Instituto de Medicina Molecular and Universidade de Lisboa, Lisbon, Portugal, and Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Tehran University of Medical Sciences, Tehran, Iran.
Arthritis Rheumatol. 2015 Oct;67(10):2742-8. doi: 10.1002/art.39240.
To independently replicate the top findings from 4 published genome-wide association studies (GWAS) of susceptibility genes in Behçet's disease (BD).
We tested 14 single-nucleotide polymorphisms (SNPs) in 13 genomic loci (excluding the major histocompatibility complex [MHC], IL10, and IL23R-IL12RB2, which have already been associated with BD in Iranians) for allelic and genotypic associations with BD in 973 patients and 828 controls from Iran and performed meta-analyses of the significantly associated markers.
Six SNPs (in decreasing order of significance, rs7616215 located 38 kb downstream of CCR1, rs2617170 [p.Asn104Ser] in KLRC4, rs17810546 in IL12A-AS1, rs7574070 in STAT4, and rs10050860 [p.Asp575Asn] and rs13154629 in ERAP1) were nominally associated with BD in both allelic association tests (5.05 × 10(-9) ≤ Pallele ≤ 7.55 × 10(-3) ) and sex-adjusted genotypic association tests (6.01 × 10(-9) ≤ adjusted P value ≤ 1.30 × 10(-2) ). For all 6 SNPs tested by meta-analysis (Pmeta ), the association with BD was strengthened, because the direction and magnitude of association were similar across populations (e.g., for rs7574070, odds ratio [OR] for A allele 1.29 [95% confidence interval (95% CI) 1.21-1.37], Pmeta = 2.34 × 10(-16) ; for rs7616215, OR for C allele 0.70 [95% CI 0.65-0.76], Pmeta = 1.54 × 10(-19) ; for rs17810546, OR for A allele 0.60 [95% CI 0.52-0.70], Pmeta = 6.34 × 10(-11) ; for rs2617170, OR for T allele 0.76 [95% CI 0.70-0.81], Pmeta = 2.75 × 10(-14) ; for rs13154629, OR for TT genotype 2.76 [95% CI 2.01-3.80], Pmeta = 3.57 × 10(-10) ).
This study reinforces the notion that CCR1, KLRC4, IL12A-AS1, STAT4, and ERAP1 are bona fide susceptibility genes for BD, in addition to the MHC, IL10, and IL23R-IL12RB2 loci. Future genetic and functional studies are now warranted to uncover the roles of these genes in the pathogenesis of BD.
独立复制已发表的四项关于 Behçet 病（BD）易感性基因的全基因组关联研究（GWAS）的顶级发现。
我们在来自伊朗的 973 名患者和 828 名对照中，对 13 个基因组座中的 14 个单核苷酸多态性（SNP）进行了等位基因和基因型关联分析，这些 SNP 位于 MHC、IL10 和 IL23R-IL12RB2 之外，这些基因已与伊朗人群中的 BD 相关。我们对显著相关的标记物进行了荟萃分析。
在等位基因关联测试（5.05×10(-9)≤Pallele≤7.55×10(-3)）和性别调整的基因型关联测试（6.01×10(-9)≤调整后 P 值≤1.30×10(-2)）中，有 6 个 SNP（按显著性降序排列，位于 CCR1 下游 38kb 的 rs7616215、KLRC4 中的 rs2617170[p.Asn104Ser]、IL12A-AS1 中的 rs17810546、STAT4 中的 rs7574070 以及 ERAP1 中的 rs10050860[p.Asp575Asn]和 rs13154629）与 BD 呈名义相关。对于通过荟萃分析（Pmeta）测试的所有 6 个 SNP，BD 的相关性得到了加强，因为不同人群之间的关联方向和程度相似（例如，对于 rs7574070，A 等位基因的比值比[OR]为 1.29[95%置信区间（95%CI）为 1.21-1.37]，Pmeta=2.34×10(-16)；对于 rs7616215，C 等位基因的 OR 为 0.70[95%CI 为 0.65-0.76]，Pmeta=1.54×10(-19)；对于 rs17810546，A 等位基因的 OR 为 0.60[95%CI 为 0.52-0.70]，Pmeta=6.34×10(-11)；对于 rs2617170，T 等位基因的 OR 为 0.76[95%CI 为 0.70-0.81]，Pmeta=2.75×10(-14)；对于 rs13154629，TT 基因型的 OR 为 2.76[95%CI 为 2.01-3.80]，Pmeta=3.57×10(-10)）。
这项研究进一步证实，CCR1、KLRC4、IL12A-AS1、STAT4 和 ERAP1 除了 MHC、IL10 和 IL23R-IL12RB2 外，也是 BD 的真正易感性基因。现在有必要进行进一步的遗传和功能研究，以揭示这些基因在 BD 发病机制中的作用。
