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1、HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol,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 w
2、ith 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
3、 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-taile
4、d; 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 correct
5、ed 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 (
6、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 numbere
7、d 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
8、 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,
9、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！,