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Variation in the ICAM1–ICAM4–ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries
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Details:
  • Pubmed ID:
    22523428
  • Pubmed Central ID:
    PMC3466387
  • Description:
    Objective

    Systemic lupus erythematosus (SLE; OMIM 152700) is a chronic autoimmune disease for which the aetiology includes genetic and environmental factors. ITGAM, integrin αΜ (complement component 3 receptor 3 subunit) encoding a ligand for intracellular adhesion molecule (ICAM) proteins, is an established SLE susceptibility locus. This study aimed to evaluate the independent and joint effects of genetic variations in the genes that encode ITGAM and ICAM.

    Methods

    The authors examined several markers in the ICAM1–ICAM4–ICAM5 locus on chromosome 19p13 and the single ITGAM polymorphism (rs1143679) using a large-scale case–control study of 17 481 unrelated participants from four ancestry populations. The single marker association and gene–gene interaction were analysed for each ancestry, and a meta-analysis across the four ancestries was performed.

    Results

    The A-allele of ICAM1–ICAM4–ICAM5 rs3093030, associated with elevated plasma levels of soluble ICAM1, and the A-allele of ITGAM rs1143679 showed the strongest association with increased SLE susceptibility in each of the ancestry populations and the trans-ancestry meta-analysis (ORmeta=1.16, 95% CI 1.11 to 1.22; p=4.88×10−10 and ORmeta=1.67, 95% CI 1.55 to 1.79; p=3.32×10−46, respectively). The effect of the ICAM single-nucleotide polymorphisms (SNPs) was independent of the effect of the ITGAM SNP rs1143679, and carriers of both ICAM rs3093030-AA and ITGAM rs1143679-AA had an OR of 4.08 compared with those with no risk allele in either SNP (95% CI 2.09 to 7.98; p=3.91×10−5).

    Conclusion

    These findings are the first to suggest that an ICAM–integrin-mediated pathway contributes to susceptibility to SLE.

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  • Funding:
    5UL1RR025777/RR/NCRR NIH HHS/United States
    AI063622/AI/NIAID NIH HHS/United States
    AI071651/AI/NIAID NIH HHS/United States
    AI082714/AI/NIAID NIH HHS/United States
    AI083194/AI/NIAID NIH HHS/United States
    AI094377/AI/NIAID NIH HHS/United States
    AI24717/AI/NIAID NIH HHS/United States
    AR042460/AR/NIAMS NIH HHS/United States
    AR043274/AR/NIAMS NIH HHS/United States
    AR043814/AR/NIAMS NIH HHS/United States
    AR044804/AR/NIAMS NIH HHS/United States
    AR048940/AR/NIAMS NIH HHS/United States
    AR052300/AR/NIAMS NIH HHS/United States
    AR053483/AR/NIAMS NIH HHS/United States
    AR058554/AR/NIAMS NIH HHS/United States
    AR060366/AR/NIAMS NIH HHS/United States
    AR43727/AR/NIAMS NIH HHS/United States
    AR62277/AR/NIAMS NIH HHS/United States
    CA141700-01/CA/NCI NIH HHS/United States
    GM063483/GM/NIGMS NIH HHS/United States
    HD07463/HD/NICHD NIH HHS/United States
    K08 AI083790/AI/NIAID NIH HHS/United States
    K08-AI083790/AI/NIAID NIH HHS/United States
    K24 AI078004/AI/NIAID NIH HHS/United States
    K24 AR002138/AR/NIAMS NIH HHS/United States
    K24-AR002138/AR/NIAMS NIH HHS/United States
    L30 AI071651/AI/NIAID NIH HHS/United States
    M01 RR000079/RR/NCRR NIH HHS/United States
    M01-RR00079/RR/NCRR NIH HHS/United States
    N01 AR062277/AR/NIAMS NIH HHS/United States
    N01-AR-6-227/AR/NIAMS NIH HHS/United States
    P01 AI083194/AI/NIAID NIH HHS/United States
    P01 AR049084/AR/NIAMS NIH HHS/United States
    P01-AR49084/AR/NIAMS NIH HHS/United States
    P20 RR015577/RR/NCRR NIH HHS/United States
    P20 RR020143/RR/NCRR NIH HHS/United States
    P30 AR053483/AR/NIAMS NIH HHS/United States
    P30 CA046934/CA/NCI NIH HHS/United States
    P30 DK042086/DK/NIDDK NIH HHS/United States
    P30-AR055385/AR/NIAMS NIH HHS/United States
    P30-DK42086/DK/NIDDK NIH HHS/United States
    P50 AR048940/AR/NIAMS NIH HHS/United States
    P60 AR030692/AR/NIAMS NIH HHS/United States
    P60 AR049459/AR/NIAMS NIH HHS/United States
    P60 AR053308/AR/NIAMS NIH HHS/United States
    P60-2-AR30692/AR/NIAMS NIH HHS/United States
    P60-AR049459/AR/NIAMS NIH HHS/United States
    P60-AR053308/AR/NIAMS NIH HHS/United States
    PR094002/PR/OCPHP CDC HHS/United States
    R01 AI063622/AI/NIAID NIH HHS/United States
    R01 AR033062/AR/NIAMS NIH HHS/United States
    R01 AR042460/AR/NIAMS NIH HHS/United States
    R01 AR042525/AR/NIAMS NIH HHS/United States
    R01 AR043274/AR/NIAMS NIH HHS/United States
    R01 AR043727/AR/NIAMS NIH HHS/United States
    R01 AR043814/AR/NIAMS NIH HHS/United States
    R01 AR044804/AR/NIAMS NIH HHS/United States
    R01 AR052300/AR/NIAMS NIH HHS/United States
    R01 AR057172/AR/NIAMS NIH HHS/United States
    R01 AR060366/AR/NIAMS NIH HHS/United States
    R01 CA141700/CA/NCI NIH HHS/United States
    R01-AR33062/AR/NIAMS NIH HHS/United States
    R21 AI070304/AI/NIAID NIH HHS/United States
    R21 AI094377/AI/NIAID NIH HHS/United States
    R21-AI070304/AI/NIAID NIH HHS/United States
    R37 AI024717/AI/NIAID NIH HHS/United States
    RC1 AR058554/AR/NIAMS NIH HHS/United States
    RR015577/RR/NCRR NIH HHS/United States
    RR020143/RR/NCRR NIH HHS/United States
    T32 GM063483/GM/NIGMS NIH HHS/United States
    T32 HD007463/HD/NICHD NIH HHS/United States
    U19 AI082714/AI/NIAID NIH HHS/United States
    UL1 RR024148/RR/NCRR NIH HHS/United States
    UL1 RR024999/RR/NCRR NIH HHS/United States
    UL1 RR025005/RR/NCRR NIH HHS/United States
    UL1 RR025741/RR/NCRR NIH HHS/United States
    UL1 RR025777/RR/NCRR NIH HHS/United States
    UL1 RR029882/RR/NCRR NIH HHS/United States
    UL1 TR000062/TR/NCATS NIH HHS/United States
    UL1 TR000154/TR/NCATS NIH HHS/United States
    UL1RR024999/RR/NCRR NIH HHS/United States
    UL1RR025005/RR/NCRR NIH HHS/United States
    UL1RR025741/RR/NCRR NIH HHS/United States
    UL1RR029882/RR/NCRR NIH HHS/United States
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