Genetic variation in NDFIP1 modifies the metabolic patterns in immune cells of multiple sclerosis patients

Autoinmunidad; Marcadores genéticos; Trastornos neurológicos Autoimmunitat; Marcadors genètics; Trastorns neurològics Autoimmunity; Genetic markers; Neurological disorders 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. This work was supported by the projects PI16/01259 and PI20/01634, integrated in the Plan Nacional de I + D + I, AES 2013–2016 and 2017–2020; funded by the ISCIII and co-funded by the European Regional Development Fund (ERDF) "A way to make Europe”. LEP is recipient of a contract from “REEM: Red Española de Esclerosis Múltiple” (RETICS-REEM RD16/0015/0013; www.reem.es). AGJ and JAZ hold contracts from the program “Promoción de empleo joven y garantía juvenil-CAM” (PEJ2018-003125-A and PEJD-2019-PRE/SAL-16662).