Background: Hashimoto thyroiditis (HT) and Graves' disease (GD) share some immunological features. Determining the genetic basis that distinguishes HT from GD is key for a better understanding of the differences between these two related diseases. Aim: The aim of this study was to identify a non-HLA susceptibility locus that is specific to either HT or GD. Design: We performed a two-stage genome-wide comparison between HT and GD in Japan. During the discovery stage, we performed a logistic regression analysis adjusting for sex using 727 413 single nucleotide polymorphisms (SNPs) for 265 HT and 261 GD patients. During the replication stage, 35 SNPs were analyzed for 181 HT and 286 GD cases. A combined meta-analysis was performed using the results from these two stages. An SNP showing a genome-wide significant level was further analyzed using 1363 healthy controls to determine the specificity of susceptibility. Results: A genome-wide direct comparison between HT and GD revealed an SNP at the VAV3 locus with genome-wide significant association signals (rs7537605: Pcombined = 3.90 × 10-8; odds ratiocombined = 1.77; 95% confidence interval = 1.44-2.17). An association analysis using healthy controls showed that rs7537605 is significantly associated with HT (P = 1.24 × 10-5; odds ratio = 1.60; 95% confidence interval = 1.30-1.97) but not with GD (P = .50), suggesting that the variant specifically affects susceptibility to HT. Conclusion: A genome-wide direct comparison between HT and GD revealed an HT-specific variant within VAV3 in the Japanese. Considering physiological roles of VAV3, such as a guanine nucleotide exchange factor, our finding provides new insight into the molecular mechanism of HT.
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