Abstract Details

Title ADA Genetic Variants Influence Central Inflammation and Clinical Characteristics in MS: Implications for Cladribine Treatment

Topic Multiple Sclerosis

Presentation(s) P4 - Poster Session 4 (5:30 PM-6:30 PM)

Poster/Presentation
Number 15-044

Objective To explore the association between single nucleotide polymorphisms (SNP) of the adenosine deaminase (ADA) gene and CSF inflammation and disease characteristics, in multiple sclerosis (MS) patients.

Background MS is a chronic autoimmune disease of the CNS characterized by demyelination and neurodegeneration. Proinflammatory molecules released by activated T and B lymphocytes and local immune cells negatively influence the disease course. Lymphocytes are sensitive to impaired nucleotide metabolism; the activity of ADA is critical in the regulation of the immune response homeostasis, as shown in ADA genetically deficient patients and in response to cladribine treatment.

Design/Methods Several ADA SNPs (rs244072, rs452159, rs181828191, rs73598374, rs244076, rs1799880) were determined in MS patients (N=590). CSF pro- and anti-inflammatory molecules were measured at MS diagnosis in a subgroup (N=234). Clinical and radiological disease characteristics were assessed at baseline, and during follow-up (median of 44 months).

Results ADA rs244072 SNP and the levels of central inflammation were significantly associated. In patients presenting the C allele, significantly higher CSF levels of TNFα (TT patients median=0.68, IQR=0–1.15; CT/CC median=1.42, IQR=0.31–3.45; p=0.023), IL-5 (TT patients median=0, IQR=0-0.63; CT/CC median=0.39, IQR=0–17.8; p=0.0274) and RANTES (TT patients median=4.49, IQR=0–99.9; CT/CC median=157.3, IQR=0.99–1129.5; p=0.0403) have been observed. In addition, patients with the C allele showed lower CSF levels of IL-10 (TT patients median=2.64, IQR=1.14-4.07; CT/CC median=1.91, IQR=0–2.94; p=0.044). Finally, a significant association emerged between the presence of the C allele and higher expanded disability status score (EDSS) at the time of diagnosis (TT patients median=2, IQR=1–3; CT/CC median=2.5, IQR=2-3.5; p=0.0158).

Conclusions ADA SNP rs244072 influences central inflammation and disease characteristics in MS patients. These results suggest that pharmacological modulation of ADA pathway with cladribine could be effective in MS by targeting a pathogenetically relevant biological mechanism.

Authors/Disclosures
PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Roberto Furlan	Roberto Furlan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche. Roberto Furlan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Roberto Furlan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Roberto Furlan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Roberto Furlan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Roberto Furlan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS.
Gerolama Marfia	No disclosure on file
Marco Salvetti, MD	Dr. Salvetti has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for sanofi. Dr. Salvetti has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for biogen. The institution of Dr. Salvetti has received research support from bms.
Antonio Uccelli, MD (Ospedale S. Martino - Genova)	An immediate family member of Dr. Uccelli has received personal compensation for serving as an employee of Biogen. The institution of Dr. Uccelli has received research support from Merck. The institution of Dr. Uccelli has received research support from Roche.
	No disclosure on file
	No disclosure on file
	No disclosure on file

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