Xavier Joana M, Shahram Farhad, Davatchi Fereydoun, Rosa Alexandra, Crespo Jorge, Abdollahi Bahar Sadeghi, Nadji Abdolhadi, Jesus Gorete, Barcelos Filipe, Patto José Vaz, Shafiee Niloofar Mojarad, Ghaderibarim Fahmida, Oliveira Sofia A
Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal.
Arthritis Rheum. 2012 Aug;64(8):2761-72. doi: 10.1002/art.34437.
Independent replication of the findings from genome-wide association studies (GWAS) remains the gold standard for results validation. Our aim was to test the association of Behçet's disease (BD) with the interleukin-10 gene (IL10) and the IL-23 receptor-IL-12 receptor β2 (IL23R-IL12RB2) locus, each of which has been previously identified as a risk factor for BD in 2 different GWAS.
Six haplotype-tagging single-nucleotide polymorphisms (SNPs) in IL10 and 42 in IL23R-IL12RB2 were genotyped in 973 Iranian patients with BD and 637 non-BD controls. Population stratification was assessed using a panel of 86 ancestry-informative markers.
Subtle evidence of population stratification was found in our data set. In IL10, rs1518111 was nominally associated with BD before and after adjustment for population stratification (odds ratio [OR] for T allele 1.20, 95% confidence interval [95% CI] 1.02-1.40, unadjusted P [P(unadj) ] = 2.53 × 10(-2) ; adjusted P [P(adj) ] = 1.43 × 10(-2) ), and rs1554286 demonstrated a trend toward association (P(unadj) = 6.14 × 10(-2) ; P(adj) = 3.21 × 10(-2) ). Six SNPs in IL23R-IL12RB2 were found to be associated with BD after Bonferroni correction for multiple testing, the most significant of which were rs17375018 (OR for G allele 1.51, 95% CI 1.27-1.78, P(unadj) = 1.93 × 10(-6) ), rs7517847 (OR for T allele 1.48, 95% CI 1.26-1.74, P(unadj) = 1.23 × 10(-6) ), and rs924080 (OR for T allele 1.29, 95% CI 1.20-1.39, P = 1.78 × 10(-5) ). SNPs rs10489629, rs1343151, and rs1495965 were also significantly associated with BD in all tests performed. Results of meta-analyses of our data combined with data from other populations further confirmed the role of rs1518111, rs17375018, rs7517847, and rs924080 in the risk of BD, but no epistatic interactions between IL10 and IL23R-IL12RB2 were detected. Results of imputation analysis highlighted the importance of IL23R regulatory regions in the susceptibility to BD.
These findings independently confirm, extend, and refine the association of BD with IL10 and IL23R-IL12RB2. These associations warrant further validation and investigation in patients with BD, as they may have implications for the development of novel therapies (e.g., immunosuppressive therapy targeted at IL-23p19).
全基因组关联研究（GWAS）结果的独立重复验证仍是结果验证的金标准。我们的目的是检验白塞病（BD）与白细胞介素-10基因（IL10）以及白细胞介素-23受体-白细胞介素-12受体β2（IL23R-IL12RB2）基因座之间的关联，此前在两项不同的GWAS中已分别将这两个基因座确定为BD的危险因素。
对973例伊朗BD患者和637例非BD对照者进行IL10基因中的6个单倍型标签单核苷酸多态性（SNP）以及IL23R-IL12RB2基因中的42个SNP基因分型。使用一组86个祖先信息标记评估群体分层情况。
在我们的数据集中发现了细微的群体分层证据。在IL10基因中，rs1518111在调整群体分层前后与BD呈名义上的关联（T等位基因的比值比[OR]为1.20，95%置信区间[95%CI]为1.02-1.40，未调整P值[P(unadj)]=2.53×10⁻²；调整后P值[P(adj)]=1.43×10⁻²），rs1554286显示出关联趋势（P(unadj)=6.14×10⁻²；P(adj)=3.21×10⁻²）。在对多重检验进行Bonferroni校正后，发现IL23R-IL12RB2基因中的6个SNP与BD相关，其中最显著的是rs17375018（G等位基因的OR为1.51，95%CI为1.27-1.78，P(unadj)=1.93×10⁻⁶）、rs7517847（T等位基因的OR为1.48，95%CI为1.26-1.74，P(unadj)=1.23×10⁻⁶）和rs924080（T等位基因的OR为1.29，95%CI为1.20-1.39，P=1.78×10⁻⁵）。在所有进行的检验中，SNP rs10489629、rs1343151和rs1495965也与BD显著相关。将我们的数据与其他群体的数据进行荟萃分析的结果进一步证实了rs1518111、rs17375018、rs7517847和rs924080在BD风险中的作用，但未检测到IL10与IL23R-IL12RB2之间的上位性相互作用。归因分析结果突出了IL23R调控区域在BD易感性中的重要性。
这些发现独立地证实、扩展并细化了BD与IL10和IL23R-IL12RB2之间的关联。这些关联值得在BD患者中进一步验证和研究，因为它们可能对新疗法（如针对IL-23p19的免疫抑制疗法）的开发具有重要意义。
