Identification of MAMDC1 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.


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.
Hellquist
Anna
A
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
Zucchelli
Marco
M
Lindgren
Cecilia M
CM
Saarialho-Kere
Ulpu
U
Järvinen
Tiina M
TM
Koskenmies
Sari
S
Julkunen
Heikki
H
Onkamo
Päivi
P
Skoog
Tiina
T
Panelius
Jaana
J
Räisänen-Sokolowski
Anne
A
Hasan
Taina
T
Widen
Elisabeth
E
Gunnarson
Iva
I
Svenungsson
Elisabet
E
Padyukov
Leonid
L
Assadi
Ghazaleh
G
Berglind
Linda
L
Mäkelä
Ville-Veikko
VV
Kivinen
Katja
K
Wong
Andrew
A
Cunningham Graham
Deborah S
DS
Vyse
Timothy J
TJ
D'Amato
Mauro
M
Kere
Juha
J
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
D016207:Cytokines; D058851:GPI-Linked Proteins; C544522:MDGA2 protein, human; D019006:Neural Cell Adhesion Molecules; D012333:RNA, Messenger