Abstract
One of the 233 polymorphisms associated with multiple sclerosis (MS) susceptibility lies within the NDFIP1 gene, and it was previously identified as eQTL in healthy controls. NDFIP1 shows interesting immune functions and is involved in the development of the central nervous system. We aimed at studying the NDFIP1 variant on activation and metabolism of immune cells. NDFIP1 mRNA and protein expression were assessed in PBMCs by qPCR and western blot in 87 MS patients and 84 healthy controls genotyped for rs4912622. Immune activation after PHA stimulation was evaluated by CD69 upregulation, and metabolic function of both basal and PHA-activated lymphocytes was studied by Seahorse Xfp-Analyzer. In minor-allele homozygous controls but not in patients, we found higher NDFIP1 expression, significantly reduced protein levels, and CD69 upregulation in B- and T-cells. PBMCs from minor-allele homozygous controls showed significantly higher basal mitochondrial respiration and ATP production compared to major-allele carriers, while minor-allele homozygous patients showed significantly lower metabolic activity than carriers of the major allele. In conclusion, we describe associations in minor-allele homozygous controls with lower levels of NDFIP1 protein, CD69 upregulation, and raised mitochondrial activity, which are not replicated in MS patients, suggesting a NDFIP1 differential effect in health and disease.
Highlights
Múltiple de Catalunya (Cemcat), Institut de Recerca Valld’Hebron (VHIR), Hospital Universitari Valld’Hebron, Universitat Autònoma, Barcelona, Spain. 4Red Española de Esclerosis Múltiple (REEM), Madrid, Spain. 5These authors contributed : Pilar López-Cotarelo, Adela González-Jiménez, Laura Espino-Paisán and Elena
The rs1036207 polymorphism has been identified as an Multiple Sclerosis (MS)-risk variant by genome-wide association studies (GWAS) and described as an eQTL for NDFIP1 in whole blood from healthy c ontrols[6]
The vast majority of GWAS polymorphisms are present in noncoding DNA sequences and are inherited as dense haploblocks
Summary
Múltiple de Catalunya (Cemcat), Institut de Recerca Valld’Hebron (VHIR), Hospital Universitari Valld’Hebron, Universitat Autònoma, Barcelona, Spain. 4Red Española de Esclerosis Múltiple (REEM), Madrid, Spain. 5These authors contributed : Pilar López-Cotarelo, Adela González-Jiménez, Laura Espino-Paisán and Elena. The ubiquitin system is a key regulatory mechanism for cellular processes including protein turnover, signal transduction, and cell-cycle control. NDFIP1 plays an important role in regulation of both immune and nervous systems. Through interaction with its downstream E3 ligases, NDFIP1 plays key roles in regulating peripheral tolerance[11,12] and T-cell differentiation and maturation. Our study aimed to examine the role of this genetic variation in NDFIP1 in both healthy controls and MS patients. We compared the metabolic program of peripheral blood mononuclear cells obtained from MS patients and healthy controls to further our understanding of MS aetiology and to provide clues for the treatment of this autoimmune disorder associated with T cell dysfunction, as targeting cell metabolism may provide new avenues to suppress immunity
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