Precision Medicine in Graves’ Disease: CD40 Gene Variants Predict Clinical Response to an Anti-CD40 Monoclonal Antibody
BackgroundCD40, a key co-stimulatory molecule expressed on antigen-presenting cells, is genetically associated with a number of autoimmune diseases including Graves’ disease (GD). Therefore, recent therapies targeting CD40 have been developed, including the anti-CD40 monoclonal antibody Iscalimab. I...
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doaj-efe29bd5598349e1a0a56fe48f09dade2021-06-04T08:34:28ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922021-06-011210.3389/fendo.2021.691781691781Precision Medicine in Graves’ Disease: CD40 Gene Variants Predict Clinical Response to an Anti-CD40 Monoclonal AntibodyLarissa C. Faustino0George J. Kahaly1Lara Frommer2Erlinda Concepcion3Mihaela Stefan-Lifshitz4Yaron Tomer5Department of Medicine, Albert Einstein College of Medicine, New York, NY, United StatesDepartment of Medicine I, Johannes Gutenberg University (JGU) Medical Center, Mainz, GermanyDepartment of Medicine I, Johannes Gutenberg University (JGU) Medical Center, Mainz, GermanyDepartment of Medicine, Albert Einstein College of Medicine, New York, NY, United StatesDepartment of Medicine, Albert Einstein College of Medicine, New York, NY, United StatesDepartment of Medicine, Albert Einstein College of Medicine, New York, NY, United StatesBackgroundCD40, a key co-stimulatory molecule expressed on antigen-presenting cells, is genetically associated with a number of autoimmune diseases including Graves’ disease (GD). Therefore, recent therapies targeting CD40 have been developed, including the anti-CD40 monoclonal antibody Iscalimab. In a recent pilot study, Iscalimab was shown to induce clinical remission in ~ 50% of GD patients, but the reason why only 50% of GD patients responded is not known. The aim of our study was to test the hypothesis that specific CD40 single nucleotide polymorphism (SNP) genotypes and haplotypes are associated with clinical response of GD patients to Iscalimab.MethodsWe extracted genomic DNA from the whole blood of 13 GD patients treated with Iscalimab, and genotyped seven CD40 single nucleotide polymorphisms (SNPs) associated with autoimmunity. Additionally, we analyzed CD40 mRNA expression levels in whole blood. The patients’ CD40 SNP genotypes and mRNA levels were tested for association with clinical response to Iscalimab.ResultsThree common haplotypes, designated haplotypes A, B, and C, were identified. Haplotypes B and C were associated with higher CD40 mRNA levels and clinical response to Iscalimab (i.e., patients achieving euthyroidism without need for additional medications), while haplotype A was associated with decreased CD40 mRNA levels and no response to Iscalimab.ConclusionOur data suggest that genetic polymorphisms in the CD40 gene drive its expression levels and response to Iscalimab. Polymorphisms associated with higher CD40 levels are also associated with clinical response to CD40-targeted therapies. These results set the stage to implementing precision medicine in the therapeutic approach to GD.https://www.frontiersin.org/articles/10.3389/fendo.2021.691781/fullgeneCD40variantGraves’ diseaseprecision medicine |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Larissa C. Faustino George J. Kahaly Lara Frommer Erlinda Concepcion Mihaela Stefan-Lifshitz Yaron Tomer |
spellingShingle |
Larissa C. Faustino George J. Kahaly Lara Frommer Erlinda Concepcion Mihaela Stefan-Lifshitz Yaron Tomer Precision Medicine in Graves’ Disease: CD40 Gene Variants Predict Clinical Response to an Anti-CD40 Monoclonal Antibody Frontiers in Endocrinology gene CD40 variant Graves’ disease precision medicine |
author_facet |
Larissa C. Faustino George J. Kahaly Lara Frommer Erlinda Concepcion Mihaela Stefan-Lifshitz Yaron Tomer |
author_sort |
Larissa C. Faustino |
title |
Precision Medicine in Graves’ Disease: CD40 Gene Variants Predict Clinical Response to an Anti-CD40 Monoclonal Antibody |
title_short |
Precision Medicine in Graves’ Disease: CD40 Gene Variants Predict Clinical Response to an Anti-CD40 Monoclonal Antibody |
title_full |
Precision Medicine in Graves’ Disease: CD40 Gene Variants Predict Clinical Response to an Anti-CD40 Monoclonal Antibody |
title_fullStr |
Precision Medicine in Graves’ Disease: CD40 Gene Variants Predict Clinical Response to an Anti-CD40 Monoclonal Antibody |
title_full_unstemmed |
Precision Medicine in Graves’ Disease: CD40 Gene Variants Predict Clinical Response to an Anti-CD40 Monoclonal Antibody |
title_sort |
precision medicine in graves’ disease: cd40 gene variants predict clinical response to an anti-cd40 monoclonal antibody |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Endocrinology |
issn |
1664-2392 |
publishDate |
2021-06-01 |
description |
BackgroundCD40, a key co-stimulatory molecule expressed on antigen-presenting cells, is genetically associated with a number of autoimmune diseases including Graves’ disease (GD). Therefore, recent therapies targeting CD40 have been developed, including the anti-CD40 monoclonal antibody Iscalimab. In a recent pilot study, Iscalimab was shown to induce clinical remission in ~ 50% of GD patients, but the reason why only 50% of GD patients responded is not known. The aim of our study was to test the hypothesis that specific CD40 single nucleotide polymorphism (SNP) genotypes and haplotypes are associated with clinical response of GD patients to Iscalimab.MethodsWe extracted genomic DNA from the whole blood of 13 GD patients treated with Iscalimab, and genotyped seven CD40 single nucleotide polymorphisms (SNPs) associated with autoimmunity. Additionally, we analyzed CD40 mRNA expression levels in whole blood. The patients’ CD40 SNP genotypes and mRNA levels were tested for association with clinical response to Iscalimab.ResultsThree common haplotypes, designated haplotypes A, B, and C, were identified. Haplotypes B and C were associated with higher CD40 mRNA levels and clinical response to Iscalimab (i.e., patients achieving euthyroidism without need for additional medications), while haplotype A was associated with decreased CD40 mRNA levels and no response to Iscalimab.ConclusionOur data suggest that genetic polymorphisms in the CD40 gene drive its expression levels and response to Iscalimab. Polymorphisms associated with higher CD40 levels are also associated with clinical response to CD40-targeted therapies. These results set the stage to implementing precision medicine in the therapeutic approach to GD. |
topic |
gene CD40 variant Graves’ disease precision medicine |
url |
https://www.frontiersin.org/articles/10.3389/fendo.2021.691781/full |
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