TY - JOUR
T1 - Identification of MAMDC1 as a candidate susceptibility gene for Systemic Lupus Erythematosus (SLE)
AU - Hellquist, Anna
AU - Zucchelli, Marco
AU - Lindgren, Cecilia M.
AU - Saarialho-Kere, Ulpu
AU - Järvinen, Tiina M.
AU - Koskenmies, Sari
AU - Julkunen, Heikki
AU - Onkamo, Päivi
AU - Skoog, Tiina
AU - Panelius, Jaana
AU - Räisänen-Sokolowski, Anne
AU - Hasan, Taina
AU - Widen, Elisabeth
AU - Gunnarson, Iva
AU - Svenungsson, Elisabet
AU - Padyukov, Leonid
AU - Assadi, Ghazaleh
AU - Berglind, Linda
AU - Mäkelä, Ville Veikko
AU - Kivinen, Katja
AU - Wong, Andrew
AU - Graham, Deborah S.Cunningham
AU - Vyse, Timothy J.
AU - D'Amato, Mauro
AU - Kere, Juha
PY - 2009/12/1
Y1 - 2009/12/1
N2 - 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-α) and interferon gamma (IFN-γ) 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.
AB - 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-α) and interferon gamma (IFN-γ) 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.
UR - http://www.scopus.com/inward/record.url?scp=77949513958&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0008037
DO - 10.1371/journal.pone.0008037
M3 - Article
C2 - 19997561
AN - SCOPUS:77949513958
SN - 1932-6203
VL - 4
JO - PLoS ONE
JF - PLoS ONE
IS - 12
M1 - e8037
ER -