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1、 HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol研发部研发部 张艳张艳1 别嘌呤醇作用别嘌呤醇作用用途：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TEN2Patients and Control Subjects Recruitmentl228 control individuals：l(135 allopurinol-tolerant subjects l93 healthy subjec
2、ts）l51 patients with allopurinolSCAR3SNP GenotypinglA total of 823 SNPs：l197 SNPs from 4Mb of the MHC regionl626 SNPs selected from genes encoding immune-related molecules and drug metabolizing enzymes4HLA GenotypinglHLA alleles A, B, C, and DRB1, were determined by sequence-specific oligonucleotide
3、 reverse lineblot l Potential ambiguities were resolved by sequencing-based typing5Statistical AnalysislCategorical 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.l All P v
4、alues were two-tailed; a P value of 0.05 was considered to indicate statistical significance.lAllelic association screen was carried out by the CochranlArmitage Trend test for each SNP . lOdds ratios were calculated with Haldanes modification, which adds 0.5 to all cells to accommodate possible zero
5、 counts . lThe corrected P (Pc) values were adjusted by using Bonferronislcorrection 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 387,600.6Characteristics of Patie
6、nts and Controls78 SJS (13 cases), SJSTEN (5 cases), TEN (3 cases), and HSS (30 cases),910Association Screen for Candidate Gene SNPsFig. 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 MH
7、C 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.11HLA Allele Frequency12DiscussionlIn fact, the association is 100% in that the HLA-B allele B*5801 was pre
8、sent in all 51 patients with allopurinol-induced SCAR, with an odds ratio exceeding that reported for the association between HLAB27 and ankylosing spondylitislgenotyping the B*5801 allele may provide a better guidance of avoiding allopurinol-induced SCAR in patients with renal insufficiency than do
9、sage adjusting.lThis 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.13lHLA-B*5801 is necessary but not sufficient for allopurinolSCAR.lThe present study revealed that CFLAR, an apoptosis regulator,could also be involved in allopurinolSCAR14 谢 谢！15
