Association of polymorphisms across the tyrosine kinase gene, TYK2 in UKSLE families

Objectives. This is a family-based association study to investigate the genetic contribution of tyrosine kinase 2 (TYK2) to disease susceptibility in 380 UK systemic lupus erythematosus (SLE) families, consisting of parents and affected offspring. Methods. Genotyping was performed using the Sequenom platform on DNA from affected individuals and their parents. Haplotypes were constructed using Haploview from the founders, and family-based association was conducted using GENEHUNTER-TDT and Family-Based Association Test. Results. There are two associated haplotypes across TYK2, both carrying alleles with distorted inheritance. One SNP shows individual association to SLE. This is the under-transmitted rare A allele of TYK2 SNP 6 (P=0.004), which tags the under-transmitted haplotype 2 (P=0.055). A second SNP shows a trend for association. This is the A allele of TYK2 SNP 13, which is unique to the over-transmitted haplotype 1 (P=0.014). We defined a 2.8kb core association region in TYK2, between these two variants, which narrows down the 5.7kb gap in the study by Sigurdsson et al. (Sigurdsson S, Nordmark G, Goring HH et al. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet 2005;76:528-37). Conclusions. We have shown association to SLE from individual SNPs and haplotypes in TYK2. The strongest individual association, which is carried on the associated haplotype, is from TYK2 SNP 6. The variant is located close to an intron/exon boundary, suggesting a role for mis-splicing events in molecular pathogenesis. The associated haplotype also carries a missense mutation at TYK2. Therefore it is likely that the allelic contribution of TYK2 to SLE is complex, our data confirm previous findings and provide additional resolution regarding the causal polymorphisms in this gene.