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)
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.
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