Associations of melatonin receptor gene polymorphisms with Graves

RESEARCH ARTICLE Associations of melatonin receptor gene polymorphisms with Graves’ disease Jiunn-Diann Lin1,2,3☯, Shun-Fa Yang4,5☯, Yuan-Hung Wang1,6, Wen-Fang Fang7, YingChin Lin7, Bing-Chun Liou1, Yuh-Feng Lin1,8, Kam-Tsun Tang9, Chao-Wen Cheng1* a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 1 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, 2 Division of Endocrinology, Department of Internal Medicine, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan, 3 Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, 4 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, 5 Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan, 6 Department of Medical Research, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan, 7 Department of Family Medicine, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan, 8 Division of Nephrology, Department of Internal Medicine, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan, 9 Division of Endocrinology and Metabolism, Department of Internal Medicine Taipei Veterans General Hospital, Taipei, Taiwan ☯ These authors contributed equally to this work. * OPEN ACCESS Citation: Lin J-D, Yang S-F, Wang Y-H, Fang W-F, Lin Y-C, Liou B-C, et al. (2017) Associations of melatonin receptor gene polymorphisms with Graves’ disease. PLoS ONE 12(9): e0185529. https://doi.org/10.1371/journal.pone.0185529 Abstract Editor: Obul Reddy Bandapalli, German Cancer Research Center (DKFZ), GERMANY Melatonin plays an important role in immunity and has been linked to autoimmune diseases. Possible associations of single-nucleotide polymorphisms (SNPs) of melatonin receptor type 1A (MTNR1A) and 1B (MTNR1B), with autoimmune thyroid disease in an ethnic Chinese (i.e., Taiwanese) population were examined. Received: April 13, 2017 Accepted: September 14, 2017 Published: September 29, 2017 Copyright: © 2017 Lin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This work was supported by a grant from the Ministry of Science and Technology of Taiwan (MOST 104-2314-B-038-048 and MOST 1062314-B-038-059) to Jiunn-Diann Lin, and was partly supported by a grant from Taipei Medical University and Shuang-Ho Hospital (104TMUSHH-09) to Chao-Wen Cheng. Competing interests: The authors have declared that no competing interests exist. Background Materials and methods Totally, 83 Hashimoto’s thyroiditis patients, 319 Graves’ disease (GD), and 369 controls were recruited. Three SNPs (rs6553010, rs13140012, and rs2119882) of MTNR1A and three SNPs (rs1387153, rs10830963, and rs1562444) of MTNR1B were genotyped. Results There were a reduced frequency of the C allele of rs2119882 and a reduced percentage of the CC+CT genotype in the GD group compared to the control group (p = 0.039, odds ratio (OR) = 0.79, 95% confidence interval (CI) = 0.63~0.99, and p = 0.032, OR = 0.72, 95% CI = 0.53~0.97, respectively). There was a significant difference in the percentage of the AT haplotype of the combination of rs13140012 and rs2119882 between the GD and control groups (p = 0.010, OR = 1.34, 95% CI = 1.07~1.67). In addition, there were significant associations of anti-thyroid peroxidase antibody titers with rs13140012 and rs2119882, and the AATT genotype of the combination of rs13140012 and rs2119882 (p = 0.003, 0.003, and 0.004, respectively). There were no significant associations of SNPs and possible haplotypes of MTNR1B with susceptibility to GD. PLOS ONE | https://doi.org/10.1371/journal.pone.0185529 September 29, 2017 1 / 14 Melatonin receptor in GD Abbreviations: AITD, autoimmune thyroid disease; anti-TPO Ab, anti-thyroid peroxidase antibody; ATA, anti-thyroglobulin antibody; GD, Graves’ disease; HT, Hashimoto’s thyroiditis; MTNR1A, melatonin receptor type 1A; MTNR1B, melatonin receptor type 1B; SNP, single-nucleotide polymorphism; T4, thyroxine; TPO, thyroid peroxide; TSH, thyroid-stimulating hormone; TSHRAb, thyroid-stimulating hormone receptor antibody. Conclusions Genetic variants of rs2119882 of MTNR1A and the AT haplotype of the combination of rs2119882 and rs13140012 were associated with GD susceptibility in an ethnic Chinese population. The results support the involvement of the melatonin pathway in the pathogenesis of GD. Introduction Melatonin exerts multiple biological functions, including promoting sleep, regulating circadian and seasonal rhythms, promoting anti-aging, antioxidation, anti-tumorigenesis, and antiapoptosis, eliminating free radicals, and controlling the onset of puberty [1,2,3,4]. In addition, evidence shows that melatonin plays a critical role in regulating both innate and adaptive immune responses and the balance of T-helper 1/T-helper 2 cytokines [5,6]. Melatonin deprivation and exogenous melatonin administration can induce immune dysregulation [7,8]. Moreover, melatonin is even considered to be the third signal triggering an immune response together with the human leukocyte antigen-processed antigen-T cell receptor and costimulatory molecule expressions [9]. Because of its strong immunoregulatory function, melatonin has been linked to several autoimmune diseases, including systemic lupus erythematosus, multiple sclerosis, type 1 diabetes mellitus, rheumatoid arthritis, and inflammatory bowel disease [10,11]. In humans, two major types of melatonin receptor (MTNR) genes, the MTNR1A gene, encoding MT1, and the MTNR1B gene, encoding MT2, were identified, and their genetic variants were linked to several diseases [12,13]. Genetic variants of MTNR1A were linked to tumor formation, coronary artery disease, scoliosis, etc. [14,15,16]. On the other hand, singlenucleotide polymorphisms (SNPs) of MTNR1B were reported to be associated with glucose intolerance, cardiovascular diseases, systemic lupus erythematosus, and rheumatoid arthritis [17,18]. It was also reported that melatonin can bind to MTNRs of immunocytes, control the downstream intracellular signaling pathway, and subsequently directly modulate immune reactions [19,20]. The potential association between melatonin and thyroid functions was described in previous studies. Lewinski et al. showed that melatonin can repress mitosis of thyroid follicular cells in vivo and in a cell culture system [21]. Wright et al. indicated that the administration of melatonin directly suppressed thyroid hormone secretion [22,23]. However, Gordon et al. demonstrated that there was no significant change in circulating thyroi (...truncated)