Copy number variants and predisposition to autoimmune diseases like rheumatoid arthritis.

A novel form of genetic variation has during the last two years been recognized to be important for human phenotypes and diseases, namely copy number variations (CNVs). CNVs have so far generally been overlooked in searches for susceptibility variants for common multifactorial diseases, however recent research point towards their involvement also in autoimmunity. Probably numerous yet unidentified disease-predisposing CNVs are concealed in the genome. We are working in the field of unraveling genetic fact ors involved in the risk of autoimmune diseases and want to be in the front by also including CNV studies. Initially, we want to focus on the genetic region of greatest impact to autoimmune disease, the major histocompatibility complex (MHC), because of o ur expertise with this multifaceted chromosomal region and because CNVs of known functional importance exist in this region. We will address the involvement of CNVs in theautoimmune disease rheumatoid arthritis (RA), for which we have statistical powerful data sets. CNVs of immunological interest will be candidates for this disease. We also hold long term follow-up data and several clinical variables, like autoantibody status and radiographic measurements of joint destruction, which enable us also to stud y the involvement of CNVs on disease progression and clinical outcome. The CNV association studies will also include integration with single nucleotide polymorphism (SNP) and other genotyping data for the MHC to investigate the architecture of the linkage disequilibrium patterns emerging when combining these genetic variants. This will provide important knowledge for future association disease studies in the MHC, as well as for our mapping process. Finally, identified risk CNVs will be studied for their i nfluence on gene expression to find functional correlates for the disease associations.