Genetic association of primary nonresponse to anti-TNFα therapy in patients with inflammatory bowel disease.

IF 16.4 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Accounts of Chemical Research Pub Date : 2022-01-01 DOI:10.1097/FPC.0000000000000445

Tanima De, Honghong Zhang, Cristina Alarcon, Bianca Lec, Juan Avitia, Erin Smithberger, Chuyu Chen, Minnie Horvath, Sara Kwan, Mary Young, Sarbani Adhikari, John Kwon, Jennifer Pacheco, Gail Jarvik, Wei-Qi Wei, Frank Mentch, Hakon Hakonarson, Patrick Sleiman, Adam Gordon, John Harley, Jim Linneman, Scott Hebbring, Loukia Parisiadou, Minoli A Perera

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引用次数: 2

Abstract

Objectives: Primary nonresponse (PNR) to antitumor necrosis factor-α (TNFα) biologics is a serious concern in patients with inflammatory bowel disease (IBD). We aimed to identify the genetic variants associated with PNR.

Patients and methods: Patients were recruited from outpatient GI clinics and PNR was determined using both clinical and endoscopic findings. A case-control genome-wide association study was performed in 589 IBD patients and associations were replicated in an independent cohort of 293 patients. Effect of the associated variant on gene expression and TNFα secretion was assessed by cell-based assays. Pleiotropic effects were investigated by Phenome-wide association study (PheWAS).

Results: We identified rs34767465 as associated with PNR to anti-TNFα therapy (odds ratio: 2.07, 95% CI, 1.46-2.94, P = 2.43 × 10-7, [replication odds ratio: 1.8, 95% CI, 1.04-3.16, P = 0.03]). rs34767465 is a multiple-tissue expression quantitative trait loci for FAM114A2. Using RNA-sequencing and protein quantification from HapMap lymphoblastoid cell lines (LCLs), we found a significant decrease in FAM114A2 mRNA and protein expression in both heterozygous and homozygous genotypes when compared to wild type LCLs. TNFα secretion was significantly higher in THP-1 cells [differentiated into macrophages] with FAM114A2 knockdown versus controls. Immunoblotting experiments showed that depletion of FAM114A2 impaired autophagy-related pathway genes suggesting autophagy-mediated TNFα secretion as a potential mechanism. PheWAS showed rs34767465 was associated with comorbid conditions found in IBD patients (derangement of joints [P = 3.7 × 10-4], pigmentary iris degeneration [P = 5.9 × 10-4], diverticulum of esophagus [P = 7 × 10-4]).

Conclusions: We identified a variant rs34767465 associated with PNR to anti-TNFα biologics, which increases TNFα secretion through mechanism related to autophagy. rs34767465 may also explain the comorbidities associated with IBD.

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炎症性肠病患者抗tnf α治疗原发性无反应的遗传关联

目的:抗肿瘤坏死因子-α (tnf -α)生物制剂的原发性无反应(PNR)是炎症性肠病(IBD)患者的一个严重问题。我们的目的是确定与PNR相关的遗传变异。患者和方法:患者从门诊胃肠道诊所招募，PNR通过临床和内镜检查结果确定。在589例IBD患者中进行了病例对照全基因组关联研究，并在293例患者的独立队列中重复了关联。通过基于细胞的检测评估相关变异对基因表达和TNFα分泌的影响。多效性效应通过全现象关联研究(PheWAS)进行了研究。结果:我们发现rs34767465与PNR与抗tnf α治疗相关(比值比:2.07,95% CI, 1.46-2.94, P = 2.43 × 10-7，[重复比值比:1.8,95% CI, 1.04-3.16, P = 0.03])。rs34767465是FAM114A2的多组织表达数量性状位点。利用来自HapMap淋巴母细胞样细胞系(LCLs)的rna测序和蛋白质定量分析，我们发现与野生型LCLs相比，杂合子和纯合子基因型的FAM114A2 mRNA和蛋白表达均显著降低。FAM114A2敲低的THP-1细胞[分化为巨噬细胞]中TNFα分泌明显高于对照组。免疫印迹实验显示，FAM114A2的缺失损害了自噬相关通路基因，提示自噬介导的TNFα分泌是一种潜在的机制。PheWAS显示rs34767465与IBD患者的合并症相关(关节紊乱[P = 3.7 × 10-4]、虹膜色素变性[P = 5.9 × 10-4]、食道憩室[P = 7 × 10-4])。结论:我们发现了一个与PNR抗tnf - α生物制剂相关的rs34767465变异，该变异通过自噬相关机制增加tnf - α分泌。rs34767465也可以解释与IBD相关的合并症。

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来源期刊

Accounts of Chemical Research 化学-化学综合

CiteScore

31.40

自引率

1.10%

发文量

312

审稿时长

2 months

期刊介绍： Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.