别嘌呤醇及β内酰胺类抗生素诱发汉族人群皮肤药物不良反应与人类白细胞抗原基因关联研究

发布时间：2018-06-27 06:10

  本文选题：皮肤药物不良反应 + 别嘌呤醇　； 参考：《复旦大学》2012年博士论文

【摘要】：目的 别嘌呤醇因其无可媲美的多重降尿酸机制,长久以来被广泛用于治疗高尿酸血症及其并发症。β内酰胺类抗生素是一类临床使用最广泛的抗菌药物。两类药物均具有重要的临床地位,但却都存在较高的皮肤药物不良反应(cutaneous adverse drug reactions, cADRs)发生率,致使患者的临床治疗受到影响。近来研究发现,人类白细胞抗原(human leukocyte antigen, HLA)与某些药物所致cADRs有关。其中HLA-B*5801与别嘌呤醇所致重症药疹(severe cutaneous adverse drug reactions, SCARs)之间存在强关联。而阿莫西林-克拉维酸钾所致药物性肝炎也与某些HLA Ⅰ类及Ⅱ类等位基因相关。因此,本课题的研究目的共分两部分,其一是在前期工作基础上对别嘌呤醇所致cADRs的相关HLA-B基因进行定位,评估其临床表型特异性及预测价值。另一方面,利用全基因组关联分析方法(genome-wide association study, GWAS)筛查阿莫西林与头孢菌素所致cADRs相关的单核苷酸多态性(single nucleotide polymorphism, SNP)并探索相关候选基因。 方法 收集2008年至2011年期间于复旦大学附属华山医院皮肤科住院确诊为单一别嘌呤醇、阿莫西林或头孢菌素所致cADRs病例。对其中38例别嘌呤醇所致cADRs进行HLA-B基因分型,包括22位发疹型药疹、13位Stevens-Johnson综合征／中毒性表皮坏死松解症型药疹以及3位药物超敏反应综合征患者。评估相关基因的临床表型特异性及预测准确性。对17例阿莫西林及16例头孢菌素所致cADRs患者,采用GWAS筛查可能相关的SNPs,通过查询其位置及与周围SNPs的连锁不平衡(linkage disequilibrium, LD)关系探索可能相关的基因。 结果 所有别嘌呤醇cADRs患者(38/38)均携带HLA-B*5801等位基因,而该基因仅存在于11.11%(7/63)的别嘌呤醇耐受组人群(OR=580.07,95%CI=32.18-10456.80,p0.0001)及13.99%(80/572)的健康对照组人群(OR=471.09,95%CI=28.66-7744.39,p0.0001)。各类型别嘌呤醇所致cADRs均与HLA-B*5801呈显著相关。除了重症药疹外(OR=248.60,95%CI=13.48-4585.35,p0.0001),HLA-B*5801等位基因在普通发疹型药疹组及对照组中也具有显著性分布差异(OR=339.00,95%CI=18.58-6186.39,p0.0001),与健康人群组相比显示同样差异(OR=275.31,95%CI=16.54-4583.53,p0.0001)。HLA-B*5801用于预测该人群中别嘌呤醇cADRs发生的敏感度为100%,特异度为88.89%,阳性及阴性预测值分别为84.44%及100%。对各临床类型的进一步分析同样显示该预测试验具有较高的准确性。 在MHC相关区域中,GWAS结果显示rs11968268(OR=7.041,p=1.90×10-6), rs61235149(OR=6.537,p=5.03×10-6), rs9258756(OR=5.551,p=3.64×105), rs9258631(OR=5.400,p=4.96×10-5), rs13207945(OR=5.148,p=3.20×10-5)与阿莫西林cADRs关联最为显著,分别位于HLA-A/W、HLA-H/G以及HLA-DRB1/DQA1区域。与头孢菌素cADRs关联密切的MHC相关区域主要位于6p21.33,相关SNPs分别为rs17206757(OR=4.091,p=7.67x10-4)、rs9765960(OR=4.079,p=7.90x10-4)和rs1076829(OR=3.988,p=5.43x10-4)。其中,NFKBIL1基因上的rs2523500(OR=3.298,p=6.04x10-4)及rs6916921(OR=3.196,p=8.18x104)分别与阿莫西林cADRs、头孢菌素cADRs呈显著相关性。除去MHC相关基因后,结果显示有多个基因可能与两类β内酰胺抗生素所致cADRs相关。包括阿莫西林cADRs组中ARHGAP10、CNTN5、KCNJ3、HOXA以及头孢菌素cADRs组中的KSR2、GPC6、FNDC3B和ENTPD3。但由于样本数量有限,有必要扩大样本量对本结果进行进一步验证。 结论 1.在华东地区大陆汉族人群中,我们观察到别嘌呤醇所致普通型及重症cADRs (MPE、SJS/TEN、DRESS)均与HLA-B*5801强关联。 2. HLA-B*5801可以作为标志基因较准确地预测别嘌呤醇所致cADRs的发生。 3.在MHC相关区域中,rs11968268,rs61235149,rs9258756,rs9258631和rs13207945与阿莫西林所致cADRs关联最为显著,分别位于HLA-A/W、HLA-H/G以及HLA-DRB1/DQA1区域。 4.与头孢菌素cADRs关系密切的MHC相关区域主要位于6p21.33。 5. NFKBIL1基因与阿莫西林及头孢菌素所致cADRs均呈显著相关性。 6. ARHGAP10、CNTN5、KCNJ3、HOXA可能与阿莫西林cADRs相关。 7. KSR2、GPC6、FNDC3B和ENTPD3可能与头孢菌素cADRs相关。
[Abstract]:objective
Allopurinol has long been widely used in the treatment of hyperuricemia and its complications because of its uncomparable multiple urinic acid mechanism. Beta lactam antibiotics are the most widely used antibiotics. Two kinds of drugs have important clinical status, but there are high adverse drug reactions (cutaneous adverse d). The incidence of rug reactions, cADRs and the clinical treatment of patients have been affected. Recent studies have found that the human leukocyte antigen (human leukocyte antigen, HLA) is associated with cADRs caused by certain drugs. There is a strong association between HLA-B*5801 and the severe drug eruption caused by allopurinol (severe cutaneous adverse). The drug hepatitis caused by moxilin potassium clavulanate is also related to some HLA class I and class II alleles. Therefore, the purpose of this study is divided into two parts. One is to locate the HLA-B gene related to the cADRs induced by allopurinol on the basis of earlier work, and to evaluate its clinical phenotypic specificity and predictive value. The single nucleotide polymorphisms (single nucleotide polymorphism, SNP) associated with amoxicillin and cephalosporin (single nucleotide polymorphism, SNP) were screened by genome-wide association study (GWAS), and the related candidate genes were explored.
