Abstract
The aryl hydrocarbon receptor (AHR) signaling pathway participates in immune regulation of multiple autoimmune diseases, including rheumatoid arthritis (RA). We conducted this study to investigate the association of AHR signaling pathway genes (AHR, ARNT, AHRR) single nucleotide polymorphisms (SNPs), as well as their methylation levels, with RA susceptibility. Nine SNPs (AHR gene rs2066853, rs2158041, rs2282885, ARNT gene rs10847, rs1889740, rs11204735, AHRR gene rs2292596, rs2672725, rs349583) were genotyped via improved multiple ligase detection reaction (iMLDR) in 479 RA patients and 496 healthy controls. We used the Illumina Hiseq platform to detect methylation levels of these genes in 122 RA patients and 123 healthy controls. A significant increase in rs11204735 C allele frequency was observed in RA patients when compared to controls. Further, rs11204735 polymorphism was associated with a decreased risk of RA under the dominant model. ARNT CCC haplotype frequency was significantly increased in RA patients in comparison to controls. In the AHRR gene, rs2672725 GG genotype, G allele frequencies were significantly related to an increased risk of RA and rs2292596, rs2672725 polymorphism were significantly associated with an increased risk of RA under the dominant model, recessive model, respectively. However, no significant association was identified between AHR gene polymorphism and RA susceptibility. The AHR methylation level in RA patients was significantly higher than the controls, while AHRR methylation level was abnormally reduced in RA patients. In addition, AHRR rs2672725 genotype distribution was significantly associated with the AHRR methylation level among RA patients. In summary, ARNT rs11204735, AHRR rs2292596, and rs2672725 polymorphisms were associated with RA susceptibility and altered AHR, AHRR methylation levels were related to the risk of RA.
Highlights
Rheumatoid arthritis (RA) is a common, chronic autoimmune disease that affects approximately 1% of the general population [1]
The genotype frequencies of aryl hydrocarbon receptor (AHR) rs2066853, rs2282885 polymorphism were similar between RA patients and healthy controls with no significant association, there was no significant difference in allele distributions of the AHR rs2066853, rs2282885 between RA patients and healthy controls
In the AHR nuclear translocation protein (ARNT) gene, we determined that the rs11204735 C allele frequency was significantly increased in RA patients when compared to healthy controls (C versus T: P = 0.037), while rs11204735 polymorphism was found to have a decreased risk of RA under the dominant model (TT versus CT+ CC: P = 0.023)
Summary
Rheumatoid arthritis (RA) is a common, chronic autoimmune disease that affects approximately 1% of the general population [1]. The immunological dysfunctions of RA were identified in various immune cells, such as T cells, B cells, macrophages, and abnormal expression levels of inflammatory cytokines, including IL-1, IL-6, IL-10, TNF-a, were observed in RA patients [3]. In addition to immunological findings, many studies have found an influence of genomic and epigenomic features, and environmental factors on disease activity, prognosis, and therapy prediction of RA [4–6]. Genome wide association study and candidate gene studies have identified a large number of RA related genes/loci in different ethnic groups, these genes/ loci only account for a small part of RA phenotypic variation [7, 8]. DNA methylation is a widely studied form of epigenetic modification, and some prior studies have suggested that an association between DNA methylation and inflammationregulated immune pathways may play an important role in the pathogenesis of RA [9]
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