The genetic risk factors for ADs might well consist of two forms: those common to many ADs and those specific to a given disorder [21
]. Combinations of common and disease-specific alleles at HLA and non-HLA genes, in interaction with epigenetic and environmental factors over time may determine the final clinical autoimmune phenotype [1
]. Since the ITGAM
SNP rs1143679 has been consistently associated SLE across multiple, diverse populations, it is important to assess its relation with other ADs. We genotyped relatively homogenous samples with ethnically matched controls to assess association between the only “causal” (to date) SLE susceptibility variant of ITGAM
and multiple ADs. Samples were collected from populations of Latin America and from European descent.
While we did not find significant association between SSc and rs1143679, our meta-analysis incorporating published data revealed modest but significant association. The other ADs assessed in this study did not yield association with rs1143679. However, we observed higher MAF from the cases in most ADs. Many of our AD groups were relatively small and may have been under-powered to detect modest associations, especially CED and T1D. However, for RA, pSS, and SSc, our meta-analyses were large enough to detect association. Therefore, with modest ORs we are confident about these results. Additionally, since the samples are from different ethnic groups there may be an impact of admixture on this population. This issue is not yet thoroughly worked out. However, based on previous work on ITGAM
association in Latin Americans samples we did not see an impact of admix on ITGAM
]. The association between ITGAM
and SLE was replicated in Latin Americans as well as the major HLA genes associated with SLE and other ADs [23
It has been postulated that patients with the ‘A’ allele of the non-synonymous coding SNP rs1143679 might express high amounts of ITGAM making these individuals prone to develop lupus nephritis or aggravate the inflammatory process by increasing initial kidney cellular infiltration [25
]. On the other hand, there is not enough evidence concerning the implications of ITGAM in the pathogenesis of SSc or its sub-phenotypes. Monocytes CD11b (ITGAM) are the predominant cell population infiltrating skin and lungs in patients with early, rapidly progressive SSc [25
]. Although ITGAM may play an important role in SSc [28
], further functional studies are required to elucidate the relation between ITGAM
polymorphism and disease outcome.
None of other ADs we assessed, including pSS, MS, RA, T1D, CED, and JIA were associated with rs1143679. Our results were consistent with recent reports which indicate that ITGAM
is not associated with RA [6
]. The first study examined the association in RA cases and controls from New Zealand and the UK [6
], and the second study in RA cases and controls from Spain [7
]. Despite sufficient power for both studies, neither study found an association between RA and ITGAM
, even when patients were stratified by clinical features of RA. Additionally, meta-analysis using our data and published reports did not reveal significant association between RA and rs1143679.
A recent report [32
] indicates that ITGAM
SNP rs1143679 is associated with discoid lupus erythematosus (DLE) in a Finnish and Swedish cohort. DLE is a chronic skin condition of sores with inflammation and scarring favoring the face, ears, and scalp and at times on other body areas. Of interest, in addition to reporting strong association of rs1143679 with lupus related renal involvement, this SNP was also strongly related to skin manifestations beyond overall SLE susceptibility [33
]. It is possible that CD11b could mediate the inflammatory processes in SLE as CD11b deficiency in mice enhanced differentiation of naive T cells to interleukin (IL) 17 producing T-helper type17 cells [35
]. Additionally, serum IL-17 concentrations were higher in patients with discoid lupus and SLE compared with normal controls [36
]. Thus far, the question for future research: what is the role of ITGAM
in predisposition for lupus-related skin manifestations. Another research question would examine if this potential association is specific to European-derived populations only.
In summary, the current study explored the role of ITGAM
in general autoimmunity in non-SLE ADs, and only found association for SSc when our results were combined with published results. ITGAM, as other SLE associated molecules such as complement C reactive protein, is involved in the immune opsonin pathway and in phagocytic clearing of nuclear antigens and apoptotic debris, which provide excessive exposure of lupus-related antigens to immune cells [37
]. Analysis of gene-gene interactions in the opsonin pathway and its relationship to SLE and SSc may provide a system-based approach to identify additional candidate genes associated with these diseases [37
]. Interestingly, the coexistence of SLE and SSc is not rare [38
] and this association is part of a cluster of polyautoimmunity [38
]. Although ITGAM
could play an important role in SSc, further functional studies are required to elucidate the relation between ITGAM
polymorphism and SSc course and outcome. Thus ITGAM
may not be a general autoimmunity gene but this variant may be specifically associated with SLE, DLE, and SSc pathogeneses.