Renal disorder was significantly correlated with the lupus risk allele in ITGAM (p=5.0 × 10(-6), OR 1.25, 95% CI 1.12 to 1.35) and in TNFSF4 (p=0.0013, OR 1.14, 95% CI 1.07 to 1.25).
Further, we confirmed the genetic association between lupus and 5 additional lupus susceptibility loci (ITGAM, MSH5, CFB, STAT4, and FCGR2A; P = 7.5 × 10⁻¹¹, P = 5.2 × 10⁻⁸, P = 8.7 × 10⁻⁷ , P = 0.0058, and P = 0.0070, respectively), and provided evidence, for the first time, of genome-wide significance for the association between lupus in African American patients and ITGAM and MSH5 (HLA region).
ITGAM and its associated 'predisposing' variant (rs1143679, Arg77His), predicted to alter the tertiary structures of the ligand-binding domain of ITGAM, may play a key role for SLE pathogenesis.
The A-allele of ICAM1-ICAM4-ICAM5 rs3093030, associated with elevated plasma levels of soluble ICAM1, and the A-allele of ITGAMrs1143679 showed the strongest association with increased SLE susceptibility in each of the ancestry populations and the trans-ancestry meta-analysis (OR(meta)=1.16, 95% CI 1.11 to 1.22; p=4.88×10(-10) and OR(meta)=1.67, 95% CI 1.55 to 1.79; p=3.32×10(-46), respectively).
The rs1143679 (rs1143679" genes_norm="3684">R77H) lupus associated variant of ITGAM (CD11b) impairs complement receptor 3 mediated functions in human monocytes.
In this review, we discuss immunological functions of the Mac-1 integrin and how defects in the genetic variant of Mac-1 may relate to SLE development.
These results underscore the need to consider multiple nonsynonymous SNPs when assessing the functional consequences of ITGAM variation on immune cell processes and the risk of SLE.
We assessed whether the variant rs1143679" genes_norm="3684">R77H, rs1143679 within ITGAM, is associated with the risk to developing SLE and the clinical manifestations of Brazilian SLE patients.
This two-pronged contribution (nucleic acid- and protein-level) of the rs1143679 risk allele to decreasing ITGAM activity provides insight into the molecular mechanisms of its potent association with SLE.
Our meta-analyses confirm that the ITGAMrs1143679 polymorphism is associated with SLE susceptibility in different ethnic groups and demonstrate that the polymorphism is associated with LN in European.
Genome-Wide Association Study in an Amerindian Ancestry Population Reveals Novel Systemic Lupus Erythematosus Risk Loci and the Role of European Admixture.
This includes a detailed examination of molecular mechanisms that could explain the risk-conferring effect of rs1143679, a single nucleotide non-synonymous Mac-1 polymorphism associated with SLE.
The rs1143679" genes_norm="3684">R77H variant of CD11b, encoded by the ITGAMrs1143679 polymorphism, is associated robustly with development of the autoimmune disease systemic lupus erythematosus (SLE) and impairs CR3 function, including its regulatory role on monocyte immune signalling.