ITGAM encodes a cell surface receptor protein (integrin) that is implicated in various adhesive interactions of monocytes, macrophages, and granulocytes as well as in mediating the uptake of complement-coated particles. After identifying variants associated with disease risk, it is important to correlate genotypic data with phenotypic expression of the disease that may provide insight into disease pathogenesis and, more importantly, new therapeutic approaches. Subsetting allows us to create more homogeneous groups of patients and thus may increase power to detect associations despite reduced of sample size.
In this study we found that SLE patients often had stronger associations between SLE and rs1143679 when patients were stratified by certain clinical ACR criteria, especially renal criteria, discoid rash, and immunologic manifestations. While results confirm that rs1143679 was strongly associated with SLE in general, SLE patients with renal criteria, discoid rash, and immunologic manifestations were enriched for the risk allele (A) and risk estimates (ORs) were substantially increased, especially for renal criteria ().
The strongest associations in individuals of European-descent were found with SLE cases positive for renal criteria compared to cases without this clinical manifestation. A similar result was recently observed among Chinese and Thai populations [4
]. Renal criteria is one of the most serious manifestations of SLE and is a major predictor of poor prognosis [7
] and mortality [8
]. Among those patients with renal criteria, nearly 70% of patients never treated with cyclophosphamide develop an end-stage renal disease outcome [8
]. As confirmed by our logistic regression analysis, diverse clinical manifestations are associated with renal criteria. It would be important to follow up this study with more clinical information and possibly information about environmental variables. Indeed, clinical and ethnic subsetting of SLE may help explain the natural history of SLE differences by ethnicity.
Our results may provide a genetic correlate into the proposed role by which ITGAM
mediates the inflammatory processes in SLE pathogenesis. ITGAM
(CD11b) expression was shown to increase DNA fragmentation, a prerequisite for apoptosis and fragmented DNA level is elevated in intravascular cells that induces IFNα [9
] in SLE mice. CD11b also induces TNFα [10
] and modulate innate immune mechanism [11
] in SLE patients. This suggest that association of this SNP in ITGAM
with molecular mechanism of immunological manifestations may be correlated. Although the molecular mechanism of discoid rash and involvement of ITGAM
has not been assessed earlier, it could be a clinical manifestation of cell-mediated immunological reactions as well. ITGAM is a major surface receptor in monocytes and monocytes are involved in clearing deposits from glomeruli [12
]. In the normal kidney, ITGAM is expressed on endothelial cells of glomerular and peritubular capillaries of Bowman’s capsule, but in renal criteria, its expression is significantly increased on tubular epithelial cells and on infiltrating mononuclear cells [13
]. In contrast, extensive series of studies by two groups [14
] suggest that C3b receptor (CR3, ITGAM
) expression is decreased in renal criteria patients in compare to control groups. It is also possible that cellular regulatory mechanisms allow ITGAM to be over expressed to cope with the loss of clearance of deposits in glomeruli by monocytes. However, whatever the disease mechanisms, this SNP changes the amino acid (R77H) in the vicinity of alpha domain (metal ion binding domain or A domain) and may overall modulate the numerous ligand binding activities of ITGAM
in monocytes and neutrophils and dendritic cells. Within this context, it is conceivable that risk allele (A) may confer its effect through mutant receptor protein with respect to ligand binding affinity, or this change may aggravate the inflammatory process by decreasing initial kidney cellular infiltration. These individuals are prone to develop renal criteria together with other manifestations like discoid rash or immunologic manifestations.
In summary, we consistently showed strong correlation between the coding variant (rs1143679) of ITGAM and renal, discoid, and immunological manifestation of lupus. The next challenges are to understand how this coding variant actually modulates molecular pathways leading to lupus kidney involvement or other associated clinical manifestations.