Expression of risk genes linked to vitamin D receptor super-enhancer regions and their association with phenotype severity in multiple sclerosis

Autor: Sarah M. Orton, Amarpreet Sangha, Mehul Gupta, Kristina Martens, Luanne M. Metz, A. P. J. de Koning, Gerald Pfeffer
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Frontiers in Neurology, Vol 13 (2022)
Druh dokumentu: article
ISSN: 1664-2295
DOI: 10.3389/fneur.2022.1064008
Popis: Multiple sclerosis (MS) is a chronic debilitating neurological condition with a wide range of phenotype variability. A complex interplay of genetic and environmental factors contributes to disease onset and progression in MS patients. Vitamin D deficiency is a known susceptibility factor for MS, however the underlying mechanism of vitamin D-gene interactions in MS etiology is still poorly understood. Vitamin D receptor super-enhancers (VSEs) are enriched in MS risk variants and may modulate these environment-gene interactions. mRNA expression in total of 64 patients with contrasting MS severity was quantified in select genes. First, RNA-seq was performed on a discovery cohort (10 mild, 10 severe MS phenotype) and ten genes regulated by VSEs that have been linked to MS risk were analyzed. Four candidates showed a significant positive association (GRINA, PLEC, PARP10, and LRG1) in the discovery cohort and were then quantified using digital droplet PCR (ddPCR) in a validation cohort (33 mild, 11 severe MS phenotype). A significant differential expression persisted in the validation cohort for three of the VSE-MS genes: GRINA (p = 0.0138), LRG1 (p = 0.0157), and PLEC (p = 0.0391). In summary, genes regulated by VSE regions that contain known MS risk variants were shown to have differential expression based on disease severity (p
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