A Refined Study of <em>FCRL</em> Genes from a Genome-Wide Association Study for Graves’ Disease

<div><p>To pinpoint the exact location of the etiological variant/s present at 1q21.1 harboring <i>FCRL1-5</i> and <i>CD5L</i> genes, we carried out a refined association study in the entire <i>FCRL</i> 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 <i>P</i><0.05 in the initial GWAS scan, the strongest signals associated with GD and correlated to <i>FCRL3</i> expression were located at a cluster of SNPs including rs7528684 and rs3761959. And the allele-specific effects for rs3761959 and rs7528684 on <i>FCRL3</i> expression level revealed that the risk alleles A of rs3761959 and C of rs7528684 were correlated with the elevated expression level of <i>FCRL3</i> 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 <i>FCRL3</i> was a susceptibility gene of GD in Chinese Han populations, and rs3761959 and rs7528684 met the genome-wide association significance level (<i>P_combined</i> = 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 <i>FCRL3</i> 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.</p>