Method
The cADRs cases caused by single allopurinol, amoxicillin or cephalosporin were collected from 2008 to 2011 in the Department of Dermatology of Huashan Hospital Affiliated to Fudan University. The HLA-B genotyping of cADRs caused by 38 cases of allopurinol, including 22 rash eruptions, 13 Stevens-Johnson syndrome / toxic epidermal necrosis, was collected. Patients with symptomatic drug eruption and 3 drug hypersensitivity syndrome. Evaluate the clinical phenotypic specificity and predictive accuracy of related genes. 17 cases of amoxicillin and 16 cases of cephalosporin induced cADRs patients were screened for possible SNPs by GWAS screening, by querying their location and linkage disequilibrium with the surrounding SNPs (linkage disequilibrium, LD). To explore genes that may be related.
Result
All allopurinol cADRs patients (38/38) were carrying HLA-B*5801 allele, which only existed in 11.11% (7/63) allopurinol tolerance group (OR=580.07,95%CI=32.18-10456.80, P0.0001) and 13.99% (80/572) healthy control group (OR=471.09,95%CI= 28.66-7744.39, P0.0001). All types of allopurinol caused cADRs and HLA-B* 5801 significant correlation was found. Except for the severe drug rash (OR=248.60,95%CI=13.48-4585.35, P0.0001), the HLA-B*5801 alleles also had significant differences in the common eruption group and the control group (OR=339.00,95%CI=18.58-6186.39, P0.0001), which showed the same difference (OR=275.31,95%CI=16.54-4583.53, P0.0001), compared with the healthy group (P0.0001).HL. A-B*5801 was used to predict the sensitivity of allopurinol cADRs in the population to be 100%, the specificity was 88.89%, the positive and negative predictive values were 84.44% and 100%., respectively, and the further analysis of various clinical types also showed that the prediction test was of high accuracy.
In MHC related areas, the results of GWAS show rs11968268 (OR=7.041, p=1.90 x 10-6), rs61235149 (OR=6.537, p=5.03 x 10-6), rs9258756 (OR=5.551, p=3.64 x 105), rs9258631 (10-5) and amoxicillin, respectively. The related regions of MHC associated with cephalosporin cADRs are mainly located in 6p21.33, and the related SNPs is rs17206757 (OR=4.091, p=7.67x10-4), rs9765960 (OR=4.079, p=7.90x10-4) and rs1076829 (OR=3.988,), respectively. CADRs, cephalosporin cADRs showed significant correlation. After removing MHC related genes, the results showed that a number of genes may be associated with cADRs related to the two class of beta lactam antibiotics, including ARHGAP10, CNTN5, KCNJ3, HOXA, and cephalosporin cADRs groups in the group cADRs of amoxicillin. The results were further verified by the enlargement of the sample size.
conclusion
1. in the Eastern Han Chinese population, we observed that cADRs and MPE (SJS/TEN, DRESS) were strongly associated with HLA-B*5801.
2. HLA-B*5801 can be used as a marker gene to accurately predict the occurrence of cADRs induced by allopurinol.
3. in MHC related areas, rs11968268, rs61235149, rs9258756, rs9258631 and rs13207945 are most associated with amoxicillin, which are located in HLA-A/W, HLA-H/G, and HLA-DRB1/DQA1 regions, respectively.
4. the MHC related region closely related to cephalosporin cADRs is mainly located in 6p21.33..
5. the NFKBIL1 gene was significantly correlated with amoxicillin and cephalosporin induced cADRs.
6. ARHGAP10, CNTN5, KCNJ3 and HOXA may be associated with amoxicillin cADRs.
7. KSR2, GPC6, FNDC3B and ENTPD3 may be related to cephalosporin cADRs.
【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R758.25

【参考文献】

相关期刊论文 前1条

1 高金明,林耀广,邱长春 ,刘怡雯,马毅,刘英;Association between HLA-DQA1, -DQB1 gene polymorphisms and susceptibility to asthma in northern Chinese subjects[J];Chinese Medical Journal;2003年07期

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