DNA Methylation of the MHC Region in Rheumatoid Arthritis: Perspectives and Challenges

Abstract

The MHC, which covers a region about 4 Mb at 6p21.3, is one of the most polymorphic regions in the human genome. With a high density of more than 200 genes, most of which are directly involved in the immune response to self or non-self antigens, MHC genes have long been associated with a wide range of complex human diseases, including autoimmune or inflammatory diseases and cancer. Rheumatoid arthritis (RA) is a systemic autoimmune disease; recent investigations in large genome-wide association studies using single-nucleotide polymorphisms have confirmed the correlation of classic HLA genes and non-classic HLA genes with RA in many populations1,2. Functional and structural analyses indicate that these genetic variants reside in the peptide-binding groove, which may affect the binding affinity of the citrullinated peptides, and eventually lead to the development of RA1,3. However, because of the heterogeneity among ethnic groups and clinical subtypes, the major RA-risk allele in MHC is quite different among different populations. For example, HLA-DRB1*04 includes the *04:01 and *04:04 alleles, which are the dominant RA-risk alleles in whites4, whereas DRB1*04:05/*0901 are the major RA-risk alleles in Asians, specifically for RA patients positive for anticitrullinated protein antibodies (ACPA)5,6. A recent … Address correspondence to W. Qiu or Y. Liu, 130 Dong An Road, Shanghai, China. Email: qiuwq{at}fudan.edu.cn; yliu39{at}fudan.edu.cn.