Identification of MAMDC 1 as a candidate susceptibility gene for systemic lupus erythematosus ( SLE )

Background: Systemic lupus erythematosus (SLE) is a complex autoimmune disorder with multiple susceptibility genes. We have previously reported suggestive linkage to the chromosomal region 14q21-q23 in Finnish SLE families. Principal Findings: Genetic fine mapping of this region in the same family material, together with a large collection of parent affected trios from UK and two independent case-control cohorts from Finland and Sweden, indicated that a novel uncharacterized gene, MAMDC1 (MAM domain containing glycosylphosphatidylinositol anchor 2, also known as MDGA2, MIM 611128), represents a putative susceptibility gene for SLE. In a combined analysis of the whole dataset, significant evidence of association was detected for the MAMDC1 intronic single nucleotide polymorphisms (SNP) rs961616 (P – value = 0.001, Odds Ratio (OR) = 1.292, 95% CI 1.103–1.513) and rs2297926 (P –value = 0.003, OR = 1.349, 95% CI 1.109– 1.640). By Northern blot, real-time PCR (qRT-PCR) and immunohistochemical (IHC) analyses, we show that MAMDC1 is expressed in several tissues and cell types, and that the corresponding mRNA is up-regulated by the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-a) and interferon gamma (IFN-c) in THP-1 monocytes. Based on its homology to known proteins with similar structure, MAMDC1 appears to be a novel member of the adhesion molecules of the immunoglobulin superfamily (IgCAM), which is involved in cell adhesion, migration, and recruitment to inflammatory sites. Remarkably, some IgCAMs have been shown to interact with ITGAM, the product of another SLE susceptibility gene recently discovered in two independent genome wide association (GWA) scans. Significance: Further studies focused on MAMDC1 and other molecules involved in these pathways might thus provide new insight into the pathogenesis of SLE. Citation: Hellquist A, Zucchelli M, Lindgren CM, Saarialho-Kere U, Järvinen TM, et al. (2009) Identification of MAMDC1 as a Candidate Susceptibility Gene for Systemic Lupus Erythematosus (SLE). PLoS ONE 4(12): e8037. doi:10.1371/journal.pone. 0008037 Editor: Alexander Idnurm, University of Missouri-Kansas City, United States of America Received June 11, 2009; Accepted October 8, 2009; Published December 7, 2009 Copyright: 2009 Hellquist et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was supported by the Academy of Finland, Sigrid Juselius Foundation and Finska Lakarsallskapet, Finland and Swedish Research Council (to JK and US-K), the Helsinki University Central Hospital Research Fund (TYH5241), the Welander-Finsen Foundation, Sweden (to TS), the Helsinki Biomedical Graduate School LERU PhD Program in Biomedicine (to TMJ), and by personal grants from the University of Helsinki Research Foundation and the Biomedicum Helsinki Foundation (TMJ). Further support came from the Swedish Heart-Lung Foundation, The Royal Physiographic Society in Lund, The King Gustaf V 80th Birthday Fund, The Åke Wiberg Foundation and ALF funding from Stockholm County Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: juha.kere@ki.se