HLA-DRB5 and rheumatoid arthritis: In addition, environmental factors, particularly smoking, have also been implicated in the development of ACPA, with genetic variants at loci such as butyrophilin like 2 (BTNL2), Major histocompatibility complex, class II, DR alpha (HLA-DRA), HLA-DRB5, major histocompatibility complex, class II, DQ Alpha 1(HLA-DQA1), major histocompatibility complex, class II, DO Beta (HLA-DOB), and transporter 2, ATP-binding cassette subfamily b member(TAP2) interacting with smoking to increase the likelihood of developing ACPA-positive RA (22).