The MAGI2 gene polymorphism rs2160322 is associated with Graves’ disease but not with Hashimoto’s thyroiditis
- 3 Downloads
Autoimmune thyroid diseases (AITDs) are chronic organ-specific autoimmune disorders, predominantly including Graves’ disease (GD), and Hashimoto’s thyroiditis (HT). This study aimed to investigate whether single-nucleotide polymorphisms (SNPs) in MAGI2 and MAGI3 gene contributed to the etiology of AITDs.
We conducted a case–control study including 1001 patients with AITDs (625 GD, 376 HT) and 846 healthy controls. Subgroup analyses in GD and HT were also performed.
The genotypes of rs2160322 in MAGI2 showed a borderline association with AITDs (P = 0.048), and they had a strong correlation with GD (P = 0.012). The frequency of the minor allele G of rs2160322 was significantly higher in the GD patients than in the controls (P = 0.027; OR 1.91; 95% CI 1.020–1.391), especially for GD females (P = 0.008; OR 1.304; 95% CI 1.072–1.587), and those who had positive family history (P = 0.011; OR 1.412; 95% CI 1.083–1.843). For genetic model analysis, the recessive model and homozygous model of rs2160322 showed significant associations with AITDs (P = 0.009; P = 0.019) and GD (P = 0.004; P = 0.005). Nevertheless, our study could not identify any relationship between these SNPs and HT. Due to the low mutation rate of rs1343126 in MAGI3, we were unable to obtain a credible conclusion on its association with AITDs.
Our study identified that MAGI2 rs2160322 was strongly associated with GD susceptibility. The potential dysfunction of tight junction proteins and aberrant epithelial barrier caused by abnormal MAGI2 expression may be a novel mechanism of GD.
KeywordsMAGI2 Single-nucleotide polymorphisms Autoimmune thyroid diseases Graves’ disease Hashimoto’s thyroiditis
The present work was supported by grants from the National Natural Science Foundation of China (nos. 81670722 and 81471004).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
The experiment was approved by the ethics committee of Jinshan Hospital of Fudan University.
Informed consent was signed in both the patient group and the control group. All subjects in this experiment were voluntary and did not receive any financial compensation.
- 5.Jabrocka-Hybel A, Skalniak A, Piatkowski J, Turek-Jabrocka R, Vyhouskaya P, Ludwig-Slomczynska A, Machlowska J, Kapusta P, Malecki M, Pach D, Trofimiuk-Muldner M, Lizis-Kolus K, Hubalewska-Dydejczyk A (2018) How much of the predisposition to Hashimoto’s thyroiditis can be explained based on previously reported associations? J Endocrinol Investig. https://doi.org/10.1007/s40618-018-0910-4 (Epub ahead of print) CrossRefGoogle Scholar
- 8.Tomer Y (2014) Mechanisms of autoimmune thyroid diseases: from genetics to epigenetics. Annu Rev Pathol 9:147–156. https://doi.org/10.1146/annurev-pathol-012513-104713 CrossRefGoogle Scholar
- 9.Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, Kuhn M, Bork P, Jensen LJ, von Mering C (2015) STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res 43(Database issue):D447–D452. https://doi.org/10.1093/nar/gku1003 CrossRefGoogle Scholar
- 13.Miyagawa H, Yamai M, Sakaguchi D, Kiyohara C, Tsukamoto H, Kimoto Y, Nakamura T, Lee JH, Tsai CY, Chiang BL, Shimoda T, Harada M, Tahira T, Hayashi K, Horiuchi T (2008) Association of polymorphisms in complement component C3 gene with susceptibility to systemic lupus erythematosus. Rheumatology 47(2):158–164. https://doi.org/10.1093/rheumatology/kem321 CrossRefGoogle Scholar
