OPEN Association between the CD24 Ala57Val SUBJECT AREAS: polymorphism and risk for multiple GENETICS RESEARCH RISK FACTORS sclerosis and systemic lupus MULTIPLE SCLEROSIS erythematosus: a meta-analysis Received Jian Huang*, Yaqi Yang*, Zibin Liang, Miaomiao Kang, Ying Kuang & Feng Li 9 September 2014 Accepted Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. 3 March 2015 Published The cluster of differentiation 24 (CD24) Ala57Val polymorphism has been implicated as a risk factor for 1 April 2015 multiple sclerosis (MS) and systemic lupus erythematosus (SLE); however, genetic studies have produced controversial results. A meta-analysis was performed on this topic. We used odds ratio (OR) and 95% confidence interval (95% CI) to investigate the strength of association. Eleven studies from nine publications Correspondence and consisting of 2466 cases and 2650 controls were included. The results suggested that the CD24 Val/Val 5 requests for materials genotypes were associated with an increased risk of MS in all study subjects and Caucasians (OR 2.28, 95% CI: 1.68–3.10, P , 0.001 and OR 5 2.30, 95% CI: 1.66–3.20, P , 0.001, respectively). Sensitivity analysis should be addressed to z z showed that no individual study was found to be significantly biasing the pooled results. Although F.L. ([email protected]. meta-analysis also suggested an association between the CD24 Val/Val genotypes and SLE risk in Caucasians edu.cn) (OR 5 1.71, 95% CI: 1.31–2.24, Pz , 0.001), sensitivity analysis demonstrated that the association was not statistically significant after removing a Spanish study. In conclusion, this meta-analysis suggests that the CD24 Ala57Val polymorphism is associated with an increased risk of MS in Caucasians. However, the * These authors available evidence is not sufficient to support an association between the CD24 Ala57Val polymorphism and contributed equally to SLE risk. this work. ultiple sclerosis (MS) and systemic lupus erythematosus (SLE) are autoimmune diseases mediated by self-reactive T cells and other cells of the adaptive and innate immune systems1,2. MS is characterized by M chronic inflammation, multifocal demyelination and axon loss that affect the central nervous system (CNS), whereas in SLE, inflammation and tissue damage can involve many organs and systems, including the skin, lungs, kidneys, and CNS. Although the etiology of these diseases remains largely unknown, it is apparent that both genetic and environmental factors play a role3. Human genetic studies have shown that the human leukocyte antigen (HLA) gene on chromosome 6p21 is the most important genetic factor for MS and SLE3. In MS, the HLA- DR15 haplotype (DRB1*1501-DQA1*0102-DQB1*0602) and its individual alleles appear to have the main role in Caucasians4. In SLE, the HLA-DR2 and DR3 alleles and the Class III variants are important genetic susceptibility factors for the disease5. However, the HLA complex does not fully explain the genetic susceptibility in these diseases. Recent advances in molecular genetic technologies have led to identification of many single nucleotide polymorphisms (SNPs) outside the HLA region for MS and SLE6,7. The exploration of non-HLA genetic risk loci may help elucidate signaling pathways involved in the pathogenesis of MS and SLE, and provide insight into genes and mechanisms shared among autoimmune diseases. Cluster of differentiation 24 (CD24) is a small cell surface protein molecule anchored by glycosyl-phospho- tidyl-inositol (GPI) in a wide variety of cell types, including T cells, B cells, dendritic cells (DCs), cancer cells and local antigen-presenting cells in the CNS8–12. CD24 has been implicated in a CD28-independent costimulatory pathway in the activation of CD41 and CD81 T cells13. It also functions as an important regulator during the early stages of B and T cell lymphopoiesis14. In addition, CD24 modulates the interaction between very late antigen (VLA)-4 and vascular cell adhesion molecule (VCAM)-115. These adhesion molecules play an important role in lymphocyte costimulation and migration to sites of inflammation. The human CD24 gene, which maps on 6q21, is considered a candidate gene for MS and SLE. A C . T single-nucleotide polymorphism (SNP) is located in the presumable GPI-anchor cleavage site of the CD24 protein (rs52812045), leading to the replacement of an alanine (CD24 Ala) by a valine (CD24 Val) (Ala57Val)16. According to the data provided by the National Center SCIENTIFIC REPORTS | 5 : 9557 | DOI: 10.1038/srep09557 1 www.nature.com/scientificreports for Biotechnology Information Entrez SNP, the Val allele frequency Results is 0.320 in a population from Centre d’Etude du Polymorphisme Characteristics of published studies. A flow diagram showing the