Zhao, Shuang-XiaLiu, WeiZhan, MingSong, Zhi-YiYang, Shao-YingXue, Li-QiongPan, Chun-MingGu, Zhao-HuiLiu, Bing-LiWang, Hai-NingLiang, LimingLiang, JunZhang, Xiao-MeiYuan, Guo-YueLi, Chang-GuiChen, Ming-DaoChen, Jia-LunGao, Guan-QiSong, Huai-Dong2013-05-082013Zhao, Shuang-Xia, Wei Liu, Ming Zhan, Zhi-Yi Song, Shao-Ying Yang, Li-Qiong Xue, Chun-Ming Pan, et al. 2013. A refined study of FCRL genes from a genome-wide association study for Graves’ disease. PLoS ONE 8(3): e57758.1932-6203http://nrs.harvard.edu/urn-3:HUL.InstRepos:10612885To pinpoint the exact location of the etiological variant/s present at 1q21.1 harboring FCRL1-5 and CD5L genes, we carried out a refined association study in the entire FCRL region in 1,536 patients with Graves’ disease (GD) and 1,516 sex-matched controls by imputation analysis, logistic regression, and cis-eQTL analysis. Among 516 SNPs with P<0.05 in the initial GWAS scan, the strongest signals associated with GD and correlated to FCRL3 expression were located at a cluster of SNPs including rs7528684 and rs3761959. And the allele-specific effects for rs3761959 and rs7528684 on FCRL3 expression level revealed that the risk alleles A of rs3761959 and C of rs7528684 were correlated with the elevated expression level of FCRL3 whether in PBMCs or its subsets, especially in \(CD19^+\) B cells and \(CD8^+\) T subsets. Next, the combined analysis with 5,300 GD cases and 4,916 control individuals confirmed FCRL3 was a susceptibility gene of GD in Chinese Han populations, and rs3761959 and rs7528684 met the genome-wide association significance level (\(P_{combined}\) = 2.27×\(10^{−12}\) and 7.11×\(10^{−13}\), respectively). Moreover, the haplotypes with the risk allele A of rs3761959 and risk allele C of rs7528684 were associated with GD risk. Finally, our epigenetic analysis suggested the disease-associated C allele of rs7528684 increased affinity for NF-KB transcription factor. Above data indicated that FCRL3 gene and its proxy SNP rs7528684 may be involved in the pathogenesis of GD by excessive inhibiting B cell receptor signaling and the impairment of suppressing function of Tregs.en-USBiologyGeneticsHuman GeneticsGenetic Association StudiesGenetics of DiseaseMolecular GeneticsGenomicsGenome Expression AnalysisImmunologyImmune CellsB CellsMonocytesT CellsAutoimmunityMedicineEndocrinologyThyroidGraves' DiseaseJournal Article2013-05-0810.1371/journal.pone.0057758