Robust evidence for five new Graves' disease risk loci from a staged genome-wide association analysis

Yang

European Journal of Endocrinology

et al. 2014

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Background: Convincing evidence has demonstrated the association of TSH receptor (TSHR) with Graves' disease (GD) in the Chinese Han population. Objective: The aim of this study was to identify the causal variants for GD in the region encompassing TSHR by a refining association study. Design and methods: GD patients (1536) and 1516 sex-matched controls were recruited in the first stage, and an additional 3832 GD patients and 3426 sex-matched controls were recruited in the replication stage. Genotyping was performed using Illumina Human660-Quad BeadChips or TaqMan single nucleotide polymorphism (SNP) Genotyping Assays and the Fluidigm EP1 platform. Results: When the results of regression analysis for 74 genotyped SNPs and 922 imputed SNPs in the first-stage cohort were combined, rs179243 and rs3783949 were the probable susceptibility SNPs associated with GD in TSHR. Eleven SNPs, including rs179243 and rs3783949, were selected to further refine the association in the replication study. Finally, rs12101261 and rs179243 were confirmed as independent GD susceptibility variants in the replication and combined populations. Further, we also found that the rate of persistent TSHR autoantibody positivity (pTRAbC) was significantly higher in the GD patients with the susceptible genotypes rs12101261 or rs179243 than in the GD patients carrying the protective genotypes, after the GD patients had been treated for more than 1 year. Conclusions: These findings indicate that rs12101261 and rs179243 are the possible causal SNPs for GD susceptibility in the TSHR gene and could serve as genetic markers to predict the outcome of pTRAbC in GD patients.

Section: Introductionsupporting

confidence: 67%

Section: Samples and Clinical Characteristicsmentioning

confidence: 99%

Section: Samples and Clinical Characteristicsmentioning

confidence: 99%

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Refined association of TSH receptor susceptibility locus to Graves' disease in the Chinese Han population

Yang

European Journal of Endocrinology

et al. 2014

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“…The residue was column-chromatographed (n-hexane/ ethyl acetate/Et 3 N = 35:4:1) to yield 17 (704.1 mg, 1.516 mmol, 92%, yellow oil). In the purification with column chromatography, Et 3 Ndeactivated silica gel was used, that is, eluents containing 3% (v/v) Et 3 N. 1 = 169.61, 155.25, 155.16, 81.46, 81.31, 79.10, 79.05, 74.97, 74.89, 74.78, 63.67, 63.53, 63.26, 63.12, 55.26, 55.20, 55.13, 43.12, 43.06, 42.99, 42.93, 30.65, 30.62 3-Hydroxypropyl 3-(2-(Undecyloxy)phenyl)propanoate (18). To a solution of 1,3-propandiol (287.1 mg, 3.773 mmol), acid 15 (301.9 mg, 0.942 mmol), and DMAP (10.9 mg, 0.0907 mmol) in CH 2 Cl 2 (5 mL), EDCI (199.5 mg, 1.041 mmol) was added at 0°C.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Structure–Activity Relationships of Lysophosphatidylserine Analogs as Agonists of G-Protein-Coupled Receptors GPR34, P2Y10, and GPR174

et al. 2015

Lysophosphatidylserine (LysoPS) is an endogenous lipid mediator generated by hydrolysis of membrane phospholipid phosphatidylserine. Recent ligand screening of orphan G-protein-coupled receptors (GPCRs) identified two LysoPS-specific human GPCRs, namely, P2Y10 (LPS2) and GPR174 (LPS3), which, together with previously reported GPR34 (LPS1), comprise a LysoPS receptor family. Herein, we examined the structure-activity relationships of a series of synthetic LysoPS analogues toward these recently deorphanized LysoPS receptors, based on the idea that LysoPS can be regarded as consisting of distinct modules (fatty acid, glycerol, and l-serine) connected by phosphodiester and ester linkages. Starting from the endogenous ligand (1-oleoyl-LysoPS, 1), we optimized the structure of each module and the ester linkage. Accordingly, we identified some structural requirements of each module for potency and for receptor subtype selectivity. Further assembly of individually structure-optimized modules yielded a series of potent and LysoPS receptor subtype-selective agonists, particularly for P2Y10 and GPR174.

“…If taken individually these genes seem to make a very modest contribution to disease predisposition, the fact that many of them participate in the regulation of the immune response has reinforced the evidence that GD is the consequence of a chronic adaptive immune response to selected thyroid antigens. The most promising GWAS detected genes associated with GD are listed in • ▶ Table 1 [10][11][12][13][14][15][16].…”

Section: Genetics Of Autoimmune Thyroid Diseases (Aitd)mentioning

confidence: 99%

Genetics of Graves’ Disease: Special Focus on the Role of TSHR Gene

et al. 2015

As most autoimmune diseases, inherited predisposition to Graves' disease (GD) is polygenic with the main contributory genes being located in the HLA region. Also, as in other autoimmune diseases, family linkage, candidate gene association, and GWAS studies have identified an expanding number of predisposing genes (CTLA4, CD40, PTPN22...) and 2 of them, TG and TSHR, are thyroid specific. In spite of this expanding number of associated genes, it has been estimated that all together they account for only a 20% of the heritability of GD. TSHR is of special interest as it codes for the target of TSHR stimulating antibodies (TSAbs), which are unequivocally pathogenic and an exception in autoimmunity by being stimulating rather than neutral, blocking, or cytotoxic. This is surprising because the generation of stimulating TSHR antibodies by immunisation of laboratory animals has been remarkably difficult, suggesting an underlying mechanism that favours stimulating over neutral or blocking anti-TSHR antibodies must be operating in GD patients. Besides, after HLA, TSHR is the gene most tightly associated to GD. The TSHR polymorphisms conferring susceptibility are located in the unusually large intron 1. Two mechanisms have been already put forward to explain its association with GD. According to one, the risk alleles determine an increase in the expression of TSHR mRNA splice variants that code for a soluble form of the receptor. The wider distribution of soluble TSHR would favour its immunogenicity and the development of an autoimmune response to it. It does not explain why it becomes immunogenic, as immunogenicity and distribution are not necessarily connected, nor why the immune response focus to the production of stimulating antibodies. According to the second mechanism proposed, the risk alleles determine a lower TSHR expression in the thymus and this would favour the escape of more TSHR reactive T cells, that is, central tolerance failure. The unexpected finding that thymocytes express TSHR and that TSAbs stimulate them lead to postulate that this would accelerate their egress from the thymus and a less efficient deletion of the TSHR self-reactive T cells. It can be envisaged that these autoreactive T cells may enhance the production of TSHR-Abs in the germinal centres of the thyroid draining lymph nodes, especially of those capable of further stimulating the egress of autoreactive T cells from the thymus. This mechanism, which does not exclude the former, provides and insight of the way in which TSAbs are favoured over neutral or blocking antibodies. Finally this would explain the frequent finding of thymic hyperplasia in GD patients.