0. 05）. Conclusion A-C-C-A may be a pathogenic factor of DILI and HLA-B gene may be a susceptibility gene of DILI.