“Identification of key genetic factors predisposing to giant cell arteritis”

Giant cell arteritis (GCA) is a chronic autoimmune systemic vasculitis that affects large and medium blood vessels. It represents the most common form of vasculitis in individuals over 50 years old in Western countries. GCA patients can develop severe clinical manifestations such as blindness and stroke. Like most autoimmune diseases, GCA shows a complex aetiology in which both environmental and genetic factors seem to be involved in its predisposition and progression. However, until recently very little was known about the genetic background of GCA, mainly due to the small sample size of the studies conducted and the lack of independent replications confirming the published findings.

During the last years, thanks to the establishment of national and international collaborations, our research group has significantly boosted the knowledge of the GCA genetic component by candidate gene studies in cohorts with a high statistical power. This collaborative effort encouraged us to perform the first large-scale genetic study in GCA taking advantage of new genotyping platforms, which was recently published in the prestigious journal "The American Journal of Human Genetics"..

The study was possible thanks to the participation of over 20 Spanish hospitals and several hospitals and international research centrers worldwide, including three large European and American consortia (the 'European Vasculitis Genetics Consortium', the 'UK GCA Consortium', and the ‘Vasculitis Clinical Research Consortium’). The research involved more than 1,600 GCA patients and more than 15,000 healthy individuals as a control group, which underwent a comprehensive bioinformatic analysis of genes involved in the immune and inflammatory response using the Immunochip, a genotyping platform through which risk genetic variants of such immune-related genes can be identified.

The results represent a very important step forward towards the understanding of the disease aetiology, as we were able to define very precisely the involvement of ‘major histocompatibility complex’ (MHC) genes in the susceptibility to develop this type of vasculitis. In this regard, we proposed a model that includes two amino acid positions of the MHC class II proteins DRβ1 and DQα1 (histocompatibility molecules expressed in the surface of antigen-presenting cells, such as B cells or monocytes) and a position of the MHC class I protein HLA-B (which is involved in the antigen presentation of self-molecules to T cells) that explains the association of the MHC region with GCA predisposition. In addition, we also identified other genes involved in T cell function (including PTPN22, LRRC32 and REL) that seem to play a major role in the pathophysiology of the disease.

In summary, this study made possible the elucidation of potential pathogenic pathways involved in GCA predisposition, which could help in the development of novel therapeutic targets that may eventually allow a more effective treatment of patients with this disease.

A Large-Scale Genetic Analysis Reveals a Strong Contribution of the HLA Class II Region to Giant Cell Arteritis Susceptibility.

http://dx.doi.org/10.1016/j.ajhg.2015.02.009. by The American Society of Human Genetics. All rights reserved.