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

- MAP2K4 rs10468473 is in statistical interaction with HLA-DRB1 shared epitope allels in ACPA-positive RA.
- rs10468473 genotype is associated with MAP2K4 expression.
- MAP2K4 gene is expressed as alternative putatively protein-coding transcripts.
- Expression of MAP2K4 transcripts reflects genetic and phenotypic features of RA.
- MAP2K4 isoforms are differentially expressed in TNF-treated lymphatic cell-lines.

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.