Association Analysis of Polymorphisms in IL-3, IL-4, IL-5, IL-9, and IL-13 with Graves' Disease

Overview

Journal J Endocrinol Invest

Publisher Springer

Specialty Endocrinology

Date 2010 Mar 25

PMID 20332709

Citations 16

Authors

W Zhu

N Liu

Y Zhao

H Jia

B Cui

G Ning

Affiliations

Soon will be listed here.

Abstract

Background: Graves' disease (GD) is a common autoimmune disorder with genetic predisposition. There is strong evidence that the Chr.5q31-33 region, which contains the immune response cytokine genes [interleukin (IL)-3, IL-4, IL-5, IL-9, and IL-13], is linked to autoimmune thyroid disorders in Chinese and Japanese populations. The aim of the present study is to elucidate whether the single nucleotide polymorphisms (SNP) and the interaction of variants in the 5 genes are associated with the development of GD and Graves' ophthalmopathy (GO).

Materials And Methods: GD patients (no.=751), with 190 of GO patients and healthy control subjects (no.=748) were included in this study. Six SNP [rs40401 (IL-3), rs2070874 (IL-4), rs2069812 (IL-5), rs1859430 (IL-9), rs2069868 (IL-9), and rs20541 (IL-13)] were genotyped by SNPstream Genotyping System.

Results: There was a significant increase of C allele of rs40401 in GD [odds ratio (OR)=1.18 [95% confidence interval (CI): 1.02-1.36], pallele=0.028] and GO [OR=1.30 (95%CI: 1.04-1.63), pallele=0.022] patients compared with those in the controls. The C allele of the rs2069812 was also significantly associated with GD [OR=1.22 (95%CI: 1.04-1.44), pallele=0.015] and GO [OR=1.45 (95%CI: 1.13-1.86), pallele=0.003] patients. Haplotype analysis showed a predominant increase of the 2 SNP (rs40401-rs2069812, CC) and all the 6 SNP (CCCCCC) haplotype in GD (OR=1.70, OR=3.70, respectively) and even stronger in GO (OR=2.18, OR=7.01, respectively) patients.

Conclusions: The results suggested that the polymorphism of IL-3 (rs40401) and IL-5 (rs2069812) were associated with GD and GO susceptibility in Chinese population. The interaction of 6-locus from the 5 genes might confer higher risk for GD and GO than single risk allele.

Citing Articles

An IL-5 Single-Nucleotide Polymorphism Influences Neuroinflammation and Prospective Disease Activity in Multiple Sclerosis.

Dolcetti E, Buttari F, Bruno A, Azzolini F, Gilio L, Borrelli A Int J Mol Sci. 2024; 25(16).

PMID: 39201794 PMC: 11354457. DOI: 10.3390/ijms25169108.

Increased interleukin-9 and Th9 cells in patients with refractory Graves' disease and interleukin-9 polymorphisms are associated with autoimmune thyroid diseases.

Yao Q, Song Z, Wang B, Du P, Qin Q, Zhao J Front Immunol. 2024; 15:1341749.

PMID: 38605942 PMC: 11007129. DOI: 10.3389/fimmu.2024.1341749.

Th2 Cytokines (Interleukin-5 and -9) Polymorphism Affects the Response to Anti-TNF Treatment in Polish Patients with Ankylosing Spondylitis.

Bialy S, Iwaszko M, Swierkot J, Bugaj B, Kolossa K, Jeka S Int J Mol Sci. 2022; 23(21).

PMID: 36361964 PMC: 9657232. DOI: 10.3390/ijms232113177.

The risk factors for Graves' ophthalmopathy.

Cao J, Su Y, Chen Z, Ma C, Xiong W Graefes Arch Clin Exp Ophthalmol. 2021; 260(4):1043-1054.

PMID: 34787691 DOI: 10.1007/s00417-021-05456-x.

and Single-Nucleotide Variants and Serum Levels in Age-Related Macular Degeneration in the Caucasian Population.

Vilkeviciute A, Cebatoriene D, Kriauciuniene L, Zemaitiene R, Liutkeviciene R Mediators Inflamm. 2021; 2021:6622934.

PMID: 33953642 PMC: 8057879. DOI: 10.1155/2021/6622934.

References

Brix T, Kyvik K, Hegedus L . A population-based study of chronic autoimmune hypothyroidism in Danish twins. J Clin Endocrinol Metab. 2000; 85(2):536-9. DOI: 10.1210/jcem.85.2.6385. View

Ueda H, Howson J, Esposito L, Heward J, Snook H, Chamberlain G . Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature. 2003; 423(6939):506-11. DOI: 10.1038/nature01621. View

Vaidya B, Kendall-Taylor P, Pearce S . The genetics of autoimmune thyroid disease. J Clin Endocrinol Metab. 2002; 87(12):5385-97. DOI: 10.1210/jc.2002-020492. View

Nagayama Y, Mizuguchi H, Hayakawa T, Niwa M, McLachlan S, Rapoport B . Prevention of autoantibody-mediated Graves'-like hyperthyroidism in mice with IL-4, a Th2 cytokine. J Immunol. 2003; 170(7):3522-7. DOI: 10.4049/jimmunol.170.7.3522. View

