Polymorphisms of the ITGAM Gene Confer Higher Risk of Discoid Cutaneous Than of Systemic Lupus Erythematosus

Tiina M Järvinen,Leonid Padyukov,Sari Koskenmies,Mauro D'Amato,Marika Kvarnström,Filippa Nyberg,Elisabet Einarsdottir,Jaana Panelius,Marie Wahren-Herlenius,Heikki Julkunen,Ulpu Saarialho-Kere,Anna Hellquist,Taina Hasan,Juha Kere

doi:10.1371/journal.pone.0014212

Abstract

BackgroundLupus erythematosus (LE) is a heterogeneous disease ranging from mainly skin-restricted manifestations (discoid LE [DLE] and subacute cutaneous LE) to a progressive multisystem disease (systemic LE [SLE]). Genetic association studies have recently identified several strong susceptibility genes for SLE, including integrin alpha M (ITGAM), also known as CD11b, whereas the genetic background of DLE is less clear.Principal FindingsTo specifically investigate whether ITGAM is a susceptibility gene not only for SLE, but also for cutaneous DLE, we genotyped 177 patients with DLE, 85 patients with sporadic SLE, 190 index cases from SLE families and 395 population control individuals from Finland for nine genetic markers at the ITGAM locus. SLE patients were further subdivided by the presence or absence of discoid rash and renal involvement. In addition, 235 Finnish and Swedish patients positive for Ro/SSA-autoantibodies were included in a subphenotype analysis. Analysis of the ITGAM coding variant rs1143679 showed highly significant association to DLE in patients without signs of systemic disease (P-value = 4.73×10−11, OR = 3.20, 95% CI = 2.23–4.57). Significant association was also detected to SLE patients (P-value = 8.29×10−6, OR = 2.14, 95% CI = 1.52–3.00), and even stronger association was found when stratifying SLE patients by presence of discoid rash (P-value = 3.59×10−8, OR = 3.76, 95% CI = 2.29–6.18).SignificanceWe propose ITGAM as a novel susceptibility gene for cutaneous DLE. The risk effect is independent of systemic involvement and has an even stronger genetic influence on the risk of DLE than of SLE.

Highlights

Lupus erythematosus (LE) is a complex autoimmune disease with variable clinical course and manifestations
These analyses showed that the magnitude of association was strongest in cutaneous discoid lupus erythematosus (DLE) (P-value $3.7610211; uncorrected P-values are reported), followed by systemic lupus erythematosus (SLE) patients with discoid rash (P-value $3.961029) and all SLE patients together (P-value $8.261026) (Table 3)
The associations were more modest in SLE patients with renal involvement (P-value $5.861025) (Table 4), in Finnish (P-value $6.361026) and Swedish (P-value $0.01) Ro/SSA-positive patients as well as in the pooled dataset positive for Ro-antibodies (P-value $6.461026) (Table 5)

Summary

Introduction

Lupus erythematosus (LE) is a complex autoimmune disease with variable clinical course and manifestations. Cutaneous lupus erythematosus (CLE) is a heterogeneous disease entity with manifestations primarily confined to the skin. ACLE is characteristic for systemic lupus erythematosus (SLE) that manifests with severe organ involvement and the presence of haematological and immunological abnormalities, whereas well demarcated, scarring plaques of the face, scalp and ears are often seen in DLE patients. Mild extracutaneous involvement may be present in 14–27% of patients with DLE [2], while only 5–10% progress to an overt SLE [3]. Lupus erythematosus (LE) is a heterogeneous disease ranging from mainly skin-restricted manifestations (discoid LE [DLE] and subacute cutaneous LE) to a progressive multisystem disease (systemic LE [SLE]). Genetic association studies have recently identified several strong susceptibility genes for SLE, including integrin alpha M (ITGAM), known as CD11b, whereas the genetic background of DLE is less clear

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