Cysteine-Altering NOTCH3 Variants Are Associated with an Increased Risk of Autoimmune Diseases

Author:

Rieder Emily12,Li Jiang3ORCID,Rodriguez-Flores Juan L.4ORCID,Taimur Malik Muhammad5,Abedi Vida36ORCID,Zand Ramin67

Affiliation:

1. Geisinger Commonwealth School of Medicine, Geisinger Health System, Scranton, PA 18510, USA

2. Department of Pediatrics, Duke University, Durham, NC 27705, USA

3. Department of Molecular and Functional Genomics, Weis Center for Research, Geisinger Health System, Danville, PA 17822, USA

4. Regeneron Genetics Center, Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA

5. Neuroscience Institute, Geisinger Health System, Danville, PA 17822, USA

6. Department of Public Health Sciences, College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA

7. Department of Neurology, College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA

Abstract

Autoimmune conditions have been reported among patients with cysteine-altering NOTCH3 variants and CADASIL. This study aimed to investigate the occurrence of autoimmune illnesses and markers of inflammation in such populations. Cases were identified who had a NOTCH3 cysteine-altering variant from the Geisinger MyCode® Community Health Initiative (MyCode®). We further performed external validation using the UK Biobank cohort. A cohort of 121 individuals with a NOTCH3 cysteine-altering variant from MyCode® was compared to a control group with no non-synonymous variation in NOTCH3 (n = 184). Medical records were evaluated for inflammatory markers and autoimmune conditions, which were grouped by the organ systems involved. A similar analysis was conducted using data from the UK Biobank (n~450,000). An overall increase in inflammatory markers among participants with a NOTCH3 cysteine-altering variant was observed when compared to an age- and sex-matched MyCode® control group (out of participants with laboratory testing: 50.9% versus 26.7%; p = 0.0047; out of total participants: 23.1% versus 10.9%; p = 0.004). Analysis of UK Biobank data indicated any autoimmune diagnosis (1.63 [1.14, 2.09], p= 2.665 × 10−3) and multiple sclerosis (3.42 [1.67, 6.02], p = 9.681 × 10−4) are associated with a NOTCH3 cysteine-altering variant in any domain. Our findings suggest a possible association between NOTCH3 cysteine-altering variants and autoimmune conditions.

Publisher

MDPI AG

Subject

General Medicine

Reference16 articles.

1. CADASIL: What component of the vessel wall is really a target for Notch 3 gene mutations?;Rafalowska;Neurol. Res.,2004

2. CADASIL: New cases and new questions;Rafalowska;Acta Neuropathol.,2003

3. CADASIL and Autoimmunity: Coexistence in a Family With the R169C Mutation at Exon 4 of the NOTCH3 Gene;Paraskevas;Cerebrovasc. Dis.,2014

4. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy vs. multiple sclerosis. Either one or sometimes both?;Paraskevas;Neuroimmunol. Neuroinflamm.,2018

5. Collongues, N., Derache, N., Blanc, F., Labauge, P., de Seze, J., and Defer, G. (2012). Inflammatory-like presentation of CADASIL: A diagnostic challenge. BMC Neurol., 12.

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