Abstract
IntroductionAIRE is a transcriptional regulator playing a functional role in thymocyte education and negative selection by controlling the expression of peripheral antigens in the thymus. Recently, the AIRE gene was identified as a genetic risk factor for rheumatoid arthritis (RA) in genome wide association (GWA) studies performed in the Japanese population. According to the available data this association is restricted to the Asian population. However, different facts could influence the lack of association in Caucasian populations. The aim of this study was to further investigate the possible role of the AIRE gene in susceptibility to RA in a Caucasian population.MethodsA total of 472 Spanish Caucasian RA patients and 475 ethnically matched controls were included in the study. Three single-nucleotide polymorphisms (SNPs) (rs2776377, rs878081 and rs1055311) with a minor allele frequency >0.05 in the Caucasian population which were not included in the high-throughput platforms used in the GWA studies performed in susceptibility to RA, and two SNPs (rs2075876 and rs1800520) associated with RA in the Japanese population, were selected and genotyped using TaqMan assays.ResultsNo significant differences in the distribution of the alleles of rs2776377, rs2075876, rs1055311 and rs1800520 SNPs between RA patients and controls were observed. Nevertheless, the frequency of the C allele of rs878081 was significantly higher among RA patients (80.5% vs. 74.6% in the control group, pc = 0.012, OR = 1.41, 95%CI 1.13-1.75). Regarding the distribution of the rs878081 genotypes, a higher frequency of CC homozygous individuals was found in the RA patient group (65.56% vs. 56.47% in the control group, pc = 0.013, OR = 1.47, 95%CI 1.12-1.93). The in silico analysis predicted lower affinity to the binding-site of a motif of the transcription NF-κB family and lower transcription levels of AIRE gene for the rs878081C risk variantConclusionsOur findings suggest that the AIRE gene is associated with susceptibility to RA in the Spanish population. Probably, this association has not been detected in the European population in the GWA studies because the earliest high-throughput platforms did not include SNP suitable markers (e.g. rs878081).
Highlights
AIRE is a transcriptional regulator playing a functional role in thymocyte education and negative selection by controlling the expression of peripheral antigens in the thymus
Three single-nucleotide polymorphisms (SNPs) with a minor allele frequency >0.05 in the Caucasian population which were not included in the high-throughput platforms used in the genome wide association (GWA) studies performed in susceptibility to rheumatoid arthritis (RA), and two SNPs associated with RA in the Japanese population, were selected and genotyped using TaqMan assays
The SNPs identified as risk markers in the Japanese population, have a much lower minor allele frequency (MAF) in the Caucasian populations included in the HapMap project (rs2075876A 0.123 in CEU and 0.096 in Tuscan in Italy (TSI) and rs760426G in 0.159 CEU and 0.163 in TSI) than in the Japanese in Tokyo (JPT) (0.347 and 0.359, respectively) and other Asian populations (0.437 and 0.389 in Han Chinese in Beijing, China (CHB) and 0.417 and 0.413 in Chinese in Metropolitan Denver, Colorado (CHD) respectively) included in this project
Summary
AIRE is a transcriptional regulator playing a functional role in thymocyte education and negative selection by controlling the expression of peripheral antigens in the thymus. Both of these studies had strong detection power, and the association of AIRE with RA, like that of PAD14, could be specific to some populations, such as in the Japanese study [4] This gene has different linkage disequilibrium (LD) blocks in European and Asian populations (Figure 1), and the earliest GWA high-throughput platforms do not include any adequate tag single-nucleotide polymorphisms (SNPs) for the European population. This fact could influence the lack of association in Caucasian populations, we decided to further investigate the possible role of the AIRE gene in susceptibility to RA in a Spanish population
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