title: A refined study of FCRL genes from a genome-wide association study for Graves' disease.
abstract: To 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.
authors.affiliation: State Key Laboratory of Medical Genomics, Molecular Medicine Center, Ruijin Hospital Affiliated to Shanghai Jiaotong University (SJTU) School of Medicine, Shanghai, China.
authors.forename: Shuang-Xia
authors.initials: SX
authors.lastname: Zhao
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Ming
authors.initials: M
authors.lastname: Zhan
authors.forename: Zhi-Yi
authors.initials: ZY
authors.lastname: Song
authors.forename: Shao-Ying
authors.initials: SY
authors.lastname: Yang
authors.forename: Li-Qiong
authors.initials: LQ
authors.lastname: Xue
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Pan
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Gu
authors.forename: Bing-Li
authors.initials: BL
authors.lastname: Liu
authors.forename: Hai-Ning
authors.initials: HN
authors.lastname: Wang
authors.forename: Liming
authors.initials: L
authors.lastname: Liang
authors.forename: Jun
authors.initials: J
authors.lastname: Liang
authors.forename: Xiao-Mei
authors.initials: XM
authors.lastname: Zhang
authors.forename: Guo-Yue
authors.initials: GY
authors.lastname: Yuan
authors.forename: Chang-Gui
authors.initials: CG
authors.lastname: Li
authors.forename: Ming-Dao
authors.initials: MD
authors.lastname: Chen
authors.forename: Jia-Lun
authors.initials: JL
authors.lastname: Chen
authors.forename: Guan-Qi
authors.initials: GQ
authors.lastname: Gao
authors.forename: Huai-Dong
authors.initials: HD
authors.lastname: Song
mesh_terms: D002878:Chromosomes, Human, Pair 1; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006111:Graves Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D011961:Receptors, Fc / Q000235:genetics*
chemical_list: C452186:FCRLA protein, human; D011961:Receptors, Fc