One high risk haplotype carrying the minor allele A of rs1143679 (ATGCATTTC;P-value =7.41012, OR =3.33, 95% CI =2.334.75) and two haplotypes with a protective effect (GATTGCCCT;P-value =7.6105, OR =0.58, 95% CI =0.440.76, and GAGTGCCCT;P-value =1.7102, OR =0.57, 95% CI =0.360.92), reaching statistical significance, were found in DLE (Figure 1B). OR = 2.14, 95% CI = 1.523.00), and even Flt4 stronger association was found when stratifying SLE patients by presence of discoid rash (P-value = 3.59108, OR = 3.76, 95% CI = 2.296.18). == Significance == We proposeITGAMas 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. == 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. CLE can be subdivided into chronic cutaneous lupus erythematosus, of which discoid lupus erythematosus (DLE) is the most common form, subacute cutaneous lupus erythematosus (SCLE), and acute cutaneous lupus erythematosus (ACLE)[1]. 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 1427% of patients with DLE[2], while only 510% progress to an overt SLE[3]. Lesions typical for DLE are seen in 1520% of SLE patients[4]. Population-based studies on the prevalence of CLE are rare, but this condition is estimated to be 23 times more frequent than SLE[5]. Although the pathogenic mechanisms underlying LE are not yet entirely established, susceptibility is influenced by multiple genetic and environmental factors, including ultraviolet (UV) radiation, certain drugs and oestrogen[5]. A complex genetic component similar to that of SLE may also underlie CLE[3]. The genetic architecture of CLE is poorly understood, but polymorphisms inHLAgenes, MSX-122 theTNF-promoter and complement molecules have been suggested as strong candidates for CLE susceptibility[6]. We have recently shown that the known SLE risk genesTYK2andIRF5also associate with CLE[7]. ITGAM,a member of the immune complex processing pathway, has been consistently replicated as an SLE susceptibility gene[8][11]. The coding variant rs1143679 (R77H) was recently shown to influence the risk of discoid rash in SLE patients[12].ITGAM(CD11b,Mac-1) encodes the -chain of M2-integrin (CD11b/CD18 or CR3), a cell surface receptor for multiple ligands, such as complement 3 cleavage fragment MSX-122 and intercellular adhesion molecule-1 (ICAM-1)[13]. The receptor is expressed on neutrophils, macrophages and dendritic cells and is involved in leukocyte adhesion, phagocytosis and regulation of apoptosis[13]. The exact disease aggravating mechanism is not known, but altered interaction with MSX-122 ligands[10]as well as defects in leukocyte trafficking and uptake of apoptotic cells or immune complexes have been suggested[14]. As abnormal removal of apoptotic cells plays an important role in evolving discoid lesions[6],ITGAMis a plausible candidate gene not only for SLE, but also for cutaneous DLE. In the present study, we investigated the role ofITGAMin a well-characterised cohort of DLE patients without signs of systemic disease. The disease risk was further compared between DLE and a cohort of SLE patients that was stratified for various clinical subtypes. == Materials and Methods == == Ethics statement == This study was conducted in accordance with the Declaration of Helsinki MSX-122 Principles. All subjects gave their written informed consent and the study was approved by the Ethical Review Boards of Helsinki and Tampere University Central Hospitals, Finland, and the Regional Human Ethics Committee at the Karolinska University Hospital, the Institutional Ethics Board and the Regional Ethics Board, Sweden. == Finnish patients and control individuals == Patients from two Finnish cohorts were included in the present study. The recruitment of the case-control cohort and its clinical characteristics have been described recently[15](Table.