Identification of MAMDC1 as a Candidate Susceptibility Gene for Systemic Lupus Erythematosus (SLE)
Year: 2009
Type: article
Study design: Observational Study
Abstract: 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-alpha) and interferon gamma (IFN-gamma) 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.
Source: PLoS ONE
Authors: Anna Hellquist, Marco Zucchelli, Cecilia M. Lindgren, Ulpu Saarialho-Kere, Tiina M. Järvinen, Sari Koskenmies, Heikki Julkunen, Päivi Onkamo, Tiina Skoog, Jaana Panelius, Anne Räisänen-Sokolowski, Taina Hasan, Elisabeth Widen, Iva Gunnarson, Elisabet Svenungsson, Leonid Padyukov, Ghazaleh Assadi, Linda Berglind, Ville-Veikko Mäkelä, Katja Kivinen, Andrew Wong, Deborah S. Cunningham Graham, Timothy J. Vyse, Mauro D'Amato, Juha Kere
Institutions: Karolinska Institutet, Centre for Human Genetics, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Helsinki, Helsinki University Hospital, Peijas Hospital, Tampere University Hospital, University of Tampere, Karolinska University Hospital, Wellcome Sanger Institute, Hammersmith Hospital, Imperial College London
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,382
OpenAlex ID: W2095268637