155-OR: Genetic Variation and Time to Progression in TN10 (Teplizumab)

IF 6.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes Pub Date : 2024-07-19 DOI:10.2337/db24-155-or

DOMINIKA A. MICHALEK, SUNA ONENGUT-GUMUSCU, WEI-MIN CHEN, TODD M. BRUSKO, ANDREA STECK, PETER GOTTLIEB, RICHARD A. ORAM, JEFFREY KRISCHER, HEMANG M. PARIKH, MARIA J. REDONDO, KEVAN C. HEROLD, STEPHEN S. RICH

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引用次数: 0

Abstract

Introduction & Objective: TN10 Anti-CD3 Prevention (TN10) was a randomized phase 2 clinical trial that showed teplizumab delayed progression to type 1 diabetes (T1D) in high-risk participants. Both HLA and non-HLA variants could influence time to progression. Here, genome-wide analysis identified variants and pathways that influence time to progression in TN10 participants. Methods: In TN10, relatives with stage 2 T1D (i.e., multiple autoantibodies and dysglycemia) received either teplizumab (N = 44) or placebo (N = 32). Samples were genotyped with a genome-wide array followed by imputation. Cox proportional hazards regression models were used to determine the effect of teplizumab, SNPs, and their interaction on time to progression to stage 3 T1D. Thousands of Polygenic Scores (PGSs) from the PGS catalogue were inferred for each of the TN10 samples, and we identified PGS traits that shared common genetic modifiers with time to progression with teplizumab. Results: A genome-wide analysis identified three loci associated with time to progression (p < 5 x 10-6). Two loci contain genes implicated in the inflammatory response (NFKBIZ) and drug metabolism effect (FMO3). SNP-drug interaction analysis identified four known T1D regions that account for progression differences in teplizumab vs placebo: CCR9 (rs34549672), SH2B3 (rs3184504), UBASH3A (rs9984852), and INS (rs3842761). Within the teplizumab group, novel loci (p < 5 x 10-6) were associated with time to progression, including ZNF385D, CCDC38, SHH, ZNF366, ITPKB and RABGAP1L. Traits with similar genetic contribution to teplizumab time to progression were vitamin B12 (AUC = 0.76) and vitamin D (AUC = 0.72). Conclusions: In individuals with stage 2 T1D, variants in inflammatory, immune-relevant, and drug-responsive genes are associated with teplizumab time to progression. Similarity of the teplizumab-responsive polygenic score with other traits implicate novel pathways that could influence teplizumab treatment. Disclosure D.A. Michalek: None. S. Onengut-Gumuscu: None. W. Chen: None. T.M. Brusko: None. A. Steck: None. P. Gottlieb: Other Relationship; IM Therapeutics. Research Support; Imcyse. Advisory Panel; Imcyse. Consultant; Juvenile Diabetes Research Foundation (JDRF). Research Support; Hemsley Charitable Trust, Novartis AG, Provention Bio, Inc., Precigen, Inc. Advisory Panel; ViaCyte, Inc. Research Support; Nova Pharmaceuticals. R.A. Oram: Research Support; Randox R & D. Consultant; Provention Bio, Inc., Sanofi. J. Krischer: None. H.M. Parikh: None. M.J. Redondo: None. K.C. Herold: Consultant; Sanofi. S.S. Rich: None. Funding National Institutes of Health (1R01DK121843-01)

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155-OR： TN10（替普珠单抗）的基因变异与病情进展时间

简介& 目的：TN10 抗 CD3 预防（TN10）是一项随机 2 期临床试验，结果表明替普利珠单抗可延缓高风险参与者发展为 1 型糖尿病（T1D）的时间。HLA和非HLA变异都会影响进展时间。在此，我们通过全基因组分析确定了影响 TN10 参与者病情进展时间的变异和途径。方法在 TN10 中，患有 T1D 2 期（即多种自身抗体和血糖异常）的亲属接受了替普利珠单抗（44 例）或安慰剂（32 例）治疗。使用全基因组阵列对样本进行基因分型，然后进行归因。采用 Cox 比例危险回归模型来确定替普利珠单抗、SNPs 及其交互作用对 T1D 进展到 3 期的时间的影响。我们从 PGS 目录中为每个 TN10 样本推断出了数千个多基因评分 (PGS)，并确定了与替普利珠单抗治疗进展时间具有共同遗传修饰因子的 PGS 性状。结果全基因组分析发现了三个与进展时间相关的基因位点（p < 5 x 10-6）。其中两个基因位点包含与炎症反应（NFKBIZ）和药物代谢作用（FMO3）有关的基因。SNP-药物相互作用分析确定了四个已知的 T1D 区域，这些区域导致了替普利珠单抗与安慰剂的进展差异：CCR9（rs34549672）、SH2B3（rs3184504）、UBASH3A（rs9984852）和INS（rs3842761）。在替普利珠单抗组中，ZNF385D、CCDC38、SHH、ZNF366、ITPKB和RABGAP1L等新基因位点（p < 5 x 10-6）与疾病进展时间相关。维生素 B12（AUC = 0.76）和维生素 D（AUC = 0.72）等性状对替普利珠单抗的病情进展时间具有相似的遗传贡献。结论在 T1D 2 期患者中，炎症基因、免疫相关基因和药物反应基因的变异与替普利珠单抗的病情进展时间相关。替普利珠单抗反应性多基因评分与其他性状的相似性意味着可能影响替普利珠单抗治疗的新途径。披露 D.A. Michalek：无。S. Onengut-Gumuscu: 无。W. Chen: None.T.M. Brusko：无：无。A. Steck：无。P. Gottlieb：其他关系；IM Therapeutics。研究支持；Imcyse.顾问团；Imcyse.顾问；青少年糖尿病研究基金会 (JDRF)。研究支持；Hemsley 慈善信托基金、诺华股份公司、Provention Bio, Inc.、Precigen, Inc.顾问团；ViaCyte, Inc.研究支持；Nova Pharmaceuticals。R.A. Oram：研究支持；Randox R &；D. 顾问；Provention Bio, Inc.、赛诺菲。J. Krischer：无。H.M. Parikh：无：无。M.J. Redondo：无。K.C. Herold：赛诺菲顾问。S.S. Rich：无。美国国立卫生研究院（1R01DK121843-01）资助

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来源期刊

Diabetes 医学-内分泌学与代谢

CiteScore

12.50

自引率

2.60%

发文量

1968

审稿时长

1 months

期刊介绍： Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes. However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.