Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, PR China; Anhui Provincial Laboratory of Population Health & Major Disease Screening and Diagnosis, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, PR China.
Mol Immunol. 2013 Dec;56(4):643-8. doi: 10.1016/j.molimm.2013.07.006. Epub 2013 Aug 2.
Recently, multiple genetic associations have been found between genes involved in nuclear factor-kappaB (NF-κB) signaling pathway and systemic lupus erythematosus (SLE) or other autoimmune diseases. This study was undertaken to replicate some of these associations and further test for genetic interactions among these genes in SLE in a Chinese population. Ten single-nucleotide polymorphisms (SNPs) in NFKB1, REL, inhibitor of κB-like (IκBL), IκB kinase β (IKBKB), tumor necrosis factor receptor associated factor 6 (TRAF6), tumor necrosis factor a-induced protein 3 (TNFAIP3), TNFAIP3 interacting protein 1 (TNIP1) were genotyped in 898 Chinese patients with SLE and 988 healthy controls by Sequenom MassArray technology. Single-marker genetic association analysis was performed, and additive and multiplicative interactions were analyzed. Associations of TNFAIP3 rs2230926 (p=1.43 × 10(-3)) and TNIP1 rs10036748 (p=4.33 × 10(-3)) with SLE were replicated in our study. Two other SNPs, NFKB1 rs28362491 and IκBL rs2071592, showed nominal evidence for association (p=4.70 × 10(-2) and p=5.90 × 10(-3), respectively) but these were not significant after applying Bonferroni correction. Additive interaction analysis revealed significant interaction between NFKB1 rs28362491 and TNFAIP3 rs2230926 (RERI=0.98, 95%CI=0.02-1.93; AP=43.2%, 95%CI=0.12-0.74). Significant multiplicative interaction was observed between NFKB1 rs28362491 and TNIP1 rs3792783 (p=0.03). Our results provide evidence for gene-gene interactions, which further support the important role of NF-κB signaling pathway in the genetic basis of SLE and the notion of genetic interactions accounting for missing heritability.
最近，已经发现参与核因子-κB（NF-κB）信号通路的基因与系统性红斑狼疮（SLE）或其他自身免疫性疾病之间存在多种遗传关联。本研究旨在复制这些关联中的一些，并在中国人群中进一步测试这些基因在 SLE 中的遗传相互作用。采用Sequenom MassArray 技术，对 898 例中国 SLE 患者和 988 例健康对照者的 NFKB1、REL、抑制κB 样（IκBL）、IκB 激酶β（IKBKB）、肿瘤坏死因子受体相关因子 6（TRAF6）、肿瘤坏死因子α诱导蛋白 3（TNFAIP3）、TNFAIP3 相互作用蛋白 1（TNIP1）中的 10 个单核苷酸多态性（SNP）进行基因分型。进行单标记遗传关联分析，并分析加性和乘法相互作用。本研究复制了 TNFAIP3 rs2230926（p=1.43×10(-3)）和 TNIP1 rs10036748（p=4.33×10(-3)）与 SLE 的关联。另外两个 SNP，NFKB1 rs28362491 和 IκBL rs2071592，虽然与关联有显著关系（p=4.70×10(-2)和 p=5.90×10(-3)），但经过 Bonferroni 校正后，这些结果并不显著。加性相互作用分析显示 NFKB1 rs28362491 与 TNFAIP3 rs2230926 之间存在显著的相互作用（RERI=0.98，95%CI=0.02-1.93；AP=43.2%，95%CI=0.12-0.74）。还观察到 NFKB1 rs28362491 与 TNIP1 rs3792783 之间存在显著的乘法相互作用（p=0.03）。本研究结果为基因-基因相互作用提供了证据，进一步支持了 NF-κB 信号通路在 SLE 遗传基础中的重要作用，以及遗传相互作用解释遗传缺失的概念。
