Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Genes Immun. 2013 Jun;14(4):217-22. doi: 10.1038/gene.2013.9. Epub 2013 Mar 28.
The type I interferon system genes IKBKE and IFIH1 are associated with the risk of systemic lupus erythematosus (SLE). To identify the sequence variants that are able to account for the disease association, we resequenced the genes IKBKE and IFIH1. Eighty-six single-nucleotide variants (SNVs) with potentially functional effect or differences in allele frequencies between patients and controls determined by sequencing were further genotyped in 1140 SLE patients and 2060 controls. In addition, 108 imputed sequence variants in IKBKE and IFIH1 were included in the association analysis. Ten IKBKE SNVs and three IFIH1 SNVs were associated with SLE. The SNVs rs1539241 and rs12142086 tagged two independent association signals in IKBKE, and the haplotype carrying their risk alleles showed an odds ratio of 1.68 (P-value=1.0 × 10(-5)). The risk allele of rs12142086 affects the binding of splicing factor 1 in vitro and could thus influence its transcriptional regulatory function. Two independent association signals were also detected in IFIH1, which were tagged by a low-frequency SNV rs78456138 and a missense SNV rs3747517. Their joint effect is protective against SLE (odds ratio=0.56; P-value=6.6 × 10(-3)). In conclusion, we have identified new SLE-associated sequence variants in IKBKE and IFIH1, and proposed functional hypotheses for the association signals.
IKBKE 和 IFIH1 这两个 I 型干扰素系统基因与系统性红斑狼疮（SLE）的发病风险相关。为了鉴定能够解释疾病关联的序列变异，我们对 IKBKE 和 IFIH1 这两个基因进行了重测序。通过测序确定的具有潜在功能效应或在患者和对照人群间等位基因频率存在差异的 86 个单核苷酸变异（SNV）进一步在 1140 名 SLE 患者和 2060 名对照中进行了基因分型。此外，我们还将 IKBKE 和 IFIH1 中的 108 个推断的序列变异纳入了关联分析。10 个 IKBKE SNV 和 3 个 IFIH1 SNV 与 SLE 相关。SNV rs1539241 和 rs12142086 标记了 IKBKE 中两个独立的关联信号，携带其风险等位基因的单倍型显示出 1.68 的比值比（P 值=1.0×10(-5)）。rs12142086 的风险等位基因影响体外剪接因子 1 的结合，因此可能影响其转录调控功能。IFIH1 中也检测到两个独立的关联信号，由低频 SNV rs78456138 和错义 SNV rs3747517 标记。它们的联合效应对 SLE 具有保护作用（比值比=0.56；P 值=6.6×10(-3)）。总之，我们在 IKBKE 和 IFIH1 中发现了新的与 SLE 相关的序列变异，并对关联信号提出了功能假说。
