HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol研发部 张艳,别嘌呤醇作用,用途：治疗痛风、高尿酸血症等相关疾病。 机理：抑制黄嘌呤氧化酶的活性 副作用：皮肤不良反应如HSS、SJS和TEN,Patients and Control Subjects Recruitment,228 control individuals： (135 allopurinol-tolerant subjects 93 healthy subjects） 51 patients with allopurinolSCAR,SNP Genotyping,A total of 823 SNPs： 197 SNPs from 4Mb of the MHC region 626 SNPs selected from genes encoding immune-related molecules and drug metabolizing enzymes,HLA Genotyping,HLA alleles A, B, C, and DRB1, were determined by sequence-specific oligonucleotide reverse lineblot Potential ambiguities were resolved by sequencing-based typing,Statistical Analysis,Categorical data were compared between groups with use of Fishers exact tests, and continuous data(presented as median, with range given in parentheses) were compared with use of t tests. All P values were two-tailed; a P value of 0.05 was considered to indicate statistical significance. Allelic association screen was carried out by the Cochran Armitage Trend test for each SNP . Odds ratios were calculated with Haldanes modification, which adds 0.5 to all cells to accommodate possible zero counts . The corrected P (Pc) values were adjusted by using Bonferronis correction for multiple comparisons to account for the observed alleles (17 for HLA-A, 40 for HLA-B, 19 for HLA-C, and 30 for HLA-DRB1). Therefore, the Pc values were multiplied by a factor of 387,600.,Characteristics of Patients and Controls,SJS (13 cases), SJSTEN (5 cases), TEN (3 cases), and HSS (30 cases),Association Screen for Candidate Gene SNPs,Fig. 1. Screening of candidate SNPs for association with allopurinol-induced SCAR. On the x axis, 823 SNPs are ordered by their chromosome positions; 197 SNPs in the MHC region are those numbered from 260 to 456. On the y axis, the log10 P values were calculated by comparison of the genotype frequencies between the allopurinolSCAR patients and tolerant group.,HLA Allele Frequency,Discussion,In fact, the association is 100% in that the HLA-B allele B*5801 was present in all 51 patients with allopurinol-induced SCAR, with an odds ratio exceeding that reported for the association between HLAB27 and ankylosing spondylitis genotyping the B*5801 allele may provide a better guidance of avoiding allopurinol-induced SCAR in patients with renal insufficiency than dosage adjusting. This study, together with the previous reports, suggests that HLA-B alleles andor other genetic polymorphisms in the MHC region might play a major role in the pathogenesis of immune-mediatedSCAR.,HLA-B*5801 is necessary but not sufficient for allopurinolSCAR. The present study revealed that CFLAR, an apoptosis regulator,could also be involved in allopurinolSCAR,谢 谢！,