Genetics of Systemic Lupus Erythematosus

Updated: Sep 28, 2015
  • Author: R Hal Scofield, MD; Chief Editor: Keith K Vaux, MD  more...
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Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disorder associated with a wide range of symptoms and physical findings. The risk of developing SLE is, at least in part, genetic, but it is a complex genetic illness with no clear mendelian pattern of inheritance. The disease tends to occur in families. Siblings of SLE patients have a risk of disease of about 2%. However, even identical twins with SLE are concordant for disease in only 25% of cases and are therefore discordant (i.e., where one twin has SLE and one does not) in about 75% of cases. [1, 2, 3, 4, 5]

The major histocompatibility complex (MHC) on chromosome 6, which contains the human lymphocyte antigens (HLA), was the first described genetic link to SLE. [1] The protein products of the HLA genes are critical components of cell-to-cell communication in the immune system. Indeed, in some cases, HLA genes are more highly related to lupus-associated autoantibodies than to the disease itself. Nonetheless, carriage of specific alleles of HLA imparts about a 2-fold risk of SLE above that of the general population.

Collection of large (several thousand strong) cohorts of SLE patients and their family members has allowed genome-wide association studies to proceed in this disease. In these studies, upwards of a million single-nucleotide polymorphisms are typed in each individual. These polymorphisms are, by definition, common population genetic variants, not rare mutations.


Clinical Implications

Although SLE is generally a complex genetic illness, there are several examples of mutations that can produce a monogenetic form of the illness. Complete deficiency of the early complement components C2, C4, and C1q results in SLE in 75%, 10%, and 90% of cases, respectively. [6] However, complete complement deficiencies are quite rare and account for only a tiny percentage of SLE cases. [7] More commonly, a low gene copy number of C4 is seen as a risk factor for SLE, whereas a high copy number of C4 is protective against SLE. [8]

Sex-chromosome copy number variations are also implicated in the risk of SLE. SLE is about 10 times more common in women than in men. However, men with SLE have 15 times the risk of Klinefelter syndrome (47,XXY) as compared with the average population, and the risk of SLE among men with 47,XXY is equal to that of women. [9] Furthermore, 47,XXX is more common among women with SLE than a control population (unpublished data). These data suggest that the predisposition of women to developing SLE is related to X chromosome copy number, not to sex or sex hormones. 

Genome-wide genetic association studies (GWAS) have been performed in large collections of SLE patients and controls. These genome-wide studies of up to 1 million single-nucleotide polymorphisms (SNPs) have identified about 50 genetic associations for SLE, [10, 11] and replication studies have confirmed these findings, in nonwhite as well as white cohorts. [12, 13, 14, 15, 16] In general, the associated SNPs so far identified increase the risk of SLE by less then 2-fold compared with individuals who do not carry the risk allele. That is, the relative risk varies from 1.1 to about 1.75. These studies, however, generally do not identify the actual genetic polymorphism that actually imparts the increased risk of disease. Instead, the identified SNP is in linkage disequilibrium with the causal variant.

In fact, only a fraction of the genetic risk for SLE has so far been identified. Rare alleles and mutations that impart a moderate risk of SLE remain undiscovered and cannot be found by GWAS. Gene-gene interaction is beginning to be explored. For example, a recent study showed synergistic interaction between risk alleles found in the following pairs of genes: HLA-CTLA4, IRF5-ITGAM, and PDCD1-IL21. [17]

Although the causative allele may not be identified, in fact the gene involved is likely to have been identified in the GWAS. Additionally, the findings do have common themes. Many of the genes implicated thus far can be categorized as involved in B-lymphocyte activation, apoptosis, or the interferon-signaling pathway. Such insight into the genetic pathogenesis of SLE may suggest new therapeutic targets for the disease in the future. [18] More recent studies of human and animal models have shown an association between variants in the POLB gene, which has a key function in base excision repair and the development of SLE. [19]


Post-GWAS SLE Genetics

With the completion of several GWAS, the study of SLE genetics has moved into a post-GWAS era in which findings need to be confirmed and causal alleles identified. To facilitate these goals, a large consortium was developed that included more than 50 research groups from around the world. Each investigator contributed SLE patients and matched controls to the project. Furthermore, a custom gene array chip was prepared based on SNPs submitted by each investigator. The investigative group has designated this study the Large Lupus Association Study 2 (LLAS2).

In total, over 13,000 SLE patients were enrolled in the study of about 38,000 SNPs. Since completion of the genetic typing and quality control work, the group has extensively published data using the results from 2011 until the present. This study included multiple ethnicities, and the ability of researchers to compare results across these groups has been critical to narrowing of the genetic interval by fine mapping a region, or even identifying the causal variant. [20] These studies have confirmed and fine-mapped previous associations, as well as identified additional genetic associations.

Functional groupings can be organized as follows: interferon signaling, [21, 22, 23] autoantibody expression, [24] DNA repair, [25] free-radical metabolism, [26] NF-kB activation, [20, 27, 28] lymphocyte trafficking, [29, 30] lymphocyte proliferation, [31] and innate immunity (complement [32] and interleukin [33] ). In addition, another study has examined the relationship of sex to genetic risk of SLE. [34]


Future of Lupus Genetics

The next phase of SLE genetics will include continued analyses of large cohorts of patients such as the one described above (LLAS2). These analyses will continue to consolidate known genetic associations by identifying causal alleles and establishing genetics across multiple ethnicities. The author anticipates work on the LLAS2 will continue for another decade. Interaction between genetic variants is just beginning to be explored.A second aspect of SLE genetics, which is only just being explored, is application of so-called next-generation sequencing. In these projects, sequencing of all exons or even the entire genome will be performed. Such studies will be able to identify rare (defined as being present in < 1% of the population) variants that impart moderate risk of disease. That is, relative risks from 2- to 10-fold over the population risk. These genetic variants might be located in protein coding regions (exons), but they also may include genetic changes in regions regulating expression and microRNA sequences. The work of next-generation sequencing in SLE patients and controls has begun in a few centers.