Association of the AIRE gene with susceptibility to rheumatoid arthritis in a European population: a case control study.
Association of the AIRE gene with susceptibility to rheumatoid arthritis in a European population: a case control study.
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DOI：
10.1186/ar4141
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发表时间：
2013-01-15
影响因子：
4.9
通讯作者：
González-Escribano MF
中科院分区：
文献类型：
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作者：
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
AIRE是一种转录调节因子，通过控制胸腺中外周抗原的表达，在胸腺细胞教育和负选择中发挥功能性作用。最近，在日本人群中进行的全基因组关联（GWA）研究中，AIRE基因被确定为类风湿性关节炎（RA）的遗传风险因素。根据现有数据，这种关联仅限于亚洲人群。然而，不同的事实可能会影响高加索人群中缺乏相关性。本研究的目的是进一步调查白人人群中AIRE基因在RA易感性中的可能作用。共有472名西班牙白人RA患者和475名种族匹配的对照被纳入研究。三种单核苷酸多态性（SNP）在高加索人群中具有>0.05的次要等位基因频率的两个SNP（rs 2776377、rs 878081和rs 1055311），其未包括在用于RA易感性的GWA研究中使用的高通量平台中，（rs 2075876和rs 1800520），并使用TaqMan分析进行基因分型。rs 2776377、rs 2075876、rs 1055311和rs 1800520单核苷酸多态性在RA患者和对照组中的分布差异无统计学意义。然而，rs 878081的C等位基因频率在RA患者中显著高于对照组（80.5%vs.74.6%，pc = 0.012，OR = 1.41，95%CI 1.13-1.75）。在rs 878081基因型的分布中，RA组CC纯合子的频率高于对照组（65.56%vs.56.47%，pc = 0.013，OR = 1.47，95%CI 1.12-1.93）。计算机模拟分析预测转录NF-κB家族的基序结合位点的亲和力较低，并且rs 878081 C风险变体的AIRE基因的转录水平较低。我们的研究结果表明，AIRE基因与西班牙人群中RA的易感性相关。在GWA研究中，可能在欧洲人群中未检测到这种关联，因为最早的高通量平台不包括SNP合适的标记物（例如rs 878081）。
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. 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. 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 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).