Lupus involves a combination of both environmental and genetic factors. Support for a genetic component includes a high sibling risk ratio [8
], high heritability (greater than 66%), and higher concordance rates between monozygotic twins (20 to 40%) as compared to other full siblings and dizygotic twins (2 to 5%) [38
]. A large number of genetic risk factors are associated with increased susceptibility to the SLE. This genetically determined increased risk status has been referred to as a “threshold liability” [40
], which is expected to be highly polygenic in nature and widely variable between individuals. Environmental factors also affect lupus susceptibility and likely interact with this “threshold liability”, but as in the case of genetic factors, there is no single environmental cause. A person may have only a few of the genetic risk variations and never get SLE despite exposure to environmental triggers. In contrast, another person may have many of these variations and then develop SLE on first exposure to an environmental trigger.
3.1. Lupus-Associated Risk Loci
Research into the etiopathogenesis of SLE has recently been advanced by several large scale case-control genetic studies, including genome-wide association scans. There is now a pool of approximately 30 genes that have been associated with SLE susceptibility with a high degree of statistical certainty and many others with probable evidence for association (reviewed in [41
]). With this large number of SLE-associated genes, we can begin to group the list of identified SLE associated genes which should provide insight into initial disease pathogenesis into functional categories. These categories include TLR and IFN signaling, apoptosis and clearance of immune complexes, and B- and T-cell signaling. Several genes affecting the interferon pathway have been associated with risk for lupus. The Interferon pathway normally serves an important function in defense against viral infection. Yet in people with genetic predisposition, environmental triggers such as viral infections may tip the scales in favor of autoimmunity.
Once a genetic variation is identified, functional inference then characterization is necessary to move from identification to an understanding of how the variation affects the etiology or pathogenesis of SLE. Since most of the genes involved in genetic susceptibility to SLE have been identified only recently, there remains much work to identify the functional differences in the genetic associations. However, work done thus far in human cohorts is promising, and the categories of genes and loci associated with risk of lupus already suggest pathways that are of high importance.
3.2. Interferon Regulatory Factors
Certain lupus-associated genetic variations have been shown to directly increase IFNα
levels or response to IFNα
signaling. Interferon regulatory factor 5 (IRF5) has been confirmed as a risk locus in several different ethnic groups [46
]. Three main functional variants in IRF5 have been described, which combine to form a risk haplotype in individuals of European descent [51
]. One of these loci, at rs2004640, creates an alternate splice site (exon 1B) in the untranslated first exon. Another is a copy number variation of a 30-bp insertion/deletion sequence in exon 6, and the final is rs10954213, which creates an alternate polyadenylation site, resulting in shorter, stabler mRNA [52
Since IRF5 activates IFNα
production, these more stable variants may pose a risk due to their ability to produce excess IFNα
. In fact, studies of this gene in human SLE cohorts have shown that the risk variant predisposes to greater serum IFN-α
, supporting the idea that the risk haplotype is a gain-of-function variant [53
]. IRF5 itself is activated by IFNα
signaling, producing a potential positive feedback loop. Another IRF, IRF7, has been highlighted by the association of the IRF7/KIAA1542 locus with lupus in recent studies [54
]. Several SNPs in this area were shown to correlate with IFNα
levels and alter autoantibody profiles in certain ethnicities [56
IRF5 and IRF7 are activated by signaling through the endosomal toll-like receptors (TLRs) 7, 8, and 9. Interestingly, both of the IRF variants which are implicated in SLE predispose to higher serum IFN-α
, but only in the presence of SLE-associated autoantibodies [53
] suggesting that these autoantibodies may provide chronic stimulation of the endosomal TLR pathway of IFN-α
generation that when combined with gain-of-function polymorphisms in the IRFs results in dysregulation of the pathway in vivo. Additionally, TLRs 8 and 9 were identified in recent studies as containing susceptibility loci to SLE [57
]. The role of TLRs in the interferon production was discussed above.
3.3. Interferon-Associated Genes
Another confirmed locus of susceptibility is in the gene encoding IL1 receptor-associated kinase 1 (IRAK1). This kinase is part of the signal transduction which follows TLR ligation. In a mouse model of lupus, IRAK deficiency eliminated most lupus symptoms, showing the importance of this key intermediate [59
]. Since this gene is on the X chromosome, gene dosage may contribute to the risk and the prevalence of the disease in women [59
Two interacting proteins involved in inflammation, TNFα
-induced protein 3 (TNFAIP3) and TNFAIP3-interacting protein 1 (TNIP1), have been identified as risk loci [60
]. TNFAIP3 encodes the protein A20, which helps turn off signaling through NFκ
B after an inflammatory response [65
]. TNIP1 interacts with TNFAIP3 and is involved in several signal transduction pathways.
Signal transducer and activator of transcription 4 (STAT4) is another risk locus with direct links to the interferon pathway. It is involved in proliferation, differentiation, and apoptosis. STAT4 has 2 risk loci, one at rs7574865 which has been shown to increase sensitivity to IFNα
], and another at rs3821236 which increases STAT4 transcription and interacts with IRF5 susceptibility loci [68
]. The presence of both of these risk alleles gives an additive effect, increasing risk to SLE [69
]. Osteopontin (OPN) is a key molecule for IFNα
production in pDCs [70
]. Presence of a lupus risk-associated form of this gene was recently tied to high IFN levels in males and young-onset female lupus patients [71
Possible interactions of the IFN-associated genes that have been linked to lupus are shown in . The risk variants of these genes influence the production of and response to IFNα, likely driving the increased levels seen in lupus patients and affecting the clinical manifestations of the disease.
Figure 2 Multiple genes involved in interferon production and regulation are associated with risk for lupus. Shown are components of the signal transduction pathway from TLR stimulation by nucleic acids to IFN production. Genes that have been associated with (more ...)