Variation in the ICAM1–ICAM4–ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries

Abstract

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.

Advances in lupus genetics and epigenetics

“…Polymorphisms in multiple members of this pathway have been associated with SLE, for example missense variants of FCGR2A / FCGR3A and ITGAM and decreased copy number variations of FCGR3B (reviewed in [47]). CD11b encoded by ITGAM together with CD18 form the complement receptor 3 (CR3) with functions in binding to tissue deposited ICs as well as leukocyte phagocytosis, apoptosis, adhesion and migration via interaction with a range of ligands, such as ICAM1 that has also show association with SLE susceptibility [46]. The SLE-risk allele of ITGAM which encodes an amino acid change from Arg to His at position 77 (R77H) in CD11b impairs the CR3-mediated phagocytosis in monocytes, neutrophils and macrophages [48–50].…”

Recent insights into the genetic basis of systemic lupus erythematosus

“…Genetic variants related to adhesion and endothelial migration of both cell types have been associated with SLE susceptibility in multiple ancestries, specifically R77H ITGAM and most recently the ICAM (intercellular adhesion molecule) locus 32 57 68 69 . ITGAM encodes the α chain of α M β 2 integrin, which regulates neutrophil and monocyte adhesion and migration from the bloodstream via interactions with a wide range of structurally unrelated ligands, including ICAM1 and ICAM2.…”

Human Neutrophil Flow Chamber Adhesion Assay

“…Neutrophil adhesion is a critical process in inflammation. Because genetic variants in multiple molecules in this process have been demonstrated to predispose to the development of autoimmune disease 1,2 , an assay system capable of quantitatively assessing human neutrophil firm adhesion is required. The method described in this protocol allows for the careful and quantitative determination of the firm adhesive potential of neutrophils in a controlled in vitro environment under sheer stress.…”

“…Such functional studies allow for the determination of the mechanisms by which naturally occurring genetic variants shape the immune response in both health and disease. In the specific example of SLE, we now know that variants in ITGAM (CD11b) and its ligand, ICAM-1, strongly associate with development of disease 1,2 . Because neutrophils are critical in inflammatory responses, the quantitative study of neutrophil adhesion may provide mechanistic insights into how genetic variants in ITGAM/ICAM alter inflammation.…”

“…Genetic variants in both β 2 integrins and in ICAM ligands are now recognized to be associated with the development of autoimmune disease 1,2 . The determination of the functional consequences of these variants in cells derived from individuals with these variants is necessary for our understanding of how these variants contribute to autoimmune disease pathogenesis.…”