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Association of the AIRE gene with susceptibility to rheumatoid arthritis in a European population: a case control study.

García-Lozano JR, Torres-Agrela B, Montes-Cano MA, Ortiz-Fernández L, Conde-Jaldón M, Teruel M, García A, Núñez-Roldán A, Martín J, González-Escribano MF - Arthritis Res. Ther. (2013)

Bottom Line: 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 variant Our 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).

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: 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. 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.

Methods: A 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.

Results: No 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 variant

Conclusions: Our 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).

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Comparison of expression levels of AIRE obtained from the GEO database according to the genotype of rs878081. Results of AIRE mRNA expression are shown in a boxplot. The P-value was obtained by the Joncheere-Terepstra method.
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Figure 2: Comparison of expression levels of AIRE obtained from the GEO database according to the genotype of rs878081. Results of AIRE mRNA expression are shown in a boxplot. The P-value was obtained by the Joncheere-Terepstra method.

Mentions: The in silico study using the HaploReg database [14], predicts a motif binding site that spans the rs878081 location for transcription factors of the nuclear factor-kappa B (NF-κB family [16] The difference between the LOD score of the T allele and the LOD score of the C allele was +2 (positive), therefore, this model predicts alterations of the affinity to regulatory motifs, which is higher for the variant T than for the C allele. Additionally, when the AIRE expression levels were analyzed using the expression profiles from the GEO database [15], a statistically significant difference in the mean levels of expression of the rs878081 alleles was found (P = 0.013). The transcription of AIRE was decreased by the C allele compared with the T allele (Figure 2).


Association of the AIRE gene with susceptibility to rheumatoid arthritis in a European population: a case control study.

García-Lozano JR, Torres-Agrela B, Montes-Cano MA, Ortiz-Fernández L, Conde-Jaldón M, Teruel M, García A, Núñez-Roldán A, Martín J, González-Escribano MF - Arthritis Res. Ther. (2013)

Comparison of expression levels of AIRE obtained from the GEO database according to the genotype of rs878081. Results of AIRE mRNA expression are shown in a boxplot. The P-value was obtained by the Joncheere-Terepstra method.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672784&req=5

Figure 2: Comparison of expression levels of AIRE obtained from the GEO database according to the genotype of rs878081. Results of AIRE mRNA expression are shown in a boxplot. The P-value was obtained by the Joncheere-Terepstra method.
Mentions: The in silico study using the HaploReg database [14], predicts a motif binding site that spans the rs878081 location for transcription factors of the nuclear factor-kappa B (NF-κB family [16] The difference between the LOD score of the T allele and the LOD score of the C allele was +2 (positive), therefore, this model predicts alterations of the affinity to regulatory motifs, which is higher for the variant T than for the C allele. Additionally, when the AIRE expression levels were analyzed using the expression profiles from the GEO database [15], a statistically significant difference in the mean levels of expression of the rs878081 alleles was found (P = 0.013). The transcription of AIRE was decreased by the C allele compared with the T allele (Figure 2).

Bottom Line: 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 variant Our 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).

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: 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. 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.

Methods: A 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.

Results: No 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 variant

Conclusions: Our 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).

Show MeSH
Related in: MedlinePlus