Pharmacogenomics of intravenous immunoglobulin response in Kawasaki disease.
Pharmacogenomics of intravenous immunoglobulin response in Kawasaki disease.
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DOI：
10.3389/fimmu.2023.1287094
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发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
川崎病(KD)是一种儿童弥漫性血管炎。大剂量静脉注射丙种球蛋白(IVIG)是主要的治疗方法，其反应因遗传背景而异。我们试图利用全基因组测序(WGS)来确定与治疗反应相关的遗传位点。我们对472名KD患者进行了WGS，其中305名IVIG应答者和167名AHA临床标准定义的无应答者。我们使用Logistic回归模型来测试整个队列和由血统信息标记定义的四个子组(白人、非裔美国人、亚洲人和西班牙裔)的加性遗传效应。我们使用FUMA进行了功能定位和注释，以检查可能涉及IVIG无反应的遗传变异。此外，我们对所有稀有和常见的变体进行了SNP集[序列]核关联测试(SKAT)。在检测到的43,288,336个SNP中(23,660,970个位于基因间隔区，16,764,594个位于内含子，556,814个位于外显子)，与IVIG无反应相关的前10个SNP分别位于FANK1，MAP2K3：KCNJ12，CA10，FRG1DP，CWH43区域。当在基于祖先的种族亚群中单独分析时，几个新基因的SNPs是相关的。通过定位和染色质定位，共定位出23个可能的致病基因。Skat分析表明，整个MANIA2、EDN1、SFMBT2和PPP2R5E基因以及CSMD2、LINC01317、HIVEPI、HSP90AB1和TTLL11基因片段之间存在关联。这项WGS研究发现了多个与IVIG反应相关的新的未研究基因。这些数据有助于了解KD的发病机制，也为开发治疗反应预测指标奠定了基础。
Kawasaki disease (KD) is a diffuse vasculitis in children. Response to high dose intravenous gamma globulin (IVIG), the primary treatment, varies according to genetic background. We sought to identify genetic loci, which associate with treatment response using whole genome sequencing (WGS). We performed WGS in 472 KD patients with 305 IVIG responders and 167 non-responders defined by AHA clinical criteria. We conducted logistic regression models to test additive genetic effect in the entire cohort and in four subgroups defined by ancestry information markers (Whites, African Americans, Asians, and Hispanics). We performed functional mapping and annotation using FUMA to examine genetic variants that are potentially involved IVIG non-response. Further, we conducted SNP-set [Sequence] Kernel Association Test (SKAT) for all rare and common variants. Of the 43,288,336 SNPs (23,660,970 in intergenic regions, 16,764,594 in introns and 556,814 in the exons) identified, the top ten hits associated with IVIG non-response were in FANK1, MAP2K3:KCNJ12, CA10, FRG1DP, CWH43 regions. When analyzed separately in ancestry-based racial subgroups, SNPs in several novel genes were associated. A total of 23 possible causal genes were pinpointed by positional and chromatin mapping. SKAT analysis demonstrated association in the entire MANIA2, EDN1, SFMBT2, and PPP2R5E genes and segments of CSMD2, LINC01317, HIVEPI, HSP90AB1, and TTLL11 genes This WGS study identified multiple predominantly novel understudied genes associated with IVIG response. These data can serve to inform regarding pathogenesis of KD, as well as lay ground work for developing treatment response predictors.
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影响因子：
3.5
作者：
Haase M;Fitze G
通讯作者：
Fitze G
DOI：
10.1186/1546-0096-11-32
发表时间：
2013-09-05
期刊：
Pediatric rheumatology online journal
影响因子：
--
作者：
Portman MA;Wiener HW;Silva M;Shendre A;Shrestha S
通讯作者：
Shrestha S
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
5.1
作者：
DEAN, AG;MELISH, ME;PALUMBO, NE
通讯作者：
PALUMBO, NE
影响因子：
3.6
作者：
Burns, JC;Capparelli, EV;Glode, MP
通讯作者：
Glode, MP