Zhou Qunmin, Rammohan Kottil, Lin Shili, Robinson Nikki, Li Ou, Liu Xingluo, Bai Xue-feng, Yin Lijie, Scarberry Bruce, Du Peishuang, You Ming, Guan Kunliang, Zheng Pan, Liu Yang
Division of Cancer Immunology and Department of Pathology, Ohio State University, Columbus, OH 43210, USA.
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15041-6. doi: 10.1073/pnas.2533866100. Epub 2003 Dec 1.
Multiple sclerosis (MS) is a chronic neurological disease of unknown etiology, but a genetic basis for the disease is undisputed. We have reported that CD24 is required for the pathogenicity of autoreactive T cells in experimental autoimmune encephalomyelitis, the mouse model of MS. Here we investigate the contribution of CD24 to MS by studying single-nucleotide polymorphism in the ORF among 242 MS patients and 207 population controls. This single-nucleotide polymorphism results in replacement of alanine (CD24a) with valine (CD24v) in the mature protein. We found that the CD24v/v renders a >2-fold increase in the relative risk of MS in the general population (P = 0.023). Among familial MS, the CD24v allele is preferentially transmitted into affected individuals (P = 0.017). Furthermore, 50% of CD24v/v patients with expanded disability status scale 6.0 reached the milestone in 5 years, whereas the CD24a/v (P = 0.00037) and CD24a/a (P = 0.0016) patients did so in 16 and 13 years, respectively. Moreover, our data suggest that the CD24v/v patients expressed higher levels of CD24 on peripheral blood T cells than did the CD24a/a patients. Transfection with CD24a and CD24v cDNA demonstrated that the CD24v allele can be expressed at higher efficiency than the CD24a alleles. Thus, CD24 polymorphism is a genetic modifier for susceptibility and progression of MS in the central Ohio cohort that we studied, perhaps by affecting the efficiency of CD24 expression on the cell surface.
多发性硬化症（MS）是一种病因不明的慢性神经疾病，但该疾病的遗传基础是无可争议的。我们已经报道，在实验性自身免疫性脑脊髓炎（MS的小鼠模型）中，自身反应性T细胞的致病性需要CD24。在此，我们通过研究242例MS患者和207名群体对照的开放阅读框中的单核苷酸多态性，来探究CD24对MS的影响。这种单核苷酸多态性导致成熟蛋白中的丙氨酸（CD24a）被缬氨酸（CD24v）取代。我们发现，在普通人群中，CD24v/v使MS的相对风险增加了2倍以上（P = 0.023）。在家族性MS中，CD24v等位基因优先传递给受影响的个体（P = 0.017）。此外，50%的残疾状况扩展量表评分为6.0的CD24v/v患者在5年内达到了该里程碑，而CD24a/v患者（P = 0.00037）和CD24a/a患者（P = 0.0016）分别在16年和13年达到该里程碑。此外，我们的数据表明，CD24v/v患者外周血T细胞上CD24的表达水平高于CD24a/a患者。用CD24a和CD24v cDNA转染表明，CD24v等位基因的表达效率高于CD24a等位基因。因此，在我们研究的俄亥俄州中部队列中，CD24多态性是MS易感性和进展的遗传修饰因子，可能是通过影响细胞表面CD24表达的效率来实现的。
