A Dinucleotide Deletion in CD24 Confers Protection against Autoimmune Diseases

Abstract

It is generally believed that susceptibility to both organ-specific and systemic autoimmune diseases is under polygenic control. Although multiple genes have been implicated in each type of autoimmune disease, few are known to have a significant impact on both. Here, we investigated the significance of polymorphisms in the human gene CD24 and the susceptibility to multiple sclerosis (MS) and systemic lupus erythematosus (SLE). We used cases/control studies to determine the association between CD24 polymorphism and the risk of MS and SLE. In addition, we also considered transmission disequilibrium tests using family data from two cohorts consisting of a total of 150 pedigrees of MS families and 187 pedigrees of SLE families. Our analyses revealed that a dinucleotide deletion at position 1527∼1528 (P1527del) from the CD24 mRNA translation start site is associated with a significantly reduced risk (odds ratio = 0.54 with 95% confidence interval = 0.34–0.82) and delayed progression (p = 0.0188) of MS. Among the SLE cohort, we found a similar reduction of risk with the same polymorphism (odds ratio = 0.38, confidence interval = 0.22–0.62). More importantly, using 150 pedigrees of MS families from two independent cohorts and the TRANSMIT software, we found that the P1527del allele was preferentially transmitted to unaffected individuals (p = 0.002). Likewise, an analysis of 187 SLE families revealed the dinucleotide-deleted allele was preferentially transmitted to unaffected individuals (p = 0.002). The mRNA levels for the dinucleotide-deletion allele were 2.5-fold less than that of the wild-type allele. The dinucleotide deletion significantly reduced the stability of CD24 mRNA. Our results demonstrate that a destabilizing dinucleotide deletion in the 3′ UTR of CD24 mRNA conveys significant protection against both MS and SLE.

CD24: from A to Z

“…Importantly, the dinucleotide deletion conferred protection against multiple sclerosis and SLE. 7 The mechanism by which CD24 regulates autoimmune disease remains to be fully elucidated. Apart from its costimulatory activity, CD24 is a genetic check point in T-cell homeostatic proliferation in lymphopenic hosts.…”

“…6 Similarly, human CD24 cDNA has a 0.24-kb openreading frame and 1.8 kb 39 UTR, and the UTR region dinucleotide deletion can affect CD24 mRNA stability. 7 The primary structure of both mouse and human CD24 shows multiple N-or O-glycosylation sites. The human CD24 molecule has additional serine and threonine residues, rendering the molecule like a mucin.…”

FUS-CREB3L2/L1–Positive Sarcomas Show a Specific Gene Expression Profile with Upregulation of CD24 and FOXL1

“…Gene expression array (cases [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19], IHC analyses (cases 1, 2, 10, 11, and 20-24), ICC (cases 5 and 6), and/or SNP array (cases 1-9) were carried out on 24 LGFMS cases listed in Table 1. The clinical, cytogenetic, and fusion transcript data on 20 of the cases have been published before (5)(6)(7)(8).…”

“…RNA from 19 LGFMS cases, and from 6 cases each of MFS, DFM, SFT, and EMCS, was of sufficient quality for the global gene expression analysis. Extraction of total RNA from frozen tumor biopsies, RNA concentration and quality measurements, and hybridization of cDNA to the Human GeneChip Gene 1.0 ST Array (Affymetrix) were carried out as described (15).…”

“…The putative regulatory region of CD24 investigated in silico in the present study extends from À3,000 to þ1,500 of the NM_013230 TSS and is part of the sequence with accession no FJ226006 (19). The alignment of FOXL1 orthologous sequences was conducted with Genome-VISTA as described (20), and the sequence which covered the most conserved regions from À3,000 to þ1,000 relative the NM_005250 TSS was chosen for further analyses.…”