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CREM基因变体rs17583959使突尼斯家族患1型糖尿病的风险增加。

CREM variant rs17583959 conferred susceptibility to T1D risk in the Tunisian families.

作者信息

Zouidi Ferjani, Bouzid D, Fourati H, Fakhfakh R, Kammoun T, Hachicha M, Penha-Gonçalves C, Masmoudi H

机构信息

Immunology Department, Habib Bourguiba Hospital, University of Sfax, Tunisie.

Immunology Department, Habib Bourguiba Hospital, University of Sfax, Tunisie.

出版信息

Immunol Lett. 2017 Jan;181:1-5. doi: 10.1016/j.imlet.2016.11.007. Epub 2016 Nov 10.

Abstract

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease caused by the destruction of insulin-producing pancreatic β-cells by autoreactive T cells. Studies in animal models, such as the non-obese diabetic (NOD) mouse reveal that this disease is under the control of several genes that encode molecules implicated in regulation of transcription factors and in T cell activation. In order to underline the role of the genes involved in this regulation pathways, we investigated, using the Sequenom MassARRAY platform, 13 single-nucleotide polymorphisms (SNPs) belonging to CREM, IRF5, STAT4, and STAT5a/b genes in 59 T1D Tunisian families. In the current study, we identified an association with rs17583959 (allele G; Z score=2.27; p=0.02; Genotype GG: score=1.96; p=0.04) of CREM gene. In LD analysis a strong LD between the 3 CREM variants (Block 1) was detected; rs2384352 was in complete LD with rs1148247. When haplotypes were constructed between CREM polymorphisms (rs1148247, rs17583959, rs2384352), AGA haplotype (H2) was significantly over-transmitted from parents to affected offspring (Z score=2.988; P=0.002) and may confer a risk for T1D disease. Whereas, AAG haplotype (H5) (Z score=-2.000; p=0.045) was less transmitted than expected to affected children suggesting its protective effect against T1D pathology. No significant association in IRF5, STAT4, and STAT5a/b genes were observed. In conclusion, this study shows an eventually involvement of CREM gene in the development of T1D pathology in Tunisian families. These facts are consistent with a major role for transcription factor genes involved in the immune pathways in the control of autoimmunity. Further researches of association and functional analysis across populations are needed to confirm these findings.

摘要

1型糖尿病(T1D)是一种慢性自身免疫性疾病,由自身反应性T细胞破坏产生胰岛素的胰腺β细胞所致。对非肥胖糖尿病(NOD)小鼠等动物模型的研究表明,这种疾病受多个基因控制,这些基因编码参与转录因子调控和T细胞活化的分子。为了强调参与该调控途径的基因的作用,我们使用Sequenom MassARRAY平台,对59个突尼斯T1D家庭中属于CREM、IRF5、STAT4和STAT5a/b基因的13个单核苷酸多态性(SNP)进行了研究。在本研究中,我们发现CREM基因的rs17583959(等位基因G;Z值=2.27;p=0.02;基因型GG:得分=1.96;p=0.04)存在关联。在连锁不平衡(LD)分析中,检测到3个CREM变体(模块1)之间存在强LD;rs2384352与rs1148247完全连锁不平衡。当构建CREM多态性(rs1148247、rs17583959、rs2384352)之间的单倍型时,AGA单倍型(H2)从父母向受影响后代的传递显著过度(Z值=2.988;P=0.002),可能赋予T1D疾病风险。而AAG单倍型(H5)(Z值=-2.000;p=0.045)传递给受影响儿童的情况低于预期,表明其对T1D病理具有保护作用。在IRF5、STAT4和STAT5a/b基因中未观察到显著关联。总之,本研究表明CREM基因最终可能参与突尼斯家庭T1D病理的发生发展。这些事实与参与免疫途径的转录因子基因在自身免疫控制中的主要作用一致。需要在不同人群中进一步进行关联研究和功能分析以证实这些发现。

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