本文選題：皮膚藥物不良反應(yīng) + 別嘌呤醇�。� 參考：《復(fù)旦大學(xué)》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(jī)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(yīng)(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(xì)胞抗原(human leukocyte antigen, HLA)與某些藥物所致cADRs有關(guān)。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(qiáng)關(guān)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(guān)。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(chǔ)上對別嘌呤醇所致cADRs的相關(guān)HLA-B基因進(jìn)行定位,評估其臨床表型特異性及預(yù)測價值。另一方面,利用全基因組關(guān)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(guān)的單核苷酸多態(tài)性(single nucleotide polymorphism, SNP)并探索相關(guān)候選基因。 方法 收集2008年至2011年期間于復(fù)旦大學(xué)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(jìn)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(yīng)綜合征患者。評估相關(guān)基因的臨床表型特異性及預(yù)測準(zhǔn)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(guān)的SNPs,通過查詢其位置及與周圍SNPs的連鎖不平衡(linkage disequilibrium, LD)關(guān)系探索可能相關(guān)的基因。 結(jié)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(guān)。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(yù)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(yù)測值分別為84.44%及100%。對各臨床類型的進(jìn)一步分析同樣顯示該預(yù)測試驗具有較高的準(zhǔn)確性。 在MHC相關(guān)區(qū)域中,GWAS結(jié)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(guān)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(guān)聯(lián)密切的MHC相關(guān)區(qū)域主要位于6p21.33,相關(guān)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(guān)性。除去MHC相關(guān)基因后,結(jié)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(guān)。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(kuò)大樣本量對本結(jié)果進(jìn)行進(jìn)一步驗證。 結(jié)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(qiáng)關(guān)聯(lián)。 2. HLA-B*5801可以作為標(biāo)志基因較準(zhǔn)確地預(yù)測別嘌呤醇所致cADRs的發(fā)生。 3.在MHC相關(guān)區(qū)域中,rs11968268,rs61235149,rs9258756,rs9258631和rs13207945與阿莫西林所致cADRs關(guān)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(guān)系密切的MHC相關(guān)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(guān)性。 6. ARHGAP10、CNTN5、KCNJ3、HOXA可能與阿莫西林cADRs相關(guān)。 7. KSR2、GPC6、FNDC3B和ENTPD3可能與頭孢菌素cADRs相關(guān)。
[Abstract]:Purpose

There is a strong association between HLA - B * 5801 and certain drug - induced cADRs .

method

The clinical phenotype - specific and predictive accuracy of the related genes were assessed in 38 patients with cADRs , including 22 drug eruption type , 13 Stevens - Johnson syndrome / toxic epidermal necrolysis type and 3 drug hypersensitivity syndrome .

Results

HLA - B * 5801 allele was significantly associated with HLA - B * 5801 ( OR = 248.60 , 95 % CI = 13.48 - 4585.35 , p < 0.0001 ) . HLA - B * 5801 allele was significantly associated with HLA - B * 5801 ( OR = 273.01 , 95 % CI = 16.54 - 4583.53 , p < 0.0001 ) . HLA - B * 5801 allele was significantly higher than that in healthy population groups ( OR = 275.31 , 95 % CI = 16.54 - 4583.53 , p < 0.0001 ) .

The association of rs9258631 ( OR = 5.400 , p = 4.96 脳 10 - 5 ) , rs9258631 ( OR = 5.400 , p = 4.96 脳 10 - 5 ) , rs9258631 ( OR = 5.400 , p = 4.96 脳 10 - 5 ) , rs13207945 ( OR = 5.148 , p = 3.20 脳 10 - 5 ) , rs9765960 ( OR = 4.079 , p = 7.9010 - 4 ) and rs1076829 ( OR = 3.988 , p = 5.4310 - 4 ) . Among them , rs2523500 ( OR = 3.298 , p = 6.04x 10 - 4 ) and rs6916921 ( OR = 3.196 , p = 8.18x104 ) on NFKBIL1 gene were significantly correlated with amoxicillin cADRs and cephalosporin cADRs . After removal of MHC - related genes , the results showed that more than one gene might be associated with cADRs induced by two classes of 尾 - lactam antibiotics .

Conclusion

1 . In the Han population in the mainland of East China , we observed that the common type and severe cADRs ( mpe , SJS / TEN ) in patients with severe cADRs 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 ppurool .

3 . In the related region of MHC , rs11968268 , rs61235149 , rs9258756 , rs9258631 and rs13207945 were most notably associated with cADRs due to amoxicillin , which were 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 at 6p21.3 .

5 . There was a significant correlation between NFKBIL1 gene and cADRs caused by amoxicillin and cephalosporin .

6 . ARHgap10 , CNTN5 , KCN3 , HOXA may be associated with amoxicillin cADRs .

7 . KSR2 , GPC6 , FNDC3B and ENTPD3 may be associated with cephalosporin cADRs .
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2012
【分類號】：R758.25

【參考文獻(xiàn)】

相關(guān)期刊論文 前1條

1 高金明,林耀廣,邱長春 ,劉怡雯,馬毅,劉英;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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本文編號：2072943