The Genetics of Lupus
The Genetics of Lupus
More than half of patients with SLE show a dysregulation in the expression of genes in the IFN pathway. The type I IFNs are potent cytokines (IFNα and IFNβ) and also mediate the Th1 response, sustain activated T cells, sustain B-cell survival, and lower the B-cell activation threshold. These responses propagate pro-inflammatory cytokines, contributing to chronic inflammation and tissue damage. IFN also acts as a bridging mechanism between the innate and adaptive immune systems. However, it is unclear whether elevated IFN is the causal effect of SLE or whether it further propagates disease intensity. Given the genetic role of IRF5 and a number of other genes in the IFN pathway, it is likely thatIFN exerts a pathway effect in the pathogenesis of disease.
IRF5, IRF7, and IRF8 are transcription factors that play a role in type 1 IFN signaling and immune cell development. SNPs in IRF5, IRF7, and IRF8 (P = 5.8 × 10, OR = 1.88; P = 3.0 × 10, OR = 0.78; and P = 1.24 × 10, OR = 1.17, respectively) (as shown in Table 1) have been shown to be associated with increased risk of SLE. These variants have been shown to increase the levels of IRF5, IRF7, and IRF8 transcript and protein expressions. Of these three loci, IRF5 exhibits the largest effect. An IRF5 risk haplotype has been observed and carries multiple mutations, including rs2004640, which has been reported to create a novel splicing variant. Another variant found at the 3' untranslated region, rs10954213, has been reported to create a more functional polyadenlyation site, which creates a more stable transcript. Variants in the IRF5 locus influence alternatively spliced transcripts, which alter or prolong IRF5 expression. Hence, increased expression of IRF5 propagates increased IFNα production. Little is reported for IRF7 and IRF8; therefore, these loci warrant further investigation to determine the functional consequences of the associated variants.
IFIH1 is a DEAD box helicase that senses intracellular RNA and induces IFN (type 1) activation. Variants at this locus have been associated with other autoimmune diseases such as T1D, autoimmune thyroid disease, and psoriasis. The top associated SNP in SLE is rs1990760 (P = 1.63 × 10, OR = 1.23), which has been shown to increase expression of IFIH1. This increased expression could contribute to an IFN cascade initiated by nucleic acids.
TYK2 plays an important role in the pro-inflammatory immune response, being involved in cytokine signaling and the phosphorylation of IFN receptors, triggering a type 1 IFN response. Variants in TYK2 have been reported to increase type 1 IFN gene expression and deregulate the Th1/Th17 response. Th17 cells are pro-inflammatory, and their differentiation is dependent on IL-6 and transforming growth factor-beta (TGFβ), both of which are cytokines that are regulated by TYK2. The top associated SNP in SLE, rs280519 (P = 3.88 × 10), has been shown to play a role in increasing gene expression and IFN production. Variants propagating increased TYK2 function have also been reported to lead to a pro-inflammatory phenotype with increased levels of Th1/Th17 cells. Multiple variants in TYK2 have been reported to be associated with other autoimmune and inflammatory diseases.
The Interferon Signature and Its Regulation in SLE
More than half of patients with SLE show a dysregulation in the expression of genes in the IFN pathway. The type I IFNs are potent cytokines (IFNα and IFNβ) and also mediate the Th1 response, sustain activated T cells, sustain B-cell survival, and lower the B-cell activation threshold. These responses propagate pro-inflammatory cytokines, contributing to chronic inflammation and tissue damage. IFN also acts as a bridging mechanism between the innate and adaptive immune systems. However, it is unclear whether elevated IFN is the causal effect of SLE or whether it further propagates disease intensity. Given the genetic role of IRF5 and a number of other genes in the IFN pathway, it is likely thatIFN exerts a pathway effect in the pathogenesis of disease.
IRF5, IRF7, and IRF8
IRF5, IRF7, and IRF8 are transcription factors that play a role in type 1 IFN signaling and immune cell development. SNPs in IRF5, IRF7, and IRF8 (P = 5.8 × 10, OR = 1.88; P = 3.0 × 10, OR = 0.78; and P = 1.24 × 10, OR = 1.17, respectively) (as shown in Table 1) have been shown to be associated with increased risk of SLE. These variants have been shown to increase the levels of IRF5, IRF7, and IRF8 transcript and protein expressions. Of these three loci, IRF5 exhibits the largest effect. An IRF5 risk haplotype has been observed and carries multiple mutations, including rs2004640, which has been reported to create a novel splicing variant. Another variant found at the 3' untranslated region, rs10954213, has been reported to create a more functional polyadenlyation site, which creates a more stable transcript. Variants in the IRF5 locus influence alternatively spliced transcripts, which alter or prolong IRF5 expression. Hence, increased expression of IRF5 propagates increased IFNα production. Little is reported for IRF7 and IRF8; therefore, these loci warrant further investigation to determine the functional consequences of the associated variants.
IFIH1
IFIH1 is a DEAD box helicase that senses intracellular RNA and induces IFN (type 1) activation. Variants at this locus have been associated with other autoimmune diseases such as T1D, autoimmune thyroid disease, and psoriasis. The top associated SNP in SLE is rs1990760 (P = 1.63 × 10, OR = 1.23), which has been shown to increase expression of IFIH1. This increased expression could contribute to an IFN cascade initiated by nucleic acids.
TYK2
TYK2 plays an important role in the pro-inflammatory immune response, being involved in cytokine signaling and the phosphorylation of IFN receptors, triggering a type 1 IFN response. Variants in TYK2 have been reported to increase type 1 IFN gene expression and deregulate the Th1/Th17 response. Th17 cells are pro-inflammatory, and their differentiation is dependent on IL-6 and transforming growth factor-beta (TGFβ), both of which are cytokines that are regulated by TYK2. The top associated SNP in SLE, rs280519 (P = 3.88 × 10), has been shown to play a role in increasing gene expression and IFN production. Variants propagating increased TYK2 function have also been reported to lead to a pro-inflammatory phenotype with increased levels of Th1/Th17 cells. Multiple variants in TYK2 have been reported to be associated with other autoimmune and inflammatory diseases.
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