Analysis of receptor tyrosine kinase genetics identifies two novel risk loci in GAS6 and PROS1 in Behcet's disease

The TAM kinase (Tyro3, Axl, Mer) and its two ligands (Gas6 and protein S) have been shown to play an important regulatory role in the innate immune response. The present study aimed to investigate whether the tag single-nucleotide polymorphisms (tag SNPs) of these 5 protein-coding genes are associated with Behcet's disease (BD). A two-stage association study was performed in a total of 907 BD patients and 1780 healthy controls. Altogether 32 polymorphisms were tested, using a Sequenom MassARRAY genotyping method in the first stage and a PCR-restriction fragment length polymorphism (PCR-RFLP) assay in the replication phase. Real-time PCR was performed to test the relative mRNA expression level of GAS6 and PROS1 from different SNP genotyped healthy individuals. The frequency of the C allele and CC genotype of rs9577873 in GAS6 (P-c = 4.92 x 10(-5), P-c = 1.91 x 10(-5), respectively) and A allele and AA genotype of rs4857037 in PROS1 (P-c = 1.85 x 10(-6), P-c = 4.52 x 10(-7), respectively) were significantly increased in BD. GAS6 expression in CC carriers of rs9577873 was significantly lower than that in CT/TT individuals (P = 0.001). Decreased expression of GAS6 and increased proinflammatory cytokines (IL-6 and IFN-gamma.: P = 4.23 x 10 (4), P = 0.011, respectively) in individuals carrying the CC genotype suggest that the TAM-GAS6/PROS1 signal pathway may be involved in the pathogenesis of BD.