- 16.McGovern DP, Taylor KD, Landers C, Derkowski C, Dutridge D, Dubinsky M, Ippoliti A, Vasiliauskas E, Mei L, Mengesha E, King L, Pressman S, Targan SR, Rotter JI (2009) MAGI2 genetic variation and inflammatory bowel disease. Inflamm Bowel Dis 15(1):75–83. https://doi.org/10.1002/ibd.20611 CrossRefGoogle Scholar
- 24.Hirao K, Hata Y, Ide N, Takeuchi M, Irie M, Yao I, Deguchi M, Toyoda A, Sudhof TC, Takai Y (1998) A novel multiple PDZ domain-containing molecule interacting with N-methyl-d-aspartate receptors and neuronal cell adhesion proteins. J Biol Chem 273(33):21105–21110. https://doi.org/10.1074/jbc.273.33.21105 CrossRefGoogle Scholar
- 25.Ingham RJ, Colwill K, Howard C, Dettwiler S, Lim CS, Yu J, Hersi K, Raaijmakers J, Gish G, Mbamalu G, Taylor L, Yeung B, Vassilovski G, Amin M, Chen F, Matskova L, Winberg G, Ernberg I, Linding R, O’Donnell P, Starostine A, Keller W, Metalnikov P, Stark C, Pawson T (2005) WW domains provide a platform for the assembly of multiprotein networks. Mol Cell Biol 25(16):7092–7106. https://doi.org/10.1128/MCB.25.16.7092-7106.2005 CrossRefGoogle Scholar
- 27.Wu X, Hepner K, Castelino-Prabhu S, Do D, Kaye MB, Yuan XJ, Wood J, Ross C, Sawyers CL, Whang YE (2000) Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multi-PDZ domain containing scaffold protein MAGI-2. Proc Natl Acad Sci USA 97(8):4233–4238. https://doi.org/10.1073/pnas.97.8.4233 CrossRefGoogle Scholar
- 30.Antonelli A, Ferrari SM, Corrado A, Franceschini SS, Gelmini S, Ferrannini E, Fallahi P (2014) Extra-ocular muscle cells from patients with Graves’ ophthalmopathy secrete alpha (CXCL10) and beta (CCL2) chemokines under the influence of cytokines that are modulated by PPARgamma. Autoimmun Rev 13(11):1160–1166. https://doi.org/10.1016/j.autrev.2014.08.025 CrossRefGoogle Scholar
- 31.Nilsson M, Husmark J, Bjorkman U, Ericson LE (1998) Cytokines and thyroid epithelial integrity: interleukin-1alpha induces dissociation of the junctional complex and paracellular leakage in filter-cultured human thyrocytes. J Clin Endocrinol Metab 83(3):945–952. https://doi.org/10.1210/jcem.83.3.4626 CrossRefGoogle Scholar
- 32.Shirata N, Ihara KI, Yamamoto-Nonaka K, Seki T, Makino SI, Oliva Trejo JA, Miyake T, Yamada H, Campbell KN, Nakagawa T, Mori K, Yanagita M, Mundel P, Nishimori K, Asanuma K (2017) Glomerulosclerosis induced by deficiency of membrane-associated guanylate kinase inverted 2 in kidney podocytes. J Am Soc Nephrol JASN 28(9):2654–2669. https://doi.org/10.1681/ASN.2016121356 CrossRefGoogle Scholar
- 33.Li X, Li Z, Li N, Qi J, Fan K, Yin P, Zhao C, Liu Y, Yao W, Cai X, Wang L, Zha X (2013) MAGI2 enhances the sensitivity of BEL-7404 human hepatocellular carcinoma cells to staurosporine-induced apoptosis by increasing PTEN stability. Int J Mol Med 32(2):439–447. https://doi.org/10.3892/ijmm.2013.1411 CrossRefGoogle Scholar
- 35.Larson SD, Jackson LN, Riall TS, Uchida T, Thomas RP, Qiu S, Evers BM (2007) Increased incidence of well-differentiated thyroid cancer associated with Hashimoto thyroiditis and the role of the PI3k/Akt pathway. J Am Coll Surg 204(5):764–773. https://doi.org/10.1016/j.jamcollsurg.2006.12.037 CrossRefGoogle Scholar
- 36.Guaraldi F, Di Nardo G, Tarani L, Bertelli L, Susca FC, Bagnulo R, Resta N (2017) Association of autoimmune thyroiditis and celiac disease with juvenile polyposis due to 10q23.1q23.31 deletion: Potential role of PI3K/Akt pathway dysregulation. Eur J Med Genet 60(7):380–384. https://doi.org/10.1016/j.ejmg.2017.04.010 CrossRefGoogle Scholar
- 37.Grossman L, Chang C, Dai J, Nikitin PA, Jima DD, Dave SS, Luftig MA (2017) Epstein-Barr virus induces adhesion receptor CD226 (DNAM-1) expression during primary B-cell transformation into lymphoblastoid cell lines. mSphere 2(6):115–123. https://doi.org/10.1128/msphere.00305-17 CrossRefGoogle Scholar