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Itm2aexpands Evidence for Genetic and Environmental Interaction In CLINICAL RESEARCH ARTICLE ITM2A Expands Evidence for Genetic and Environmental Interaction in Graves Disease Pathogenesis Xiao-Ping Ye,1,2* Fei-Fei Yuan,1,2* Le-Le Zhang,2* Yu-Ru Ma,2 Man-Man Zhang,2 Wei Liu,2 Feng Sun,2 Jing Wu,2 Meng Lu,2 Li-Qiong Xue,2 Jing-Yi Shi,1 Shuang-Xia Zhao,2 Huai-Dong Song,1,2 Jun Liang3,4 and Cui-Xia Zheng,2 for The China Consortium for the Genetics of Autoimmune Thyroid Disease Downloaded from https://academic.oup.com/jcem/article/102/2/652/2972067 by guest on 27 September 2021 1State Key Laboratory of Medical Genomics, Shanghai Institute of Endocrinology and Metabolism, Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200025, China; 2Research Center for Clinical Medicine, Department of Respiration and Endocrinology, The Ninth People’s Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200011, China; 3Department of Endocrinology, The Central Hospital of Xuzhou Affiliated to Xuzhou Medical College, Xuzhou, Jiangsu Province 221109, China; and 4Xuzhou Clinical School of Xuzhou Medical College, The Affiliated XuZhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu Province 221009, China Context: Graves disease (GD) is a common autoimmune disease triggered by genetic predisposition and environmental factors. However, the mechanisms of interaction between genetic and envi- ronmental factors contributing to the development of GD remain unknown. Objective: We aimed to identify GD susceptibility variants and genes on Xq21.1 locus and interpret the contribution of interaction between genetic predisposition on Xq21.1 and environmental factors to GD. Design: We performed refining study on Xq21.1 in a 2-stage study and carried out expression quantitative trait locus analysis of the best association signal with GD. Setting and Participants: A total of 4316 GD patients and 4374 sex-matched controls were collected from the Chinese Han population by cooperation with multiple hospitals. Results: We identified that rs3827440 or its linkage single nucleotide polymorphisms (SNPs) were probably the causal variant in the Xq21.1 locus, with the most substantial association with GD in our 2 combined cohorts (P = 2.45 3 10 15). The genotypes of rs3827440 were correlated with the ex- pression of ITM2A in monocytes and peripheral blood mononuclear cells (PBMCs) from healthy volunteers. Notably, the expression of ITM2A in monocytes after lipopolysaccharide (LPS) and interferon-g (INF-g) stimulation showed substantial difference among the volunteers that carried different genotypes of rs3827440 (P = 9.40 3 1027 and P = 1.26 3 1025 for 24 hours’ LPS and INF-g stimulation, respectively). Moreover, ITM2A expression was significantly decreased in PBMCs from untreated GD patients than that from controls. Conclusion: The results suggest that ITM2A might be a susceptibility gene for GD in the Xq21.1 locus, and environmental factors, such as viral and bacterial infections, probably contribute to GD pathogenesis by interacting with the risk SNP rs3827440 mediating the regulation of ITM2A expression. (J Clin Endocrinol Metab 102: 652–660, 2017) ISSN Print 0021-972X ISSN Online 1945-7197 *These authors contributed equally to this study. Printed in USA Abbreviations: CI, confidence interval; CT, cycle threshold; EBV, Epstein-Barr virus; eQTL, Copyright © 2017 by the Endocrine Society expression quantitative trait locus; eSNP, expression SNP; GD, Graves disease; GWAS, Received 9 July 2016. Accepted 24 October 2016. genome-wide association study; HCV, hepatitis C virus; IFN, interferon; LPS, lipopoly- First Published Online 3 November 2016 saccharide; OR, odds ratio; PBMC, peripheral blood mononuclear cell; PCR, polymerase chain reaction; SNP, single nucleotide polymorphism; TSHR, thyroid-stimulating hormone receptor; Th, T-helper; YE, Yersinia enterocolitica. 652 press.endocrine.org/journal/jcem J Clin Endocrinol Metab, February 2017, 102(2):652–660 doi: 10.1210/jc.2016-2625 doi: 10.1210/jc.2016-2625 press.endocrine.org/journal/jcem 653 raves disease (GD) is a common and complex au- found many gene expressions and their responses to LPS Gtoimmune disease caused by interaction of genetic or IFN-g stimulation showed substantial difference factors and environmental triggers (1). The prevalence of among subjects carrying different SNP genotypes (cis- GD in the Chinese Han population is approximately expression quantitative trait locus [cis-eQTL] genes) (17). 