AbstractsBiology & Animal Science

Gene-environment interactions in rheumatoid arthritis : quantification and characterization of contributing factors

by Xia Jiang

Institution: Karolinska Institute
Year: 2015
Record ID: 1343246
Full text PDF: http://hdl.handle.net/10616/44690


Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterised by persistent synovitis, systemic inflammation and autoantibodies. RA has a complex aetiology with the involvement of genetic factors and environmental triggers, and their interactions. The inherited risk for RA is mostly attributed to multiple gene loci, of which the largest contribution is made by the major histocompatibility complex (MHC), also known as the human leukocyte antigen (HLA) genes, in particular linked to the MHC class II region. Shared epitope (SE) comprises a small part of the extensive MHC class II polymorphisms, and has been identified as the strongest genetic risk factor with each allele being associated with approximately a 2-fold increased RA risk. Cigarette smoking is the best-known environmental trigger and also increases RA risk approximately 2-fold. A profound SE–smoking interaction effect has been well described among different populations. The aim of the current thesis is to further characterise and quantify this gene–environment interaction, specifically: 1) to identify more gene–environment interaction signals using genome-wide materials; 2) to further explore the synergistic effect by identifying the interacting components (e.g. which chemical component in cigarette smoke triggers RA, the nicotine or the particles?); 3) to determine which amino acid positions of MHC class II loci interact with smoking, the traditional SE positions at HLA-DR or other regions such as HLA-B and HLA-DPB; and 4) to evaluate present understanding of the familial risk and heritability of RA, taking into account all the currently identified risk factors. In Study I, we conducted a gene–smoking interaction analysis using the genetic information from the Immunochip and genome-wide association studies, in two separate Swedish case–control populations (the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study in Stockholm and a cohort from Umeå). We found no significant interaction signals outside of chromosome 6, in either anti-citrullinated protein/peptide antibody (ACPA)-positive or ACPA-negative RA, indicating that HLA remains a region of great importance, and well-powered studies with larger sample size are warranted to identify new signals. In Study II, we performed association analysis between smokeless tobacco (snuff) and RA among EIRA subjects. We found that moist snuff use (current or past) was not related to the risk of either ACPA-positive or ACPA-negative RA. Analyses restricted to never smokers, or stratified by gender, provided similar results. We conclude that the use of moist snuff is not associated with the risk of either ACPA-positive or ACPA-negative RA, and the increased RA risk associated with smoking is therefore most probably not due to nicotine. In Study III, we carried out interaction analysis between heavy smoking and RA-related amino acid positions (11, 13, 71, and 74 in HLA-DRβ1, 9 in HLA-B and 9 in HLA-DPβ1) using three separate case–control populations (EIRA, the Nurses‟ Health…