Myelin Basic Protein as a Novel Genetic Risk Factor in Rheumatoid Arthritis—A Genome-Wide Study Combined with Immunological Analyses

Abstract

Rheumatoid arthritis (RA) is a major cause of adult chronic inflammatory arthritis and a typical complex trait. Although several genetic determinants have been identified, they account for only a part of the genetic susceptibility. We conducted a genome-wide association study of RA in Japanese using 225,079 SNPs genotyped in 990 cases and 1,236 controls from two independent collections (658 cases and 934 controls in collection1; 332 cases and 302 controls in collection2), followed by replication studies in two additional collections (874 cases and 855 controls in collection3; 1,264 cases and 948 controls in collection4). SNPs showing p<0.005 in the first two collections and p<10−4 by meta-analysis were further genotyped in the latter two collections. A novel risk variant, rs2000811, in intron2 of the myelin basic protein (MBP) at chromosome 18q23 showed strong association with RA (p = 2.7×10−8, OR 1.23, 95% CI: 1.14–1.32). The transcription of MBP was significantly elevated with the risk allele compared to the alternative allele (p<0.001). We also established by immunohistochemistry that MBP was expressed in the synovial lining layer of RA patients, the main target of inflammation in the disease. Circulating autoantibody against MBP derived from human brain was quantified by ELISA between patients with RA, other connective tissue diseases and healthy controls. As a result, the titer of anti-MBP antibody was markedly higher in plasma of RA patients compared to healthy controls (p<0.001) and patients with other connective tissue disorders (p<0.001). ELISA experiment using citrullinated recombinant MBP revealed that a large fraction of anti-MBP antibody in RA patients recognized citrullinated MBP. This is the first report of a genetic study in RA implicating MBP as a potential autoantigen and its involvement in pathogenesis of the disease.

A Contra Capture Protein Array Platform for Studying Post-translationally Modified (PTM) Auto-antigenomes

“…Previous studies using arrays spotted with cit-MBP peptides detected anti-cit-MBP-peptide antibodies in the experimental autoimmune encephalomyelitis (EAE) mouse model for MS but not in collagen-induced arthritis (CIA) mouse model (71). Here, we detected anti-cit-MBP antibodies in a large fraction of RA patients (ϳ80% of CCPϩ samples), which agrees with a previous report on the expression of MBP in the synovial lining and the presence of anti-cit-MBP in RA, although the prevalence of response has not been previously determined (64).…”

“…We used MBP as an example. We were particularly interested in mapping the epitope(s) for MBP, because it represented a poorly studied citrullinated antigen for RA and there was only one report of anti-cit-MBP in RA patients (64). Two isoforms of MBP were used for epitope mapping.…”

Significant association of periodontal disease with anti-citrullinated peptide antibody in a Japanese healthy population – The Nagahama study

“…Environmental and genetic factors have been shown to be important for the onset of RA [1,2]. Anti-citrullinated peptide antibody (ACPA) and rheumatoid factor (RF) are autoantibodies frequently found in patients with RA [3e5].…”

A genome-wide association study of serum levels of prostate-specific antigen in the Japanese population

“…African-American population has the highest risk for PCa, while Asians have the lowest 2. Recent technological developments have enabled us to perform genome-wide association study (GWAS) to detect associated genes or loci with diseases or quantitative trait in an unbiased approach 4. Previous genetic studies including GWAS have revealed more than 70 susceptibility genes to PCa 5.…”