Gene-gene interaction of ATG5, ATG7, BLK and BANK1 in systemic lupus erythematosus
Gene-gene interaction of ATG5, ATG7, BLK and BANK1 in systemic lupus erythematosus
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DOI：
10.1111/1756-185x.12768
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发表时间：
2016-12-01
影响因子：
2.5
通讯作者：
Liu, Qiji
中科院分区：
文献类型：
--
作者：
Dang, Jie;Li, Jiangxia;Liu, Qiji
目的：自噬相关基因5 （ATG5）、ATG7、b淋巴样酪氨酸激酶（BLK）和b细胞支架蛋白与锚蛋白重复序列1 （BANK1）参与b细胞信号转导；一些全基因组关联研究发现这些基因是系统性红斑狼疮（SLE）的候选基因。我们的目的是复制这些基因与中国汉族SLE的关联，并寻找可能的基因-基因相互作用。方法：采用TaqMan单核苷酸多态性（SNP）基因分型方法，对382例SLE患者和660例健康对照进行检测，检测ATG5基因中rss548234、rs665791、ATG7基因中rs11706903、BLK基因中rs2736340、BANK1基因中rs10516487。采用logistic回归、多因素降维和线性回归分析上位效应。结果：SLE与rss548234 （P = 0.010；比值比[OR] = 1.298）、rs2736340 (P = 2.47 × 10(-5)；OR = 1.574)和rs10516487 （P = 0.002; OR = 0.642）。虽然3个自噬相关基因位点之间或与rs2736340和rs10516487之间没有互作效应，但在logistic回归分析（P = 0.013; or = 1.205）、MDR （P < 0.0001）和线性回归分析（P = 0.0017; R-2 = 0.1806）中，BLK和BANK1的互作效应最为密切。rs2736340高危基因型TT与BLK信使RNA水平降低相关；SLE患者的BLK转录水平低于健康对照组。结论：我们证实了rss548234、rs2736340和rs10516487与中国汉族SLE的相关性，并强化了它们在SLE中调控b细胞信号传导的作用。
Aim: Autophagy-related gene 5 (ATG5), ATG7, B-lymphoid tyrosine kinase (BLK) and B-cell scaffold protein with ankyrin repeats 1 (BANK1) are involved in B-cell signaling; several genome-wide association studies detected these genes as candidates involved in systemic lupus erythematosus (SLE). We aimed to replicate the association of these genes with SLE in Chinese Han and to search for possible gene-gene interactions.Methods: TaqMan single-nucleotide polymorphism (SNP) genotyping was used to detect rs548234, rs665791 in ATG5, rs11706903 in ATG7, rs2736340 in BLK and rs10516487 in BANK1 in 382 SLE patients and 660 healthy controls. The epistasis effect was analyzed by logistic regression, multifactor dimensionality reduction (MDR) and linear regression analysis.Results: SLE was associated with frequency of rs548234 (P = 0.010; odds ratio [OR] = 1.298), rs2736340 (P = 2.47 x 10(-5); OR = 1.574) and rs10516487 (P = 0.002; OR = 0.642). Although no epistasis effects were found among three autophagy-related gene loci or with rs2736340 and rs10516487, BLK and BANK1 had the closest interaction effect on logistic regression analysis (P = 0.013; OR = 1.205), MDR (P < 0.0001), and linear regression analysis (P = 0.0017; R-2 = 0.1806). The risk genotype TT of rs2736340 was associated with decreased messenger RNA level of BLK; BLK transcript level was lower in SLE patients than healthy controls.Conclusion: We confirmed the association of rs548234, rs2736340 and rs10516487 with SLE in Chinese Han and reinforced our hypothesis of their epistasis effect in regulating B-cell signaling in SLE.