0.25% to 1.0% with a strong female preponderance, The identification of functional regulatory variants and consistent with that of many other autoimmune diseases associated modulated genes is key to interpreting GWAS (2,3). However, the reason that GD is more prevalent findings and establishing how genes are associated with among women is unknown. A reasonable explanation disease (18). The levels of LPS and IFN-g are increased in is that genes located on the X-chromosome may be humans when infected by bacteria or viruses; therefore, contributed to the development of GD. Studies have those findings by Fairfax et al. laid the foundation for reported that the Xp11 region is associated with auto- our investigation into the role of interaction between Downloaded from https://academic.oup.com/jcem/article/102/2/652/2972067 by guest on 27 September 2021 immune thyroid disease in the United Kingdom pop- genetic and environmental factors, such as infections, in ulation and that transcription levels of the forkhead the pathogenesis of GD. box P3 gene (FOXP3) in Xp11 are associated with In the current study, we performed refining study on susceptibility to autoimmune thyroid disease in the Cau- Xq21.1 in a large-scale sample of cohorts including 4316 casians but not in the Japanese and Chinese Han pop- GD patients and 4374 controls and identified rs3827440 215 ulations (4–6). (PCombined =2.453 10 ) was the best SNP associated In our previous genome-wide association study (GWAS), with GD on Xq21.1. Interestingly, the levels of ITM2A we confirmed 4 GD-associated loci previously reported and expression in monocytes after either LPS or IFN-g stimu- identified 2 susceptibility loci in the Chinese Han pop- lation showed substantial difference among the individuals ulation (7). Another extension of this study identified 5 GD who carried distinct genotypes of rs3827440. Moreover, risk loci (8). In the extension study, rs5912838, located the transcription levels of ITM2A in peripheral blood between the immune receptor G protein–coupled receptor mononuclear cells (PBMCs) were down-regulated in un- 174 gene (GPR174) and integral membrane protein 2A treated GD patients when compared with those of controls. gene (ITM2A), was identified as an important association These findings suggest that environmental triggers, such signal on Xq21.1 in the Chinese Han population. ITM2A, as infection, indicated by LPS or IFN-g stimulation, prob- but not GPR174, escaping X-chromosome inactivation, ably contribute to the development of GD by interacting was arbitrarily considered a susceptibility gene for GD (8). with risk variant rs3827440, mediating the regulation of Moreover, rs3827440, a nonsynonymous single nucleotide ITM2A expression. polymorphism (SNP) in GPR174 highly linked with rs5912838 on Xq21.1, has been identified associated with Materials and Methods GD in 2 independent studies. One was performed in a Caucasian population and the other was in another group Subjects and sample collection of the Chinese Han population (9,10); moreover, rs3827440 All subjects in the current study were from the Chinese Han was also found to be associated with autoimmune Addison population by cooperation with multiple hospitals in China disease in a UK cohort (11). Therefore, the Xq21.1 region (19). This program was approved by the local institutional review board. As previously reported, 1536 patients with GD was considered a susceptibility locus to GD, but the sus- and 1516 sex-matched controls were recruited in the initial ceptibility of SNPs or genes in this region is controversial. GWAS stage (7). Next, an additional 2874 GD patients and Infections by Yersinia enterocolitica (YE), hepatitis 2906 sex-matched controls were collected for the replication C virus (HCV), and Epstein-Barr virus (EBV) have been study. Diagnosis of GD was based on the principles previously frequently cited as major environmental triggers of GD reported (7). Genomic DNA of all subjects was extracted from (12–16). However, many of the individuals infected by YE, peripheral blood leukocytes by using FUJIFILM QuickGene- 610 system (Kurabo Biomedical, Tokyo, Japan). HCV, or EBV were not suffering from GD; this may be explained by their interaction with different genetic pre- Genotyping and quality control dispositions. Although the interaction between genetic GWAS was performed by Illumina Human660-Quad Bead predisposition and environmental factors contributed to Chips in the Chinese National Human Genome Center the pathogenesis of GD, the evidence supporting the (Shanghai, China). We then obtained the imputed SNPs by hypothesis was scarce. performing imputation analysis on IMPUTE2 based on the Most recently, Fairfax et al. investigated correlation 1000 Genomes Project (June 2011) (20). All of the genotyped and imputed SNPs were filtered by stringent quality control. of SNP genotypes in the whole genome with the levels 2 SNPs with a Hardy-Weinberg equilibrium P . 1 3 10 6 and of gene transcription in monocytes recruited from 432 missing call rates #0.05 and minor allele
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