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. 2012;4(3):347-56.
Epub 2012 Jul 29.

A hypermorphic SP1-binding CD24 variant associates with risk and progression of multiple sclerosis

Lizhong Wang, Runhua Liu, Dongling Li, Shili Lin, Xianfeng Fang, Grant Backer, Mandy Kain, Kottil Rammoham, Pan Zheng, Yang Liu

A hypermorphic SP1-binding CD24 variant associates with risk and progression of multiple sclerosis

Lizhong Wang et al. Am J Transl Res. 2012.

Abstract

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=7x10(-4)). Our data revealed a potential role for SP1-mediated transcriptional regulation in MS pathogenesis.

Keywords: Multiple sclerosis (MS); SP-binding CD24; promoter; risk alleles; single nucleotide polymorphisms (SNP).

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Figures

Figure 1
Figure 1
Identification of 7 new SNPs in CD24 promoter. A diagram of the SNP in the CD24 gene identified by sequencing of 301 Caucasians. All SNP in exon 2 are the same as previously reported, while all SNPs in the promoter region are new. The consensus sites for transcriptional factors are indicated in the promoter region.
Figure 2
Figure 2
CD24 polymorphism and MS progression. Data shown are Kaplan Meier survival curves depicting the relationship between CD24 genotypes and the time to EDSS6.0. Ho: CD24CGC homozygous; Hy. CD24CGC heterozygous; Other, no CD24CGC allele. P values are calculated by log rank tests.
Figure 3
Figure 3
CD24 promoter polymorphism regulates CD24 transcription. A. CD24 transcript levels in PBL of MS patients, as determined by real-time PCR. The CD24 genotypes were indicated in X-axis while the levels of CD24 transcripts were expressed as % of GADPH gene. P values are provided in the panel. B. Promoter activity of the predominant CD24 allele (AGCCCA), risk allele (CGCCCG) and a control minor allele (AGTCCA) that show suggestive protective effect. The top panel shows a diagram 5’ of CD24 gene, highlighting the position of the SNPs and the composition luciferase reporter construct.
Figure 4
Figure 4
A. An essential role for SP1 in polymorphism CD24 promoter activity. As in b, except that SP1 is silenced by ShRNA prior to luciferase assay. The efficacy of ShRNA is demonstrated by Western blot. B. Endogenous SP1 preferentially interacts with MS risk allele (CD24CGC) in a CD24AGT/CGC cell line, a human breast cancer cell line MDA-MD453. The data shown are PCR-based measurement of SP1-associated CD24 promoter, as revealed by chromatin immunoprecipitation. The top panel shows photograph of undigested PCR products, while the middle panel shows BsrFI digestion of the PCR products. These data show that while the input DNA is heterozygous, essentially all promoters DNA bound to SP1 were of the risk allele, based on P-534A/C-specific RFLP. A quantitative data of the precipitated promoter is shown in the bottom panel. All data in this figure has been repeated three times, error bars are standard derivations of data from independent experiments.
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