Genetic predisposition to lupus
SLE constitutes an enigmatic disease as its pathology is often mistakenly diagnosed for something else. As with the majority of autoimmune diseases, the precise aetiology is unknown and disease management mainly relies on the administration of anti-inflammatory and immunosuppressive drugs.Accumulating evidence indicates that there is a genetic component that contributes to SLE development. Among the identified susceptibility genes, the major histocompatibility complex loci — an array of genes that encode surface molecules implicated in immune cell interaction — show the strongest association. Given the small-scale nature of previous studies, the EU-funded 'Genetics of systemic lupus erythematosus in northern and southern European populations' (GENETICS OF SLE) project worked to expand on patient numbers and perform a large-scale genome-wide association study (GWAS) in northern and southern Europe.Researchers carried out the largest-to-date GWAS of SLE, screening over 4 000 cases and 8 000 controls. Additionally, they performed meta-analysis on previous European studies, adding a further 1 698 cases and 4 650 controls. An overall 52 loci were identified with potential SLE association, among which 15 loci were novel. These findings were further confirmed in an independent genetic study of 1 630 cases and over 9 000 controls.Research efforts were particularly focused on genetic polymorphisms of the Fc-gamma receptors (FCGR) responsible for antibody binding and phagocytosis. A previously associated copy number variation in FCGR3B was shown to reduce receptor expression on all cell types and to induce expression of another family member, FCGR2B. However, FCGR2B is associated with reduced clearance of immune complexes, possibly leading to pathological inflammation and thereby increasing the risk for SLE.Overall the GENETICS OF SLE study is proof of how a large GWAS could lead to the discovery of robust genetic factors and allow a full description of the genetic architecture underlying a particular disease. This information could form the first step towards understanding how these genetic variants are responsible for disease pathology. From a clinical perspective, the outcome of the study could be implemented for the development of genetic tests and provision of genetic counselling.
Keywords
Systemic lupus erythematosus, genome-wide association study, major histocompatibility complex, disease pathology, susceptibility genes