Association of LncRNA-GAS5 gene polymorphisms and PBMC LncRNA-GAS5 level with risk of systemic lupus erythematosus in Chinese population.
Association of LncRNA-GAS5 gene polymorphisms and PBMC LncRNA-GAS5 level with risk of systemic lupus erythematosus in Chinese population.
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DOI：
10.1111/jcmm.16438
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发表时间：
2021-04
影响因子：
5.3
通讯作者：
Lan Y
中科院分区：
文献类型：
--
作者：
Liu CH;Lu YL;Huang HT;Wang CF;Luo HC;Wei GJ;Lei M;Tan T;Wang Y;Huang YY;Wei YS;Lan Y
生长停滞特异性5（GAS 5）是一类长链非编码RNA（lncRNA）。先前的研究表明，LncRNA-GAS 5的下调参与了系统性红斑狼疮（SLE）的发展。然而，LncRNA-GAS 5在SLE中表达下调的调控机制仍不清楚。在这项研究中，我们的目的是研究LncRNA-GAS 5多态性与SLE风险的关系。并进一步探讨LncRNA-GAS 5如何参与SLE的发生。在这里，我们评估了发生SLE的风险与LncRNA-GAS 5启动子区5个碱基对（AGGCA/-）插入/缺失（I/D）多态性（rs 145204276）之间的关系。使用定制的36位SNP扫描试剂盒对LncRNA-GAS 5多态性进行基因分型。使用生物信息学软件进行LncRNA-GAS 5和miR-21靶标预测。采用酶联免疫吸附试验（ELISA）和定量真实的-时间PCR（qRT-PCR）评估GAS 5和miR-21 mRNA表达以及PTEN蛋白表达。结果表明，rs 145204276导致SLE风险降低（DD基因型vs II基因型：调整后OR = 0.538，95% CI，0.30 - 0.97，P = 0.039; ID基因型vs II基因型：调整后OR = 0.641，95% CI，0.46 - 0.89，P = 0.007; ID/DD基因型vs II基因型：调整后OR = 0.538，95% CI，0.30 - 0.97，P = 0.007）校正OR = 0.621，95% CI，0.46 - 0.84，P = 0.002; D等位基因vs I等位基因：校正OR = 0.680，95% CI，0.53 - 0.87，P = 0.002）。发现SLE中肾脏疾病的发生率降低与ID/DD基因型和D等位基因相关（ID/DD基因型vs II基因型：OR = 0.57，95% CI，0.36 - 0.92，P = 0.020; D等位基因vs I等位基因：OR = 0.63，95% CI，0.43 - 0.93，P = 0.019）。然而，未观察到rs 2235095、rs6790、rs 2067079和rs 1951625多态性与SLE风险的显著关联（P > 0.05）。此外，单倍型分析显示，A-A-C-G-D单倍型导致SLE风险降低（OR = 0.67，95% CI，0.49 - 0.91，P = 0.010）。此外，SLE组患者的LncRNA-GAS 5和PTEN表达较健康志愿者下调;然而，与携带II基因型的患者相比，携带rs 145204276 ID/DD基因型的患者的LncRNA-GAS 5和PTEN表达上调。此外，SLE组中miR-21水平显著高于健康志愿者，rs 145204276 ID/DD基因型患者的miR-21水平低于II基因型患者。因此，我们发现LncRNA-GAS 5/miR-21/PTEN信号通路参与了SLE的发生，其中LncRNA-GAS 5作为miR-21的靶点，而miR-21调节PTEN的表达。这些发现表明，LncRNA-GAS 5基因启动子区域的rs 145204276 ID/DD基因型可能通过上调LncRNA-GAS 5的表达而保护SLE，LncRNA-GAS 5连续调节miR-21和PTEN水平。
Growth arrest‐specific 5 (GAS5) is a kind of long non‐coding RNAs (lncRNAs). Previous studies showed that down‐regulation of LncRNA‐GAS5 was involved in the development of systemic lupus erythematosus (SLE). However, the regulatory mechanism of down‐expressed LncRNA‐GAS5 in SLE remains obscure. In this study, we aimed to investigate the association of LncRNA‐GAS5 polymorphism with SLE risk. And further explore how LncRNA‐GAS5 is involved in the occurrence of SLE. Here, we evaluated the relationship between the risk for the development of SLE and the 5‐base pair (AGGCA/‐) insertion/deletion (I/D) polymorphism (rs145204276) in the LncRNA‐GAS5 promoter region. A custom 36‐Plex SNPscan kit was used for genotyping the LncRNA‐GAS5 polymorphisms. The LncRNA‐GAS5 and miR‐21 target prediction was performed using bioinformatics software. Enzyme‐linked immunosorbent assay (ELISA) and quantitative real‐time PCR (qRT‐PCR) were performed to assess GAS5 and miR‐21 mRNA expression and PTEN protein expression. The results revealed that rs145204276 resulted in a decreased risk of SLE (DD genotypes vs II genotypes: adjusted OR = 0.538, 95% CI, 0.30‐0.97, P = .039; ID genotypes vs II genotypes: adjusted OR = 0.641, 95% CI, 0.46‐0.89, P = .007; ID/DD genotypes vs II genotypes: adjusted OR = 0.621, 95% CI, 0.46‐0.84, P = .002; D alleles vs I alleles: adjusted OR = 0.680, 95% CI, 0.53‐0.87, P = .002). A reduced incidence of renal disorders in SLE was found to be related to ID/DD genotypes and D alleles (ID/DD genotypes vs II genotypes: OR = 0.57, 95% CI, 0.36‐0.92, P = .020; D alleles vs I alleles: OR = 0.63, 95% CI, 0.43‐0.93, P = .019). However, no significant association of rs2235095, rs6790, rs2067079 and rs1951625 polymorphisms with SLE risk was observed (P > .05). Additionally, haplotype analysis showed that a decreased SLE risk resulted from the A‐A‐C‐G‐D haplotype (OR = 0.67, 95% CI, 0.49‐0.91, P = .010). Also, patients in the SLE group showed a down‐regulated expression of LncRNA‐GAS5 and PTEN than the healthy volunteers; however, patients with rs145204276 ID/DD genotypes showed up‐regulated expression of LncRNA‐GAS5 and PTEN compared with patients carrying the II genotype. Furthermore, the miR‐21 levels were considerably up‐regulated in the SLE group than the healthy volunteers, and patients with rs145204276 ID/DD genotype had lower miR‐21 levels than the ones with the II genotype. Thus, we found that the LncRNA‐GAS5/miR‐21/PTEN signalling pathway was involved in the development of SLE, where LncRNA‐GAS5 acted as an miR‐21 target, and miR‐21 regulated the expression of PTEN. These findings indicated that the rs145204276 ID/DD genotypes in the LncRNA‐GAS5 gene promoter region may be protected against SLE by up‐regulating the expression of LncRNA‐GAS5, which consecutively regulated miR‐21 and PTEN levels.
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影响因子：
11.1
作者：
Bonasio R;Shiekhattar R
通讯作者：
Shiekhattar R
DOI：
10.15403/jgld.2014.1121.271.qjl
发表时间：
2018-03-01
影响因子：
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作者：
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通讯作者：
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影响因子：
4.2
作者：
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通讯作者：
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