Saturday, 8 September 2012

Research: CD24 a risk variant for Progression


Wang L, Liu R, Li D, Lin S, Fang X, Backer G, Kain M, Rammoham K, Zheng P, Liu Y. A hypermorphic SP1-binding CD24 variant associates with risk and progression of multiple sclerosis. Am J Transl Res. 2012;4(3):347-56. Epub 2012 Jul 29.

A large number of risk alleles have been identified for multiple sclerosis (MS). However, how genetic variations may affect pathogenesis remains largely unknown for most risk alleles. Through direct sequencing of CD24 promoter region, we identified a cluster of 7 new single nucleotide polymorphisms in the CD24 promoter. A hypermorphic haplotype consisting of 3 SNPs was identified through association studies consisting of 935 control and 764 MS patients (P=0.001, odds ratio 1.3). The variant is also associated with more rapid progression of MS (P=0.016, log rank test). In cells that are heterozygous for the risk allele, chromatin immunoprecipitation revealed that risk allele specifically bind to a transcription factor SP1, which is selectively required for the hypermorphic promoter activity of the variant. In MS patients, the CD24 transcript levels associate with the SP1-binding variant in a dose-dependent manner (P= 0.0007). Our data revealed a potential role for SP1-mediated transcriptional regulation in MS pathogenesis.

Signal transducer CD24 also known as cluster of differentiation 24 or heat stable antigen CD24 (HSA) is a protein that in humans is encoded by the CD24 gene.CD24 is a cell adhesion molecule.CD24 is a glycoprotein expressed at the surface of most B lymphocytes and differentiating neuroblasts. This gene encodes asialoglycoprotein that is expressed on mature granulocytes and in many B cells. The encoded protein is anchored via a glycosyl phosphatidylinositol (GPI) link to the cell surface. Switching-on a gene requires activation of the promoter which is upstream of the DNA sequence. The promoter activity can determine how much of the DNA will be transcribed for protein production. This study found genetic variants in the promoter of CD24 that binds to a transcription factor SP1 (not to be confused with S1P =sphingosine-1-phosphate) which is required for activation of CD24 promoter. This variant was associated with a more rapid progression.

However before you go and get ourself genotyped the genetic significant is around one in ten thousand, which is too low to be linked to disease. For single gene effects this requires about ten to the power 15 not ten to the power 4 = 10 x 10 x 10 x 10 = one in 10,000 chance. The gene most associated to MS is about ten to the power 800.Many of these genes never get replicated in other studies but the group sizes in this study are reasonable. However, if this gene is involved in a more repaid progression this study leaves to no clue of how this great may be involved.

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