Genetic Study in a Large Cohort Supported Different Pathogenesis of Graves’ Disease and Hashimoto’s Hypothyroidism

Abstract

Context Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) are the 2 main autoimmune thyroid diseases that have both similarities and differences. Determining the genetic basis that distinguishes HT from GD is key for a better understanding of the differences between these closely related diseases. Objects To identify the susceptibility genes for HT in the Chinese cohort and compare susceptibility genes between GD and HT. Design In the current study, 18 SNPs from 18 established GD risk loci were selected and then genotyped in 2682 patients with HT, 4980 patients with GD, and 3892 controls. The association analysis between HT and controls and heterogeneity analysis between HT and GD were performed on SPSS, with the logistic regression analysis adjusted for sex and age. Results We identified 11 susceptibility loci for HT in the Chinese Han population, with 4 loci, including the rs1265883 in SLAMF6 locus, rs1024161 in CTLA4, rs1521 in HLA-B, and rs5912838 in GPR174/ ITM2A at X chromosome, reaching genome-wide significance of 5 × 10–8. Five loci were reported to be associated with HT for the first time. We also identified 6 susceptibility loci with heterogeneity between GD and HT. Out of them, 4 loci were associated with GD but not with HT, including HLA-DPB1, CD40, TSHR, and TG; the association of HLA-B with GD was stronger than that with HT, but the association of SLAMF6 was reversed. Conclusion Our findings suggested that the pathogenesis of HT and GD was different.

Precision Medicine in Graves’ Disease: CD40 Gene Variants Predict Clinical Response to an Anti-CD40 Monoclonal Antibody

“…Furthermore, we have shown that the GD risk allele (C) increased the expression of CD40 (23,36), and that increased expression of CD40 on thyroid cells was associated with targeting the autoimmune response to the thyroid in GD (37,38). The association of CD40 with GD has now been confirmed in many studies in different ethnic and geographic populations (39)(40)(41)(42)(43)(44)(45). Moreover, some studies have shown that CD40 polymorphisms can predict remission and relapse of GD (25,44).…”

Urinary Iodine and Genetic Predisposition to Hashimoto's Thyroiditis in a Chinese Han Population: A Case–Control Study

“…We selected and genotyped 13 HT-associated SNPs that reached the Bonferroni corrected significance p threshold calculated as 0.05 divided by the effective number of independent tests, based on our recent candidate-gene approach studies performed in Chinese Han population (30), with the largest number of samples to date. The detailed list of these SNPs is provided in Table 1.…”

“…The genotyping of these SNPs was performed in Fluidigm EP1 platform with the 192.24 Dynamic Array integrated fluidic circuit (Fluidigm Corp., South San 129 Francisco, CA) using fast TaqMan assays (Applied Biosystems, Foster City, CA) in accordance with the manufacturer's instructions. Stringent quality control criteria, as detailed previously (30,37), were used to select both individuals and genotyped SNPs for analysis. No linkage disequilibrium was found between the SNPs (r 2 < 0.8), and the concordance rate was more than 99% based on 100 duplicates genotyping.…”

“…When iodine-to-creatinine was further analyzed in the regression models using the same statistical methods as urinary iodine concentration, it demonstrated that the results of iodine-to-creatinine were in agreement with that of urinary iodine in our study (data not shown). A further limitation is that our GRSs captured the combined information from the 13 established HT associated loci that have been identified in Asians to date (30), but it contains only a small amount of variation in HT. Further genetic studies that might account for a significantly larger proportion of HT heritability are needed.…”

“…The considerable heritability of HT (about 75%) instigated extensive efforts to unravel its genetic background (22), but so far, the majority of HT-susceptible genes were based on candidate gene studies with relatively small sample sizes (23)(24)(25)(26)(27), leaving potential susceptibility gene variants still poorly understood (28,29). More recently, our group performed studies in the largest number of samples to date of Chinese Han ancestry (30) and identified or replicated 13 susceptibility loci for HT, providing valuable tools to examine the impact of gene-environment interaction on HT, especially in Chinese population. On the basis of this, in the current study, by constructing genetic risk scores (GRSs), which present the combined effect of 13 genetic variations, we conducted a case-control study to assess the association of urinary iodine as well as GRSs with HT risk and further to investigate whether the HT risk-related GRSs might modify the effects of urinary iodine on HT risk in a Chinese Han population aged 18 years or older.…”