Human pedigrees. Several studies have investigated the relationship selection process of studies included in the present analysis is shown 17–25 of the CD24 Ala57Val polymorphism with MS and SLE ; how- in Fig. 1. After title and abstract evaluation, 273 publications were ever, results from individual studies are not consistent. This likely excluded either because they were irrelevant, not about human stems from several facors, including underpowered sample sizes, subjects, or the record was a duplicate search result. Five publications ethnic differences and minor genetic effects. We therefore performed were excluded after evaluating the remaining 14 publications in their a meta-analysis of published case-control studies to evaluate the entirety. Overall, 11 studies from nine publications met our inclusion association between the CD24 Ala57Val polymorphism and risk criteria with a total of 2466 cases and 2650 controls17–25.Intermsof for MS and SLE. disease, six studies with 899 cases and 1127 controls evaluated the association between the CD24 Ala57Val polymorphism and MS 17–19,21,23,24 Methods risk , whereas five studies with 1567 cases and 1523 controls Search strategy and identification of studies. An electronic search of the medical from three publications assessed the relationship of this SNP with 20,22,25 literature was conducted to identify genetic association studies assessing the SLE . It was noteworthy that the study by Sa´nchez et al. included relationship of the CD24 Ala57Val polymorphism with MS and SLE. PubMed, three cohorts: a Spanish cohort,aGermancohortandaSwedish Scopus, Web of Knowledge, China National Knowledge Infrastructure (CNKI) and cohort20. In terms of ethnicity, nine studies from seven publications Wanfang databases were searched for papers published until January 2015 without were undertaken in Cancasians17,19–24, whereas two studies were language restrictions. Search terms included ‘‘multiple sclerosis’’, ‘‘MS’’, ‘‘systemic 18,25 lupus erythematosus’’, ‘‘SLE’’, ‘‘cluster of differentiation 24’’, ‘‘CD24’’, ‘‘genetics’’, conducted in Asians . The Val allele frequency in controls ranged ‘‘polymorphism’’, ‘‘SNP’’, ‘‘rs52812045’’, and ‘‘association’’. The reference lists of from 23.8% to 31.0% among Caucasian studies, and the pooled retrieved publications were also reviewed to identify other relevant studies missed by frequency was 27.6 (95% CI: 25.7–29.5). Table 1 summarizes the the database search. The following inclusion criteria were used for study selection: (1) characteristics of the eligible studies included in this meta-analysis. case-control design; (2) genotype frequency data for both cases and controls were available; (3) literature published in English or Chinese. Studies were excluded if they CD24 met the following criteria: (1) studies on animal populations; (2) no control subjects; Association between the Ala57Val polymorphism and MS. (3) duplicate data; (4) insufficient data. Reviewers screened study reports by first For this polymorphism, five studies containing 816 cases and 1017 screening titles and abstracts to select publications for full-text evaluation, then controls were undertaken in Caucasians, whereas one study with 83 screening full-text publications to confirm eligibility of the studies. cases and 110 controls were conducted in Asians. Genotype-specific – , odds ratios OR1, OR2, and OR3 were 2.47 (95% CI: 1.79 3.40, Pz Data extraction. Data were extracted by two of the authors, and differences were – 5 – 0.001), 1.17 (95% CI: 0.97 1.42, Pz 0.104), and 2.09 (95% CI: 1.51 resolved by consensus. For each study, the following data were extracted: first author , name, publication year, country, ethnicity, disease, sample size, genotypic frequencies 2.90, Pz 0.001), respectively. These genotype-specific ORs were of the CD24 Ala57Val SNP, diagnostic criteria and genotyping method. We assumed most suggestive of a recessive model (Val/Val vs Ala/Val 1 Ala/ study subjects to be Caucasians, if Caucasians comprised 90% of the subjects. When a Ala). In this model, meta-analysis demonstrated a significant publication reported results on different subpopulations according to country, each association between the CD24 Ala57Val polymorphism and MS risk subpopulation was considered as a separate study in this meta-analysis. 5 – , in all study subjects (OR 2.28, 95% CI: 1.68 3.10, Pz 0.001) Methodological quality assessment. The quality of selected studies was assessed by (Table 2 and Fig. 2). Subgroup analysis according to ethnicity scoring according to the Newcastle Ottawa Scale (NOS) (www.ohri.ca/programs/ demonstrated a significant association between the CD24 Ala57Val clinical_epidemiology/oxford.asp), awarding points based on selection of cases