PLoS ONE (Jan 2013)

A refined study of FCRL genes from a genome-wide association study for Graves' disease.

  • Shuang-Xia Zhao,
  • Wei Liu,
  • Ming Zhan,
  • Zhi-Yi Song,
  • Shao-Ying Yang,
  • Li-Qiong Xue,
  • Chun-Ming Pan,
  • Zhao-Hui Gu,
  • Bing-Li Liu,
  • Hai-Ning Wang,
  • Liming Liang,
  • Jun Liang,
  • Xiao-Mei Zhang,
  • Guo-Yue Yuan,
  • Chang-Gui Li,
  • Ming-Dao Chen,
  • Jia-Lun Chen,
  • Guan-Qi Gao,
  • Huai-Dong Song,
  • China Consortium for the Genetics of Autoimmune Thyroid Disease

DOI
https://doi.org/10.1371/journal.pone.0057758
Journal volume & issue
Vol. 8, no. 3
p. e57758

Abstract

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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.