State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital of Medical College, Zhejiang University, Hangzhou, China.
PLoS One. 2012;7(8):e42104. doi: 10.1371/journal.pone.0042104. Epub 2012 Aug 6.
Genes encoding IRF1 and IRF8 protein have been proposed as candidate tuberculosis susceptibility genes. In order to elucidate whether the IRF1 and IRF8 variants were associated with tuberculosis susceptibility, we conducted a case-control study consisting of 495 controls and 452 ethnically matched cases with tuberculosis in a Chinese population. Seven haplotype tagging single-nucleotide polymorphisms (tagSNPs) (rs2057656; rs2706381; rs2070724; rs2070721; rs2549008; rs2549007; rs2706386) from HapMap database were analyzed, which provided an almost complete coverage of the genetic variations in the IRF1 gene. Fifteen tagSNPs (rs12924316; rs182511; rs305080; rs2292980; rs925994; rs424971; rs16939967; rs11117415; rs4843860; rs9926411; rs8064189; rs12929551; rs10514611; rs1044873; rs6638) were observed in the IRF8 gene. All these tagSNPs were genotyped by SNPstream genotyping and SNaPshot typing. None of the seven tagSNPs was individually associated with tuberculosis in the IRF1 gene. In the IRF8 gene, interestingly, we found that three tagSNPs (rs925994 and rs11117415 located in the intron region; rs10514611 located in the 3'UTR) were associated with risk of tuberculosis after Bonferroni correction. Per allele OR was 1.75 (95% CI 1.35 ~ 2.27, P = 0.002), 4.75 (95% CI 2.16 ~ 10.43, P = 0.002) and 3.39 (95% CI 1.60 ~ 7.20, P = 0.015) respectively. Luciferase reporter gene assay showed that the construct that contained the non-risk allele C of rs10514611 showed significantly higher luciferase activity than did the risk T allele (P<0.01), which implied rs10514611 was a potential functional SNP site. Our results indicated that the IRF8 gene might participate in genetic susceptibility to tuberculosis in a Chinese population.
基因编码 IRF1 和 IRF8 蛋白已被提议为候选结核病易感性基因。为了阐明 IRF1 和 IRF8 变体是否与结核病易感性相关，我们在中国人群中进行了一项病例对照研究，包括 495 名对照和 452 名匹配的结核病病例。对 HapMap 数据库中的七个单核苷酸多态性（tagSNP）（rs2057656；rs2706381；rs2070724；rs2070721；rs2549008；rs2549007；rs2706386）进行了分析，这为 IRF1 基因中的遗传变异提供了几乎完整的覆盖。在 IRF8 基因中观察到 15 个 tagSNP（rs12924316；rs182511；rs305080；rs2292980；rs925994；rs424971；rs16939967；rs11117415；rs4843860；rs9926411；rs8064189；rs12929551；rs10514611；rs1044873；rs6638）。所有这些 tagSNP 均通过 SNPstream 基因分型和 SNaPshot 分型进行了基因分型。IRF1 基因中没有一个 tagSNP 与结核病单独相关。有趣的是，在 IRF8 基因中，我们发现三个 tagSNP（位于内含子区域的 rs925994 和 rs11117415；位于 3'UTR 的 rs10514611）在经过 Bonferroni 校正后与结核病风险相关。每个等位基因的 OR 为 1.75（95%CI 1.352.27，P=0.002）、4.75（95%CI 2.1610.43，P=0.002）和 3.39（95%CI 1.60~7.20，P=0.015）。荧光素酶报告基因检测表明，包含 rs10514611 的非风险等位基因 C 的构建体显示出明显高于风险 T 等位基因的荧光素酶活性（P<0.01），这表明 rs10514611 是一个潜在的功能 SNP 位点。我们的结果表明，IRF8 基因可能参与了中国人群结核病的遗传易感性。
