Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease caused by both genetic and environmental factors. Genome scans in families with SLE point to multiple potential chromosomal regions that harbor SLE susceptibility genes, and association studies in different populations have suggested several susceptibility alleles for SLE. Increased production of type I interferon (IFN) and expression of IFN-inducible genes is commonly observed in SLE and may be pivotal in the molecular pathogenesis of the disease. We analyzed 44 single-nucleotide polymorphisms (SNPs) in 13 genes from the type I IFN pathway in 679 Swedish, Finnish, and Icelandic patients with SLE, in 798 unaffected family members, and in 438 unrelated control individuals for joint linkage and association with SLE. In two of the genes--the tyrosine kinase 2 (TYK2) and IFN regulatory factor 5 (IRF5) genes--we identified SNPs that displayed strong signals in joint analysis of linkage and association (unadjusted P<10(-7)) with SLE. TYK2 binds to the type I IFN receptor complex and IRF5 is a regulator of type I IFN gene expression. Thus, our results support a disease mechanism in SLE that involves key components of the type I IFN system.

Figure A1

Pairwise LD values determined using the Haploview program for 11 SNPs in the tyrosine kinase 2 (TYK2) gene and 6 SNPs in the IFN regulatory factor 5 (IRF5) gene in control individuals from the Swedish population (n=256) and the Finnish population (n=121). The dbSNP rs numbers for the SNPs are given to the left and above the boxes in the diagrams. D′ values are given in the lower left half and R² values in the upper right half of the diagrams.

Figure  1

Schematic illustration of the structure of TYK2 and IRF5. The positions of exons are shown as numbered gray boxes, and the translation initiation sites are shown by arrows on both genes. The positions of the 11 TYK2 SNPs and the 6 IRF5 SNPs analyzed in the study are shown by vertical lines and dbSNP rs numbers. SNPs with low P values in joint linkage and association analysis in the Swedish and/or Finnish sample sets are marked with an asterisk (*). The D′ and r² values for pairwise linkage disequilibrium for the TYK2 SNPs were calculated from the genotypes of Swedish unrelated control individuals, and the D′ and r² values for the IRF5 SNPs were calculated from Finnish unrelated control individuals, by use of the Haploview program (Barrett et al. 2005). ns=nonsignificant.