Association of TYK2 rs34536443 polymorphism with Susceptibility to Systemic Lupus Erythematous in the Iranian Population

Abstract

Systemic lupus erythematous (SLE) is a multifactorial autoimmune disorder which affects many organs and displays various symptoms. Genetic components contribute to the incidence and development of SLE. A rare functional variant within the tyrosine kinase 2 (TYK2) gene (rs34536443) is a common genetic candidate for several autoimmune diseases, including SLE. This case control study was performed to investigate the possible association of TYK2 single nucleotide polymorphism (SNP) with a predisposition for and clinical features of SLE in the Iranian population. Genotyping was conducted on 600 patients with SLE and 600 sex-, age-and ethnicity-matched control subjects from the Iranian population. Patient and control samples were genotyped for one SNP (rs34536443) by applying allelic discrimination real-time PCR. Statistical analysis of the allele distribution revealed no significant association (OR = 0.67, CI: 0.38-1.17, P value = 0.163) between the rs34536443 C allele and susceptibility to SLE. The CC genotype was not detected in either the patients or controls. Moreover, the CG genotypes showed no significant association with the risk of SLE (OR = 0.66, CI: 0.37-1.72, P value = 0.15). These findings suggest that TYK2 rs34536443 is not associated with SLE susceptibility in the Iranian population. Further investigation is required to examine the mechanisms by which polymorphisms in this gene lead to SLE development.

Identifying pathogenic variants related to systemic lupus erythematosus by integrating genomic databases and a bioinformatic approach

“…Furthermore, a previous study by Faezi et al [ 27 ] found that the C allele of rs34536443 in the Iranian population had no impact on SLE susceptibility. This highlighted the importance of genetic divergence in diverse populations and the contribution of different genes to the etiopathogenesis of a multigenic disease like SLE [ 27 ]. Meanwhile, the rs34536443 allele was associated with autoimmune disease in the European population.…”

“…Numerous studies have considered the IFN-1 pathway in the pathogenesis of SLE. Serum IFN-α levels are increased in patients with SLE; therefore, the secretion of IFN-1 may play a role in the etiology of SLE [ 26 , 27 ].…”

“…The rare TYK2 gene variant rs34536443 causes the substitution of a G nucleotide with a C nucleotide, resulting in a Pro1104Ala (P1104A) variant in the TYK2 protein. This alteration has been hypothesized to promote a conformational change, affecting the folding and function of the TYK2 protein [ 27 ].…”

Discovery of a Potent and Selective Tyrosine Kinase 2 Inhibitor: TAK-279

“…These cytokines each play a critical role in the function of Th1 and Th17 cells and consequently play a key role in a range of autoimmune and chronic inflammatory diseases. Genome-wide association studies have identified loss-of-function (LoF) mutations of TYK2 in humans, which have been shown to be protective for a number of inflammatory diseases. − These LoF variants reduce the function of TYK2 to mediate cytokine signaling, which in turn confers protection against a number of diseases. ,− Importantly, analysis of data from subjects carrying the rs34536443 single nucleotide polymorphism (SNP) revealed a greater level of protection conferred by homozygous mutations compared to heterozygous mutations . The homozygous C / C mutation affords more than double the protective effect as the heterozygous C / G mutant against ankylosing spondylitis, Crohn’s disease, multiple sclerosis, psoriasis, and ulcerative colitis.…”