Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients.
Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients.
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DOI：
10.1212/wnl.0000000000004853
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发表时间：
2018-01-23
期刊：
影响因子：
9.9
通讯作者：
Cavalleri GL
中科院分区：
文献类型：
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作者：
McCormack M;Gui H;Ingason A;Speed D;Wright GEB;Zhang EJ;Secolin R;Yasuda C;Kwok M;Wolking S;Becker F;Rau S;Avbersek A;Heggeli K;Leu C;Depondt C;Sills GJ;Marson AG;Auce P;Brodie MJ;Francis B;Johnson MR;Koeleman BPC;Striano P;Coppola A;Zara F;Kunz WS;Sander JW;Lerche H;Klein KM;Weckhuysen S;Krenn M;Gudmundsson LJ;Stefánsson K;Krause R;Shear N;Ross CJD;Delanty N;EPIGEN Consortium;;Pirmohamed M;Carleton BC;Canadian Pharmacogenomics Network for Drug Safety;;Cendes F;Lopes-Cendes I;Liao WP;O'Brien TJ;Sisodiya SM;EpiPGX Consortium;;Cherny S;Kwan P;Baum L;International League Against Epilepsy Consortium on Complex Epilepsies;;Cavalleri GL
在欧洲和中国汉族人群中，描述斑丘疹外展（MPE）的遗传预测因子，MPE是抗癫痫药物常见的皮肤药物不良反应。我们对来自北方欧洲人和中国汉族血统的癫痫队列的323例病例和1，321名药物耐受对照进行了一项常染色体基因型（包括I类和II类人类白细胞抗原（HLA）等位基因）的病例对照全基因组关联研究。对每个队列的结果进行荟萃分析。我们报告了补体因子H相关4（CFHR 4）基因的一种罕见变异与欧洲人苯妥英诱导的MPE之间的相关性（p = 4.5 × 10-11;比值比[95%置信区间] 7 [3.2-16]）。该变体与补体因子H（CFH）基因中的错义变体（N1050 Y）处于完全连锁不平衡。此外，我们的研究结果加强了HLA-A*31：01和卡马西平过敏之间的关联。在中国汉族患者中，我们没有发现与MPE有显著的遗传关联。在CFHR 4和CFH（补体因子H相关蛋白家族的成员）中，MPE的遗传预测因子的鉴定表明，在欧洲祖先患者中，补体系统旁路途径的调节与苯妥英诱导的超敏反应之间存在新的联系。
To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. We report an association between a rare variant in the complement factor H–related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10–11; odds ratio [95% confidence interval] 7 [3.2–16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H–related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients.