A Destabilizing Di-nucleotide Deletion in 3’-Untranslated Region of Human CD24 mRNA Confers Protection against Multiple Sclerosis (129.1)

Abstract

Abstract Single-nucleodie polymorphism (SNP) has a profound impact upon one’s susceptibility to autoimmune diseases such as multiple sclerosis (MS). Although it is well established that 3’UTR play a major role in regulating RNA stability, the contribution of SNP in the 3’UTR to the risk of autoimmune diseases has not well characterized. We have proviously reported the contribution of mouse CD24 3’UTR to its mRNA stability, so we investigated the significance of SNPs in the hCD24 3’UTR to MS susceptibility. Our analysis of the 316 MS patients and 342 controls revealed that a di-nucleotide deletion at position 1580 (P1580) of hCD24 mRNA is associated with significantly reduced risk (odds ratio OR = 0.53 with 95% confidence interval = 0.34–0.81) and delayed progression (p = 0.016). More importantly, using 150 families from two independent cohorts, we have found that the P1580del allele is preferentially transmitted to unaffected individuals (p = 0.003). In heterozygous individuals, the mRNA levels for the the di-nucleotide-deletion allele is 2.5-fold less than that of the wild-type allele (p = 0.004). Our transfection studies revealed that the di-nucleotide deletion dramatically reduced the stability of hCD24 mRNA (p < 0.001). Our results demonstrate that a destabilizing di-nucleotide deletion in the 3’UTR of hCD24 mRNA substantially reduces the risk and delays the progression of MS.