A Single Nucleotide ADA Genetic Variant Is Associated to Central Inflammation and Clinical Presentation in MS: Implications for Cladribine Treatment.
Mario Stampanoni BassiFabio ButtariIlaria SimonelliLuana GilioRoberto FurlanAnnamaria FinardiGirolama Alessandra MarfiaAndrea ViscontiAndrea PaolilloMarianna StortoStefano GambardellaRosangela FereseMarco SalvettiAntonio UccelliGiuseppe MatareseDiego CentonzeFrancesca De VitoPublished in: Genes (2020)
In multiple sclerosis (MS), activated T and B lymphocytes and microglial cells release various proinflammatory cytokines, promoting neuroinflammation and negatively affecting the course of the disease. The immune response homeostasis is crucially regulated by the activity of the enzyme adenosine deaminase (ADA), as evidenced in patients with genetic ADA deficiency and in those treated with cladribine tablets. We investigated in a group of patients with MS the associations of a single nucleotide polymorphism (SNP) of ADA gene with disease characteristics and cerebrospinal fluid (CSF) inflammation. The SNP rs244072 of the ADA gene was determined in 561 patients with MS. Disease characteristics were assessed at the time of diagnosis; furthermore, in 258 patients, proinflammatory and anti-inflammatory molecules were measured in the CSF. We found a significant association between rs244072 and both clinical characteristics and central inflammation. In C-carriers, significantly enhanced disability and increased CSF levels of TNF, IL-5 and RANTES was observed. In addition, lower CSF levels of the anti-inflammatory cytokine IL-10 were found. Finally, the presence of the C allele was associated with a tendency of increased lymphocyte count. In MS patients, ADA SNP rs244072 is associated with CSF inflammation and disability. The selective targeting of the ADA pathway through cladribine tablet therapy could be effective in MS by acting on a pathogenically relevant biological mechanism.
Keyphrases
- multiple sclerosis
- genome wide
- mass spectrometry
- ms ms
- cerebrospinal fluid
- oxidative stress
- end stage renal disease
- newly diagnosed
- immune response
- ejection fraction
- copy number
- white matter
- chronic kidney disease
- prognostic factors
- rheumatoid arthritis
- peripheral blood
- dna methylation
- lipopolysaccharide induced
- peritoneal dialysis
- gene expression
- spinal cord injury
- spinal cord
- bone marrow
- transcription factor
- dendritic cells
- patient reported outcomes
- genome wide identification
- blood brain barrier
- cognitive impairment
- patient reported
- cerebral ischemia
- pi k akt
- genome wide analysis