本文選題：皮膚藥物不良反應 + 別嘌呤醇　； 參考：《復旦大學》2012年博士論文

【摘要】：目的 別嘌呤醇因其無可媲美的多重降尿酸機制,長久以來被廣泛用于治療高尿酸血癥及其并發(fā)癥。β內(nèi)酰胺類抗生素是一類臨床使用最廣泛的抗菌藥物。兩類藥物均具有重要的臨床地位,但卻都存在較高的皮膚藥物不良反應(cutaneous adverse drug reactions, cADRs)發(fā)生率,致使患者的臨床治療受到影響。近來研究發(fā)現(xiàn),人類白細胞抗原(human leukocyte antigen, HLA)與某些藥物所致cADRs有關。其中HLA-B*5801與別嘌呤醇所致重癥藥疹(severe cutaneous adverse drug reactions, SCARs)之間存在強關聯(lián)。而阿莫西林-克拉維酸鉀所致藥物性肝炎也與某些HLA Ⅰ類及Ⅱ類等位基因相關。因此,本課題的研究目的共分兩部分,其一是在前期工作基礎上對別嘌呤醇所致cADRs的相關HLA-B基因進行定位,評估其臨床表型特異性及預測價值。另一方面,利用全基因組關聯(lián)分析方法(genome-wide association study, GWAS)篩查阿莫西林與頭孢菌素所致cADRs相關的單核苷酸多態(tài)性(single nucleotide polymorphism, SNP)并探索相關候選基因。 方法 收集2008年至2011年期間于復旦大學附屬華山醫(yī)院皮膚科住院確診為單一別嘌呤醇、阿莫西林或頭孢菌素所致cADRs病例。對其中38例別嘌呤醇所致cADRs進行HLA-B基因分型,包括22位發(fā)疹型藥疹、13位Stevens-Johnson綜合征／中毒性表皮壞死松解癥型藥疹以及3位藥物超敏反應綜合征患者。評估相關基因的臨床表型特異性及預測準確性。對17例阿莫西林及16例頭孢菌素所致cADRs患者,采用GWAS篩查可能相關的SNPs,通過查詢其位置及與周圍SNPs的連鎖不平衡(linkage disequilibrium, LD)關系探索可能相關的基因。 結果 所有別嘌呤醇cADRs患者(38/38)均攜帶HLA-B*5801等位基因,而該基因僅存在于11.11%(7/63)的別嘌呤醇耐受組人群(OR=580.07,95%CI=32.18-10456.80,p0.0001)及13.99%(80/572)的健康對照組人群(OR=471.09,95%CI=28.66-7744.39,p0.0001)。各類型別嘌呤醇所致cADRs均與HLA-B*5801呈顯著相關。除了重癥藥疹外(OR=248.60,95%CI=13.48-4585.35,p0.0001),HLA-B*5801等位基因在普通發(fā)疹型藥疹組及對照組中也具有顯著性分布差異(OR=339.00,95%CI=18.58-6186.39,p0.0001),與健康人群組相比顯示同樣差異(OR=275.31,95%CI=16.54-4583.53,p0.0001)。HLA-B*5801用于預測該人群中別嘌呤醇cADRs發(fā)生的敏感度為100%,特異度為88.89%,陽性及陰性預測值分別為84.44%及100%。對各臨床類型的進一步分析同樣顯示該預測試驗具有較高的準確性。 在MHC相關區(qū)域中,GWAS結果顯示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)與阿莫西林cADRs關聯(lián)最為顯著,分別位于HLA-A/W、HLA-H/G以及HLA-DRB1/DQA1區(qū)域。與頭孢菌素cADRs關聯(lián)密切的MHC相關區(qū)域主要位于6p21.33,相關SNPs分別為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)分別與阿莫西林cADRs、頭孢菌素cADRs呈顯著相關性。除去MHC相關基因后,結果顯示有多個基因可能與兩類β內(nèi)酰胺抗生素所致cADRs相關。包括阿莫西林cADRs組中ARHGAP10、CNTN5、KCNJ3、HOXA以及頭孢菌素cADRs組中的KSR2、GPC6、FNDC3B和ENTPD3。但由于樣本數(shù)量有限,有必要擴大樣本量對本結果進行進一步驗證。 結論 1.在華東地區(qū)大陸漢族人群中,我們觀察到別嘌呤醇所致普通型及重癥cADRs (MPE、SJS/TEN、DRESS)均與HLA-B*5801強關聯(lián)。 2. HLA-B*5801可以作為標志基因較準確地預測別嘌呤醇所致cADRs的發(fā)生。 3.在MHC相關區(qū)域中,rs11968268,rs61235149,rs9258756,rs9258631和rs13207945與阿莫西林所致cADRs關聯(lián)最為顯著,分別位于HLA-A/W、HLA-H/G以及HLA-DRB1/DQA1區(qū)域。 4.與頭孢菌素cADRs關系密切的MHC相關區(qū)域主要位于6p21.33。 5. NFKBIL1基因與阿莫西林及頭孢菌素所致cADRs均呈顯著相關性。 6. ARHGAP10、CNTN5、KCNJ3、HOXA可能與阿莫西林cADRs相關。 7. KSR2、GPC6、FNDC3B和ENTPD3可能與頭孢菌素cADRs相關。
[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.
【學位授予單位】：復旦大學
【學位級別】：博士
【學位授予年份】：2012
【分類號】：R758.25

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相關期刊論文 前1條

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本文編號：2072944