Association of GTF2I, NFKB1, and TYK2 Regional Polymorphisms With Systemic Sclerosis in a Chinese Han Population

Abstract

ObjectivesSystemic sclerosis (SSc) is an uncommon autoimmune disease that varies with ethnicity. Single nucleotide polymorphisms (SNPs) in the GTFSI, NFKB1, and TYK2 genes have been reported to be associated with SSc in other populations and in individuals with various autoimmune diseases. This study aimed to investigate the association between these SNPs and susceptibility to SSc in a Chinese Han population.MethodA case-control study was performed in 343 patients with SSc and 694 ethnically matched healthy controls. SNPs in GTF2I, NFKB1, and TYK2 were genotyped using a Sequenom MassArray iPLEX system. Association analyses were performed using PLINK v1.90 software.ResultOur study demonstrated that the GTF2I rs117026326 T allele and the GTF2I rs73366469 C allele were strongly associated with patients with SSc (P = 6.97E-10 and P = 1.33E-08, respectively). Patients carrying the GTF2I rs117026326 TT genotype and the GTF2I rs73366469 CC genotype had a strongly increased risk of SSc (P = 6.25E-09 and P = 1.67E-08, respectively), and those carrying the NFKB1 rs1599961 AA genotype had a suggestively significantly increased risk of SSc (P = 0.014). Moreover, rs117026326 and rs73366469 were associated with SSc in different genetic models (additive model, dominant model, and recessive model) (P < 0.05) whereas rs1599961 was associated with SSc in the dominant genetic model but not in the addictive and recessive models (P = 0.0026). TYK2 rs2304256 was not significantly associated with SSc in this study.ConclusionGTF2I rs117026326 and rs73366469 SNPs were strongly associated with SSc in this Chinese Han population. NFKB1 rs1599961 showed a suggestive association with SSc, and no significant association was found between TYK2 rs2304256 and SSc in this Chinese Han population.

Meta-Analysis and Systematic Review of the Association between a Hypoactive NCF1 Variant and Various Autoimmune Diseases

“…Our meta-analysis showed a strong association of the GTF2I rs117026326 polymorphism with SLE, where the minor allele conferred an approximate 3-fold risk for the disease (OR = 3.04; 95% CI = 2.81–3.30, p < 1 × 10 −16 ) ( Figure 4 B). Meta-analysis also revealed a significant association between the GTF2I rs117026326 polymorphism and SSc with two case–control studies [ 6 , 16 ] (OR = 1.77; 95% CI = 1.49–2.11, p = 9.36 × 10 −11 ) ( Figure 4 C). The association between the GTF2I rs117026326 polymorphism and NMOSD has been investigated in two case–control studies where both have shown a significant association [ 7 , 15 ].…”

“…The highest frequency (17.6%) was reported in Changchun, a city in Northeast China [ 7 ]. The frequency decreases toward the south and west China, showing 14.9% and 13.9% in Beijing [ 5 , 6 ], and 11.9% in Shanghai [ 9 ], 11.9% and 9.4% in Chengdu [ 14 , 15 ], 11.5% in Xiamen [ 4 ], and 10.4% in Taiwan [ 16 ]. This polymorphism is also prevalent in other Eastern Asia populations, with allele frequencies of 11.4% in Korean [ 9 ] and 8.0% in Japanese [ 17 ].…”

“…The OR, 95% CI and p values for the meta-analysis are indicated by bold text. Information regarding individual case–control studies, including the first author name and year of publication, are indicated [ 3 , 4 , 5 , 6 , 7 , 9 , 14 , 15 , 16 , 17 ].…”

“…In 2013, a strong susceptibility loci within the GTF2I – NCF1 intergenic region at 7q11.23 was identified for primary Sjögren’s syndrome (pSS), with the GTF2I rs117026326 as the most significant polymorphism (OR = 2.20, p = 1.31 × 10 −53 ) [ 3 ]. Subsequently, this strong association has been confirmed [ 4 ] and extended to other autoimmune disorders, including systemic lupus erythematosus (SLE) [ 5 ], systemic sclerosis (SSc) [ 6 ], and neuromyelitis optica spectrum disorder (NMOSD) [ 7 ].…”

Human thymoma-associated mutation of the GTF2I transcription factor impairs thymic epithelial progenitor differentiation in mice

“…Although we cannot rule out the possibility that the lack of immunopathology in our mice is the result of a species-specific difference, we consider it more likely that autoimmunity emerges only when the thymic microenvironment is composed of a mosaic of wild-type and mutant epithelium. Interestingly, recent genome-wide association studies suggested a link between GTF2I and autoimmune disorders, such as primary Sjögren´s syndrome 34 and others [35][36][37][38] . However, most pertinent to the present discussion is the fact that the relevant single nucleotide polymorphisms (SNPs) are situated in non-coding regions of the gene, and that one SNP (rs117026326) is associated with increased expression of GTF2I in salivary gland cells 39 .…”