Practice Essentials
Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disorder associated with a wide range of symptoms and physical findings. It is characterized by loss of tolerance to self-antigens, formation of immune complexes, and an activated type I interferon system. [1, 2, 3, 4] The genetic contribution to the development of SLE is considerably high, which is estimated to be 66% of heritability in twin studies. 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 (ie, one twin has SLE and one does not) in about 75% of cases. [5, 1, 2, 6, 7, 8, 9]
The major histocompatibility complex (MHC) on chromosome 6, which contains the human lymphocyte antigens (HLA), was the first described genetic link to SLE. [10] 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.
Although some single genes have been implicated to play a causative role in SLE, current knowledge points toward a large number of genes being involved in a multifactorial-type inheritance pattern in most patients. Genome-wide association studies have identified more than 100 genetic loci for SLE susceptibility across populations, with most of the genetic risk shared across borders and ethnicities. [1, 11, 3, 2, 12, 13, 5]
A genome-wide study in a northern European population replicated the association of SLE with susceptibility genes related to B-cell receptor pathway signaling, as well as confirmed the association of SLE with genes at the interferon regulatory factor 5 (IRF5)-TNPO3 locus. The investigators also confirmed other loci associations with SLE (TNFAIP3, FAM167A-BLK, BANK1 and KIAA1542); however, those loci had a lower significance level and a lower contribution to individual risk for SLE. [14]
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. [15] However, complete complement deficiencies are quite rare and account for only a tiny percentage of SLE cases. [16] 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. [17]
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 to the average population, and the risk of SLE in men with 47,XXY is equal to that in women. [18] Furthermore, 47,XXX has been seen to be more more common in women with SLE than in a control population. These data suggest that the predisposition of women to developing SLE is related to X chromosome copy number, not to sex or sex hormones.
The higher risk of SLE in women and men with Klinefelter syndrome may be associated with enhanced expression of toll-like receptor 7 (TLR7), a key pathogenic factor in SLE that is encoded on an X chromosome locus. Souyris et al reported that in both females and males with Klinefelter syndrome, substantial fractions of primary B lymphocytes, monocytes, and plasmacytoid dendritic cells express TLR7 on both X chromosomes, leading to greater immunoglobulin secretion. [19]
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, [20, 21] and replication studies have confirmed these findings, in nonwhite as well as white cohorts. [22, 23, 24, 25, 26] In general, the associated SNPs that have so far been identified increase the risk of SLE by less then 2-fold, as compared to 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 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, one study showed synergistic interaction between risk alleles found in the following pairs of genes: HLA-CTLA4, IRF5-ITGAM, and PDCD1-IL21. [27]
Although the causative allele may not be identified, 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. [28] 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. [29]
GWAS has been found to be useful in prioritizing causal genes in SLE loci with other biological information and locating some approved SLE drugs and repurposable drugs in the protein-protein networks derived from SLE-susceptibility genes. [30, 31, 32]
In a study by Chen et al using 3 European and 2 Chinese GWAS, the performance of genetic risk scores (GRS) was investigated for predicting the susceptibility and severity of SLE using renal disease as a proxy for severity. They found a significant positive correlation between a GRS and renal disease in 2 independent European GWAS and a significant negative correlation with age of SLE onset. They found that the GRS performed better in predicting renal disease in the later-onset group than in the earlier-onset group. [1]
Another study, by Reid et al, found that a high GRS was associated with increased risk of organ damage, renal dysfunction, and all-cause mortality, indicating that genetic profiling may be useful for predicting outcomes in patients with SLE. [11]
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. [33] 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, [34, 35, 36] autoantibody expression, [37] DNA repair, [38] free-radical metabolism, [39] NF-kB activation, [33, 40, 41] lymphocyte trafficking, [42, 43] lymphocyte proliferation, [44] and innate immunity (complement [45] and interleukin [46] ). In addition, another study has examined the relationship of sex to genetic risk of SLE. [47]
The introduction of high throughput methods, such as deep sequencing, has allowed for an even more comprehensive study of gene expression in complex and multigenic diseases. With the advent of high throughput technology such as microarrays and chip-based tools, differential expression of microRNAs have been identified in peripheral blood mononuclear cells (PBMC) from patients with SLE. [2]
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. A second aspect of SLE genetics 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 discovery of more SLE-risk variants will provide important clues to SLE-relevant cell types and signaling pathways involved in the pathogenesis of SLE and should lead to increased diagnostic and prognostic biomarkers of SLE. [30]
