Gene–gene interaction and RNA splicing profiles of MAP2K4 gene in rheumatoid arthritis

• Published in: Clinical immunology (Orlando, Fla.) Vol. 158; no. 1; pp. 19 - 28
• Main Authors: Shchetynsky, Klementy, Protsyuk, Darya, Ronninger, Marcus, Diaz-Gallo, Lina-Marcela, Klareskog, Lars, Padyukov, Leonid
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2015
• Subjects: Allergy and Immunology; Alternative splicing; Alternative Splicing - drug effects; Alternative Splicing - genetics; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - metabolism; Blotting, Western; Case-Control Studies; Cell Line; Epistasis, Genetic; Epitopes; Gene–gene interaction; HLA-DRB1 Chains - genetics; Humans; MAP Kinase Kinase 4 - drug effects; MAP Kinase Kinase 4 - genetics; MAP Kinase Kinase 4 - metabolism; MAP2K4; Medicin och hälsovetenskap; Polymorphism, Single Nucleotide; Rheumatoid arthritis; RNA expression; RNA, Messenger - drug effects; RNA, Messenger - metabolism; Tumor Necrosis Factors - pharmacology; RNA expression; Gene–gene interaction; MAP2K4; Alternative splicing; Rheumatoid arthritis
• ISSN: 1521-6616; 1521-7035; 1521-7035
• DOI: 10.1016/j.clim.2015.02.011

Abstract 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.