Current status of lupus genetics

Systemic lupus erythematosus (SLE) has long been appreciated to arise from both genetic and environmental factors. Although environmental factors, such as the Epstein-Barr virus, are clearly important [1], this review focuses on genetic factors that are involved in SLE. Evidence for the genetic origins of the disease come from the observation of familial aggregation [2] (up to 10% of patients with SLE have another family member with the disease) and increased concordance in monozygotic twins [3]. The patterns of inheritance are complex, however, and it is generally thought that variations in a number of genes are involved, each contributing a small amount to the overall genetic risk [4]. Two major strategies have been used to search for the 'lupus genes': genome-wide screening, using multiplex families and linkage analysis; and candidate gene studies, usually performed on trios or case-control collections. With either strategy, a high threshold is necessary to establish genetic risk, and follow-up testing of an independent cohort is required to confirm the results.The genetic basis of SLE is well established, but the genetic transmission of SLE has proven to be highly complex. Consequently, gene identification has been accomplished for only a handful of genes. Genome-wide linkage scanning is a comprehensive and unbiased approach to identifying chromosomal loci that may be linked to complex diseases [5]. Testing for genome-wide linkage is fundamentally a statistical process that evaluates for co-inheritance of genetic markers (such as DNA polymorphisms) with the disease phenotype in families with multiple affected members. Consistent co-inheritance of the marker with the disease in families means that they are 'linked' and indicates that the actual disease gene is in close proximity. As with other complex diseases, genome scans for SLE susceptibility genes suffer from low power to detect true-positive linkages. Causes of this include relatively small study population