Investigation of JAK1 and STAT3 polymorphisms and their gene-gene interactions in nonspecific digestive disorder of rabbits

Abstract

Acting in a cellular signaling pathway, Janus kinase 1 (JAK1) and signal transducer and activator of transcription 3 (STAT3) play critical roles in several kinds of physiological and pathological responses, including inflammatory response. In this study, we detected three coding single nucleotide polymorphisms (cSNPs) of JAK1 and four cSNPs of STAT3 in New Zealand White rabbits. We analyzed their association with genetic resistance to nonspecific digestive disorder (NSDD) based on a case-control study (253 cases and 227 controls). The rabbits were genotyped for c.1421 C>T and c.3036 G>A in JAK1 using restriction fragment length polymorphisms and for c.831 T>C and c.399 G>A of STAT3 using high-resolution melting technology. The frequencies of the alleles and genotypes differed significantly between the case and control groups (P<0.05). The case-control association analysis revealed that in JAK1, allele C increased the risk of NSDD (OR: 1.60, 95% CI 1.166-2.185, P=0.003), whereas allele A played a potentially protective role against NSDD (OR: 0.74, 95% CI 0.572-0.952, P=0.019). We used five inheritance models to evaluate the importance of the associated genotypes. Under the dominant inheritance model, the association analysis suggested that the CT/TT genotype increased the risk of NSDD (OR: 1.65, 95% CI 1.13-2.40, P=0.009). A haplotype analysis showed that allele H2 (the two cSNPs: CG; OR: 1.354, 95% CI 1.050-1.747, P=0.019) markedly increased the risk of the disorder. The association analysis revealed that in STAT3, allele G played a potentially protective role against NSDD (OR: 0.74; 95% CI 0.569-0.951; P=0.019), whereas allele C increased the risk of NSDD (OR: 1.37; 95% CI 1.059-1.760; P=0.016). Recessive inheritance was shown to be the best fitting model for c.399 and c.831. Under the recessive inheritance model, the association analysis suggested that the G/G genotype increased the risk of NSDD (OR: 1.73; 95% CI 1.07-2.80; P=0.025). A haplotype analysis showed that H1' (the two cSNPs: AC; OR: 1.365; CI 1.059-1.760; P=0.016) significantly increased the risk of the disorder. The CATMOD program (SAS 9.2) and the multifactor dimensionality reduction method were used to analyze the genetic interactions between JAK1 and STAT3. Data on the genetic interactions revealed that the JAK1 and STAT3 risk alleles described above contribute to NSDD susceptibility in combination with each other, and that model (c1421, c3036, c831) was the best model (OR: 2.7262; 95% CI: 4.7408-5.1986; P<0.0001). To our knowledge, this is the first report of the genetic polymorphisms of the JAK1 and STAT3 genes and their associations with the incidence of NSDD in rabbits.

Keywords: HRM; JAK1/STAT3; MDR; NSDD; RFLP.