Zeitlin A, Heward J, Newby P, Carr-Smith J, Franklyn J, Gough S . Analysis of HLA class II genes in Hashimoto's thyroiditis reveals differences compared to Graves' disease. Genes Immun. 2008; 9(4):358-63. DOI: 10.1038/gene.2008.26. View

Ellis M, Zhao Z, Chen H, Montgomery G, Li Y, McManus D . Analysis of the 5q31 33 locus shows an association between single nucleotide polymorphism variants in the IL-5 gene and symptomatic infection with the human blood fluke, Schistosoma japonicum. J Immunol. 2007; 179(12):8366-71. PMC: 2757302. DOI: 10.4049/jimmunol.179.12.8366. View

Hiromatsu Y, Fukutani T, Ichimura M, Mukai T, Kaku H, Nakayama H . Interleukin-13 gene polymorphisms confer the susceptibility of Japanese populations to Graves' disease. J Clin Endocrinol Metab. 2004; 90(1):296-301. DOI: 10.1210/jc.2004-0931. View

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira M, Bender D . PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007; 81(3):559-75. PMC: 1950838. DOI: 10.1086/519795. View

Chen R, Chang C, Wang T, Chen C, Tsai C, Tsai F . Lack of association between interleukin-4 gene polymorphisms and autoimmune thyroid diseases amongst Taiwanese Chinese. Endocrine. 2007; 32(2):170-4. DOI: 10.1007/s12020-007-9027-9. View

10.

Meller J, Jauho A, Hufner M, Gratz S, Becker W . Disseminated thyroid autonomy or Graves' disease: reevaluation by a second generation TSH receptor antibody assay. Thyroid. 2001; 10(12):1073-9. DOI: 10.1089/thy.2000.10.1073. View

11.

Song H, Liang J, Shi J, Zhao S, Liu Z, Zhao J . Functional SNPs in the SCGB3A2 promoter are associated with susceptibility to Graves' disease. Hum Mol Genet. 2009; 18(6):1156-70. DOI: 10.1093/hmg/ddn442. View

12.

Park B, Kim L, Choi Y, Lee J, Rhim T, Lee Y . Interleukin 3 (IL3) polymorphisms associated with decreased risk of asthma and atopy. J Hum Genet. 2004; 49(10):517-527. DOI: 10.1007/s10038-004-0184-x. View

13.

Chu X, Dong C, Lei R, Sun L, Wang Z, Dong Y . Polymorphisms in the interleukin 3 gene show strong association with susceptibility to Graves' disease in Chinese population. Genes Immun. 2009; 10(3):260-6. DOI: 10.1038/gene.2009.3. View

14.

Tomer Y, Concepcion E, Greenberg D . A C/T single-nucleotide polymorphism in the region of the CD40 gene is associated with Graves' disease. Thyroid. 2003; 12(12):1129-35. DOI: 10.1089/105072502321085234. View

15.

Taylor J, Gough S, Hunt P, Brix T, Chatterjee K, Connell J . A genome-wide screen in 1119 relative pairs with autoimmune thyroid disease. J Clin Endocrinol Metab. 2005; 91(2):646-53. DOI: 10.1210/jc.2005-0686. View

16.

Jin Y, Teng W, Ben S, Xiong X, Zhang J, Xu S . Genome-wide scan of Graves' disease: evidence for linkage on chromosome 5q31 in Chinese Han pedigrees. J Clin Endocrinol Metab. 2003; 88(4):1798-803. DOI: 10.1210/jc.2001-011980. View

17.

Simmonds M, Howson J, Heward J, Cordell H, Foxall H, Carr-Smith J . Regression mapping of association between the human leukocyte antigen region and Graves disease. Am J Hum Genet. 2004; 76(1):157-63. PMC: 1196419. DOI: 10.1086/426947. View

18.

Phenekos C, Vryonidou A, Gritzapis A, Baxevanis C, Goula M, Papamichail M . Th1 and Th2 serum cytokine profiles characterize patients with Hashimoto's thyroiditis (Th1) and Graves' disease (Th2). Neuroimmunomodulation. 2004; 11(4):209-13. DOI: 10.1159/000078438. View

19.

Sakai K, Shirasawa S, Ishikawa N, Ito K, Tamai H, Kuma K . Identification of susceptibility loci for autoimmune thyroid disease to 5q31-q33 and Hashimoto's thyroiditis to 8q23-q24 by multipoint affected sib-pair linkage analysis in Japanese. Hum Mol Genet. 2001; 10(13):1379-86. DOI: 10.1093/hmg/10.13.1379. View

20.

Chen B, Tsui S, Boeglin W, Douglas R, Brash A, Smith T . Interleukin-4 induces 15-lipoxygenase-1 expression in human orbital fibroblasts from patients with Graves disease. Evidence for anatomic site-selective actions of Th2 cytokines. J Biol Chem. 2006; 281(27):18296-306. DOI: 10.1074/jbc.M603484200. View