Association Study of ITGAM, ITGAX, and CD58 Autoimmune Risk Loci in Systemic Sclerosis: Results from 2 Large European Caucasian Cohorts

Systemic sclerosis (SSc) is a chronic autoimmune disease with a complex pathogenesis that is driven by a combination of genetic risk factors and environmental events1. Accumulating data have demonstrated shared autoimmunity pathways and genetic susceptibility factors among various autoimmune diseases. Most of these genetic susceptibility factors are frequently replicated in different diseases such as insulin-dependent diabetes mellitus, multiple sclerosis (MS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), juvenile idiopathic arthritis, celiac disease, and others2. Regarding SSc, recent data have shown that the main shared genetic factors that contribute the most to susceptibility are the major histocompatibility complex (MHC), IRF5, STAT4, BANK1, PTPN22, and TNFAIP33,4. These genes and pathways are, strikingly, all known to contribute to susceptibility to SLE. In SLE, some new risk loci have recently been identified. Among these, ITGAM and ITGAX were identified first in association studies performed in large cohorts. Proteins encoded by these latter genes all belong to the integrin family. Among integrin molecules, very late antigen-4 (VLA-4) and lymphocyte function associated-1 (LFA-1) have been implicated in both SLE and SSc5,6. Some hypotheses suggest their participation in maintaining the pathogenic cells in targeted tissues, thereby promoting tissue damage7. ITGAM, also known as CD11b, is located in chromosome 16p11.2 and encodes for the α-chain of the αMβ2– integrin. This leukocyte-specific integrin regulates cell activation and adhesion of neutrophils and monocytes, permitting endothelium stimulation and phagocytosis of complement-coated particles. Particular involvement in immune complex clearance can be linked to the demonstrated impairment of this function in SLE8. Indeed, a deficiency of ITGAM leads to enhanced production of interleukin 6 by antigen-presenting cells9. rs9937837 and other genetic variants located on chromosome 16p11.12 near the gene ITGAM were found to contribute to SLE susceptibility in a genome-wide association study (OR 1.28, p = 7 × 10−7)10. At the same time, another strong genetic variant of ITGAM rs1143679 was reported to be associated with SLE (OR 1.78, p = 1.7 × 10−17)11. A metaanalysis strengthened these results and a strong association of ITGAM rs9937837 (OR 0.47) and rs1143679 (OR 3.04) was shown to influence disease severity12,13,14. This latter finding was convincingly reported as the putative causal variant15. ITGAX encodes the integrin α-X chain protein, which forms by association with β-chain, another leukocyte-specific integrin that overlaps the properties of ITGAM. ITGAM variants have been found to be associated with SLE (OR 1.3). However, linkage disequilibrium data with ITGAM have questioned its role as an independent signal10. This assumption was emphasized by the role of rs114367915. MS and RA also share genetic susceptibility factors with other autoimmune diseases. Another new risk locus shown to be associated with MS is CD58, also known as LFA-3. It encodes a member of the immunoglobulin superfamily, a ligand of the T lymphocyte CD2 protein, and has been implicated in adhesion and activation of T lymphocytes. The rs12044852 variant of CD58 was found to be associated in a large genome-wide association study (OR 1.48)16 in MS and was independently replicated17. Another CD58 variant was also found to be associated with RA (OR 1.14)18. Taking into account (1) the autoimmune background of SSc; (2) the contribution of shared autoimmunity in this condition; (3) the recent report of new autoimmune susceptibility risk factors belonging to integrin genes for autoimmune diseases10; and (4) implication of integrins in SSc, we investigated whether ITGAM, ITGAX, and CD58 variants may confer susceptibility to SSc.