title: 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 approximately 1528 (P1527(del)) 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 P1527(del) 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.
authors.affiliation: Division of Immunotherapy, Department of Surgery, Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Lizhong
authors.initials: L
authors.lastname: Wang
authors.forename: Shili
authors.initials: S
authors.lastname: Lin
authors.forename: Kottil W
authors.initials: KW
authors.lastname: Rammohan
authors.forename: Zhenqiu
authors.initials: Z
authors.lastname: Liu
authors.forename: Jin-qing
authors.initials: JQ
authors.lastname: Liu
authors.forename: Run-hua
authors.initials: RH
authors.lastname: Liu
authors.forename: Nikki
authors.initials: N
authors.lastname: Guinther
authors.forename: Judy
authors.initials: J
authors.lastname: Lima
authors.forename: Qunmin
authors.initials: Q
authors.lastname: Zhou
authors.forename: Tony
authors.initials: T
authors.lastname: Wang
authors.forename: Xincheng
authors.initials: X
authors.lastname: Zheng
authors.forename: Dan J
authors.initials: DJ
authors.lastname: Birmingham
authors.forename: Brad H
authors.initials: BH
authors.lastname: Rovin
authors.forename: Lee A
authors.initials: LA
authors.lastname: Hebert
authors.forename: Yeeling
authors.initials: Y
authors.lastname: Wu
authors.forename: D Joanne
authors.initials: DJ
authors.lastname: Lynn
authors.forename: Glenn
authors.initials: G
authors.lastname: Cooke
authors.forename: C Yung
authors.initials: CY
authors.lastname: Yu
authors.forename: Pan
authors.initials: P
authors.lastname: Zheng
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000483:Alleles; D000818:Animals; D051927:CD24 Antigen / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D016466:CHO Cells; D016022:Case-Control Studies; D002877:Chromosomes, Human / Q000235:genetics; D006224:Cricetinae; D003412:Cricetulus; D018900:Dinucleotide Repeats / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology / Q000517:prevention & control*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D051927:CD24 Antigen; D012333:RNA, Messenger