Gene-gene interaction and RNA splicing profiles of MAP2K4 gene in rheumatoid arthritis.
We performed gene-gene interaction analysis, with HLA-DRB1 shared epitope (SE) alleles for 195 SNPs within immunologically important MAP2K, MAP3K and MAP4K gene families, in 2010 rheumatoid arthritis (RA) patients and 2280 healthy controls. We found a significant statistical interaction for rs10468473 with SE alleles in autoantibody-positive RA. Individuals heterozygous for rs10468473 demonstrated higher expression of total MAP2K4 mRNA in blood, compared to A-allele homozygous. We discovered a novel, putatively translated, "cassette exon" RNA splice form of MAP2K4, differentially expressed in peripheral blood mononuclear cells from 88 RA cases and controls. Within the group of RA patients, we observed a correlation of MAP2K4 isoform expression with carried SE alleles, autoantibody, and rheumatoid factor profiles. TNF-dependent modulation of isoform expression pattern was detected in the Jurkat cell line. Our data suggest a genetic interaction between MAP2K4 and HLA-DRB1, and the importance of rs10468473 and MAP2K4 splice variants in the development of autoantibody-positive RA.
Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. Electronic address: klementy.shchetynsky@ki.se.
Klementy
K
Shchetynsky
Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Darya
D
Protsyuk
Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Marcus
M
Ronninger
Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Lina-Marcela
LM
Diaz-Gallo
Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Lars
L
Klareskog
Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Leonid
L
Padyukov
D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D002460:Cell Line; D004843:Epistasis, Genetic; D000939:Epitopes; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000494:pharmacology
D000939:Epitopes; D059811:HLA-DRB1 Chains; D012333:RNA, Messenger; D048069:Tumor Necrosis Factors; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human
Alternative splicing; Gene–gene interaction; MAP2K4; RNA expression; Rheumatoid arthritis