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Am J Transl Res 2012;4(3):347-356
Original Article
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
Divisions of Immunotherapy and Molecular and Medical Genetics, Departments of Surgery, Pathology and Internal
Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan, USA; Institute of Biophysics, Chinese
Academy of Science, Beijing, China; Department of Statistics, the Ohio State University, Columbus, Ohio, USA;
Department of Neurology, the Ohio State University, Columbus, Ohio, USA
Received July 16, 2012; accepted July 27, 2012; Epub July 29, 2012; Published August 15, 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)
Address all correspondence to:
Dr. Yang Liu or Dr. Pan Zheng
Divisions of Immunotherapy and Molecular and Medical Genetics
Departments of Surgery, Pathology and Internal Medicine
University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
E-mail: yangl@umich.edu; panz@umich.edu
Original Article
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
Divisions of Immunotherapy and Molecular and Medical Genetics, Departments of Surgery, Pathology and Internal
Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan, USA; Institute of Biophysics, Chinese
Academy of Science, Beijing, China; Department of Statistics, the Ohio State University, Columbus, Ohio, USA;
Department of Neurology, the Ohio State University, Columbus, Ohio, USA
Received July 16, 2012; accepted July 27, 2012; Epub July 29, 2012; Published August 15, 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)
Address all correspondence to:
Dr. Yang Liu or Dr. Pan Zheng
Divisions of Immunotherapy and Molecular and Medical Genetics
Departments of Surgery, Pathology and Internal Medicine
University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
E-mail: yangl@umich.edu; panz@umich.edu
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