Genome-wide Association Study Identifies Variations in 6p21.3 Associated With Nevirapine-Induced Rash
Genome-wide Association Study Identifies Variations in 6p21.3 Associated With Nevirapine-Induced Rash
复制标题
DOI：
10.1093/cid/cir403
复制
发表时间：
2011-08-15
影响因子：
11.8
通讯作者：
Nakamura, Yusuke
中科院分区：
文献类型：
--
作者：
Chantarangsu, Soranun;Mushiroda, Taisei;Nakamura, Yusuke
背景资料。我们的目标是使用全基因组单核苷酸多态(SNPs)作为遗传标记来识别奈韦拉平引起皮疹的致病变异。在72例人类免疫缺陷病毒感染的泰国奈韦拉平皮疹患者和77例奈韦拉平耐受患者中，使用类似的550000个标记进行了全基因组关联研究，然后在复制集中进一步评估候选SNP(88例奈韦拉平皮疹患者和145例奈韦拉平耐受患者)。对候选SNPs的全基因组关联分析和复制研究发现，奈韦拉平引起的皮疹与染色体6p21.3上CCHCR1内的2个SNPs(rs1265112和rs746647)显著相关(P(Gwas)=1.6 x 10(-4)；P(复制)=2.6 x 10(-5)；P(组合)=1.2 x 10(-8))。显性模型下危险基因的优势比(OR)为4.36(95%可信区间为2.58~7.36)。非编码SNP rs1265112和rs746647与与银屑病相关的非同义SNP rs1576处于完全连锁不平衡状态(r(2)=1.00)。Logistic回归分析还显示CCHCR1基因变异与皮疹显著相关，OR为2.59(95%CI，1.82~3.68；P=0.007)。受试者工作特征曲线显示，该算法的曲线下面积为76.4%，是由rs1576*G状态、人类白细胞抗原B*3505状态、未接受规定的奈韦拉平导入、药物过敏史和奈韦拉平治疗前的CD4细胞计数5个因素综合而成的。我们证明CCHCR1的遗传变异与奈韦拉平引起的皮疹密切相关。包括奈韦拉平相关皮疹的遗传和临床风险因素的预测模型可能有助于降低HIV感染患者中奈韦拉平相关皮疹的发生率。
Background. We aimed to identify disease-predisposing variations with nevirapine-induced rash using genome-wide single-nucleotide polymorphisms (SNPs) as genetic markers.Methods. A genome-wide association study (GWAS) was performed using similar to 550000 markers in 72 human immunodeficiency virus (HIV)-infected Thai patients with nevirapine-induced rash and 77 nevirapine-tolerant patients, and then candidate SNPs were further evaluated in a replication set (88 patients with nevirapine-induced rash and 145 nevirapine-tolerant patients).Results. The genome-wide association analysis and replication studies of candidate SNPs identified significant associations of nevirapine-induced rash with 2 SNPs (rs1265112 and rs746647) within CCHCR1 on chromosome 6p21.3 (P(GWAS) = 1.6 x 10(-4); P(replication) = 2.6 x 10(-5); P(combined) = 1.2 x 10(-8)). The odds ratio (OR) of the risk genotypes under a dominant model was 4.36 (95% confidence interval [CI], 2.58-7.36). The noncoding SNPs rs1265112 and rs746647 were in complete linkage disequilibrium with the nonsynonymous SNP rs1576 (r(2) = 1.00), which has been associated with psoriasis. The logistic regression analysis also indicated genetic variations in CCHCR1 to be significantly associated with rash, with an OR of 2.59 (95% CI, 1.82-3.68; P = .007). The receiver operating characteristic curve showed that the algorithm had an area under the curve of 76.4%, which was developed with 5 factors: rs1576*G status, HLA-B*3505 status, not receiving prescribed lead-in of nevirapine, history of drug allergy, and CD4 cell count prior to the nevirapine treatment.Conclusions. We demonstrated that genetic variations in CCHCR1 are strongly associated with nevirapine-induced rash. A predictive model that includes genetic and clinical risk factors for nevirapine-associated rash might be useful in lowering the incidence of rash associated with nevirapine initiation among HIV-infected patients.