Systemic sclerosis (SSc) is a chronic fibrotic autoimmune disease of complex aetiology which shares genetic similarities with systemic lupus erythematosus (SLE).1 2 One of the novel risk loci that have been recently associated with SLE is the integrin α M (ITGAM) gene, which encodes the α subunit of the αMβ2-integrin.3 4 The most likely causal polymorphism that best explains this association is a non-synonymous single-nucleotide polymorphism (SNP) at the exon 3, rs1143679, which changes the 77th amino acid residue arginine to histidine (R77H). This functional SNP represents one of the highest associated signals with SLE and is predicted to alter the structure and function of the integrin.4 5 To determine whether ITGAM rs1143679 is also associated with SSc susceptibility and clinical manifestations, we genotyped a total of 3735 SSc patients and 3930 matched healthy individuals from seven independent European cohorts of Caucasian origin (Spain, Germany, The Netherlands, Italy, Norway, Sweden and UK) using a predesigned TaqMan® assay (ID: C___2847895_1_) in an ABI 7900HT (both from Applied Biosystems, Foster City, California, USA). Case sets were subdivided based on the degree of their skin involvement into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc), and by autoantibody status in relation to the presence/absence of anti-centromere (ACA) and anti-topoisomerase antibodies (ATA). Clinical features of the patients have been described before.6 In all cohorts, the genotyping success rate was >95%, and there was no significant departure from Hardy–Weinberg equilibrium (p<0.01). In addition, control allelic frequencies, which showed a striking North–South gradient, were similar to those previously reported in other European Caucasian populations.7 Significant association between ITGAM rs1143679*A and SSc was observed in both the Spanish cohort (p=0.036, OR=1.17) and the combined meta-analysis (p=0.019, OR=1.12) including the seven cohorts (figure 1). This condition was fulfilled because no significant heterogeneity in the ORs was detected (Breslow–Day p=0.64). The lack of association in the replication cohorts independently could be a consequence of a loss of power due to considerably smaller sample sizes. The analysis on data stratified by SSc subtype almost reached significance in the Spanish lcSSc group (p=0.051, OR=1.19), and a slight but significant association between rs1143679*A and the lcSSc subtype was observed in the meta-analysis (p=0.041, OR=1.12). A trend of association with ACA+ patients (p=0.086, OR=1.19) was also observed only in the Spanish subpopulation. On the other hand, data from a previous genome-wide association study in SSc from our group6 showed two clear positive signals within the ITGAM region in rs9888739 (p_GC-adjusted=0.0042, OR=1.17) and rs9937837 (p_GC-adjusted=0.0011, OR=1.14), which have been reported to be highly linked (r²>0.90) with the functional variant rs1143679 analysed in this study.5 Hence, although moderate, the association between this SNP and SSc seems to be reliable. The reduced effect magnitude observed indicates that this ITGAM variant may contribute to a lesser extent to SSc genetic susceptibility compared with SLE, likely due to the immunological mechanisms that are specific to each disease.

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Figure 1

Genotype and allele distribution of the ITGAM polymorphism rs1143679 in SSc patients and healthy controls from Caucasian European populations. The overall statistical power of the analysis was 100% to detect associations with OR=1.3 at significance level=0.05, according to Power Calculator for Genetic Studies 2006 (http://www.sph.umich.edu/csg/abecasis/CaTS/reference.html). Data analysis was performed using PLINK (v1.07) (http://pngu.mgh.harvard.edu/purcell/plink/). 2×2 contingency tables were used and χ² test and/or Fisher's exact test were performed to obtain p values, ORs and 95% CIs. p Values below 0.05 were considered as statistically significant. The forest plot was obtained with StatsDirect statistical software version 2.6.6 (StatsDirect, Cheshire, UK). *OR for the minor allele; †Mantel–Haenszel test under fixed effects. MAF, minor allele frequency; SSc, systemic sclerosis.

ITGAM rs1143679 may play a role in to endothelial injury and impairment of immune complexes clearance in SLE patients.4 8 9 Interestingly, vascular damage of small blood vessels characterise the early events in SSc, and recent evidences indicate that vasculopathy is a key heritable component in this disease.10 Thus, ITGAM rs1143679 could be also implicated in the vascular lesions of SSc patients.

In conclusion, this is the first study that reports a potential influence of ITGAM in SSc pathophysiology. However, since the ORs are relatively modest, additional independent cohorts may be analysed to definitively confirm this finding.