title: Identification of MAMDC1 as a candidate susceptibility gene for systemic lupus erythematosus (SLE).
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Further studies focused on MAMDC1 and other molecules involved in these pathways might thus provide new insight into the pathogenesis of SLE.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Hellquist
authors.forename: Marco
authors.initials: M
authors.lastname: Zucchelli
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Lindgren
authors.forename: Ulpu
authors.initials: U
authors.lastname: Saarialho-Kere
authors.forename: Tiina M
authors.initials: TM
authors.lastname: Järvinen
authors.forename: Sari
authors.initials: S
authors.lastname: Koskenmies
authors.forename: Heikki
authors.initials: H
authors.lastname: Julkunen
authors.forename: Päivi
authors.initials: P
authors.lastname: Onkamo
authors.forename: Tiina
authors.initials: T
authors.lastname: Skoog
authors.forename: Jaana
authors.initials: J
authors.lastname: Panelius
authors.forename: Anne
authors.initials: A
authors.lastname: Räisänen-Sokolowski
authors.forename: Taina
authors.initials: T
authors.lastname: Hasan
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Widen
authors.forename: Iva
authors.initials: I
authors.lastname: Gunnarson
authors.forename: Elisabet
authors.initials: E
authors.lastname: Svenungsson
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Assadi
authors.forename: Linda
authors.initials: L
authors.lastname: Berglind
authors.forename: Ville-Veikko
authors.initials: VV
authors.lastname: Mäkelä
authors.forename: Katja
authors.initials: K
authors.lastname: Kivinen
authors.forename: Andrew
authors.initials: A
authors.lastname: Wong
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Cunningham Graham
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Vyse
authors.forename: Mauro
authors.initials: M
authors.lastname: D'Amato
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
mesh_terms: D002460:Cell Line; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000473:pathology; D009000:Monocytes / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics*; D016017:Odds Ratio; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D016207:Cytokines; D058851:GPI-Linked Proteins; C544522:MDGA2 protein, human; D019006:Neural Cell Adhesion Molecules; D012333:RNA, Messenger