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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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Haplotype blocks described in the region Chr21:44529072..44541978 of the HapMap Project in the CEU and the JPT populations. The linkage disequilibrium (LD) solid spine approach was used to define haplotype blocks. Standard color-coding was used for LD plots: white (r2 = 0), shaded gray (0 <r2 < 1), black (r2 = 1). Squares without a number indicate D' = 1. CEU, Utah residents with Northern and Western European ancestry from the CEPH collection; JPT, Japanese in Tokyo, Japan.
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Figure 1: Haplotype blocks described in the region Chr21:44529072..44541978 of the HapMap Project in the CEU and the JPT populations. The linkage disequilibrium (LD) solid spine approach was used to define haplotype blocks. Standard color-coding was used for LD plots: white (r2 = 0), shaded gray (0 <r2 < 1), black (r2 = 1). Squares without a number indicate D' = 1. CEU, Utah residents with Northern and Western European ancestry from the CEPH collection; JPT, Japanese in Tokyo, Japan.

Mentions: Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that often leads to disability from joint damage and inflammation. Although RA is an uncommon disease with a worldwide prevalence of approximately 1%, this pathology has a large economic and societal cost in terms of work-related disability [1]. Both environmental and genetic factors are considered to be associated with the onset and progression of this disease. Genome-wide associations (GWA) studies have identified common genetic variations associated with numerous complex diseases [2]. Contrary to the candidate gene approach, in which a limited number of genes chosen on the basis of known or suspected biological considerations are tested, the aim of GWA studies is to check association in the whole genome without a priori hypotheses. Many gene loci have been identified as risk factors for RA in different GWA studies in European and East Asian populations. Some of these loci have been found to be restricted to a particular ethnic group but others, such as, CCR6, STAT4 and TNFAIP3, have been described as associated with RA in different populations [3]. Recently, the AIRE gene was identified as a genetic risk factor for RA in a GWA study performed in a Japanese population [4]. AIRE is a transcriptional regulator primarily expressed in medullary thymic epithelial cells, playing a functional role in thymocyte education and negative selection by controlling the expression of peripheral antigens in the thymus [5]. Therefore, AIRE is a good functional candidate in autoimmune diseases regardless of the population. In fact, mutations in this gene cause autoimmune polyendocrinopathy syndrome (APS1), which is one of the few known monogenic autoimmune diseases. Nevertheless, AIRE has not been identified as associated to RA in the European population, either in a large-scale GWA study or in a meta-analysis of GWA studies [6-10]. However, both of these studies had strong detection power, and therefore, the association of AIRE with RA, like that of PAD14, could be specific to some populations, such as in the Japanese study [4]. However, 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, therefore, we decided to further investigate the possible role of the AIRE gene in susceptibility to RA in a Spanish population.


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)

Haplotype blocks described in the region Chr21:44529072..44541978 of the HapMap Project in the CEU and the JPT populations. The linkage disequilibrium (LD) solid spine approach was used to define haplotype blocks. Standard color-coding was used for LD plots: white (r2 = 0), shaded gray (0 <r2 < 1), black (r2 = 1). Squares without a number indicate D' = 1. CEU, Utah residents with Northern and Western European ancestry from the CEPH collection; JPT, Japanese in Tokyo, Japan.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Haplotype blocks described in the region Chr21:44529072..44541978 of the HapMap Project in the CEU and the JPT populations. The linkage disequilibrium (LD) solid spine approach was used to define haplotype blocks. Standard color-coding was used for LD plots: white (r2 = 0), shaded gray (0 <r2 < 1), black (r2 = 1). Squares without a number indicate D' = 1. CEU, Utah residents with Northern and Western European ancestry from the CEPH collection; JPT, Japanese in Tokyo, Japan.
Mentions: Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that often leads to disability from joint damage and inflammation. Although RA is an uncommon disease with a worldwide prevalence of approximately 1%, this pathology has a large economic and societal cost in terms of work-related disability [1]. Both environmental and genetic factors are considered to be associated with the onset and progression of this disease. Genome-wide associations (GWA) studies have identified common genetic variations associated with numerous complex diseases [2]. Contrary to the candidate gene approach, in which a limited number of genes chosen on the basis of known or suspected biological considerations are tested, the aim of GWA studies is to check association in the whole genome without a priori hypotheses. Many gene loci have been identified as risk factors for RA in different GWA studies in European and East Asian populations. Some of these loci have been found to be restricted to a particular ethnic group but others, such as, CCR6, STAT4 and TNFAIP3, have been described as associated with RA in different populations [3]. Recently, the AIRE gene was identified as a genetic risk factor for RA in a GWA study performed in a Japanese population [4]. AIRE is a transcriptional regulator primarily expressed in medullary thymic epithelial cells, playing a functional role in thymocyte education and negative selection by controlling the expression of peripheral antigens in the thymus [5]. Therefore, AIRE is a good functional candidate in autoimmune diseases regardless of the population. In fact, mutations in this gene cause autoimmune polyendocrinopathy syndrome (APS1), which is one of the few known monogenic autoimmune diseases. Nevertheless, AIRE has not been identified as associated to RA in the European population, either in a large-scale GWA study or in a meta-analysis of GWA studies [6-10]. However, both of these studies had strong detection power, and therefore, the association of AIRE with RA, like that of PAD14, could be specific to some populations, such as in the Japanese study [4]. However, 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, therefore, we decided to further investigate the possible role of the AIRE gene in susceptibility to RA in a Spanish population.

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