STAT4: genetics, mechanisms, and implications for autoimmunity

Abstract

Recent advances in genetics and technology have led to breakthroughs in understanding the genes that predispose individuals to autoimmune diseases. A common haplotype of the signal transducer and activator of transcription 4 (STAT4) gene has been shown to be associated with susceptibility to rheumatoid arthritis, systemic lupus erythematosus, and primary Sjögren's syndrome. STAT4 is a transcription factor that transduces interleukin-12, interleukin-23, and type 1 interferon cytokine signals in T cells and monocytes, leading to T-helper type 1 and T-helper type 17 differentiation, monocyte activation, and interferon-gamma production. Although the evidence for this association is very strong and well replicated, the exact mechanism by which polymorphisms in this gene lead to disease remains unknown. In concert with the identification of other disease-associated loci, elucidating how the variant form of STAT4 modulates immune function should lead to an improved understanding of the pathophysiology of autoimmunity.

Figure 1

Linkage disequilibrium (LD) and haplotype map of STAT4 gene. This diagram shows the LD structure (D′) across the 150-kb STAT4 region with single nucleotide polymorphisms (SNPs), with greater than 20% minor allele frequency shown in chromosomal order on the x axis and with increasing intensity of fill indicating higher levels of LD between pairs of SNPs (white: D′ = 0; darkest: D′ = 1). The region of the third intron in which disease-associated SNPs are located is highlighted on the gene exon-intron map at the top of the figure. The inset haplotype map shows blocks of SNPs inherited together in an extended STAT4 LD block, with dark shading representing the common and light shading the variant form of each SNP. The frequency of each haplotype in the HapMap CEPH-Utah residents with ancestry from northern and western Europe (CEU) samples is shown. Disease-associated SNPs, including rs7574865, are marked at the top of the haplotype inset and can be found in the variant form only on the second haplotype.