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Summary: Objective: We aimed to investigate the six susceptibility loci of GD identified from European population in Chinese Han population and further to estimate the genetic heterogeneity of them in stratification of our GD patients. Design: Dense mapping studies based on GWAS. Patients: A total of 1536 GD patients and 1516 controls in GWAS stage and 1994 GD patients and 2085 controls and 5033 GD patients and 5389 controls in two replication stages. Measurements: Based on our previous GWAS data, independently GD‐associated SNPs in each region were identified by TagSNP analysis and logistic regression analysis. The association of these SNPs was investigated in 1994 GD patients and 2085 controls, and then, the significantly associated SNPs (P < 0.05) were further genotyped in a second cohort including 5033 GD patients and 5389 controls. Results: After the first replication stage, four SNPs from three regions with Pfirst < 0.05 were further selected and genotyped in another independent cohort. The association of two SNPs with GD was confirmed in combined Chinese cohorts: rs12575636 at 11q21 (Pcombined = 7.55 × 10−11, OR = 1.27) and rs1881145 in TRIB2 at 2p25.1 (Pcombined = 5.59 × 10−8, OR = 1.14). Further study disclosed no significant difference for these SNPs between GD subsets. However, eQTL data revealed that SESN3 could be a potential susceptibility gene of GD in 11q21 region. Conclusions: Out of the six susceptibility loci of GD identified from European population, two risk loci were confirmed in a large Chinese Han population. There is variability in GD genetic susceptibility in different ethnic groups. SESN3 is a potential susceptible gene of GD in 11q21. [ABSTRACT FROM AUTHOR]

Objective Associations between IL2 RA and various autoimmune diseases have been reported in Caucasians. We investigated whether genetic polymorphisms at the IL2 RA locus were associated with Graves' disease ( GD) in the Chinese Han population. Design We performed a genome-wide association study ( GWAS) in 1 536 GD patients and 1 516 controls. The 1000 Genomes Project data were adopted as references for imputation analysis. After forward and conditional logistic regressions, we found that rs11256313 was the major risk variant in the CD25/ IL2 RA region. Thus, we further genotyped rs11256313 in a replication cohort with 3 694 GD patients and 3 510 controls using ABI 7900 HT TaqMan Real-Time PCR System. Results Nine single nucleotide polymorphisms ( SNPs) in the IL2 RA block were nominally associated with GD in our GWAS (0·01 < P < 0·05). After imputation analysis, 13 imputed SNPs in the IL2 RA block were weakly associated with GD ( P ≤ 0·05). Logistic regression analysis suggested that the imputed rs11256313 could represent the IL2 RA block ( P = 0·003). However, we failed to replicate the association of rs11256313 in a larger cohort ( P = 0·145). A subphenotype analysis of rs11256313 on thyroid hormone receptor antibody ( TRAb) and gender showed that there was no association in any of the subphenotype groups ( P > 0·05). Conclusions The results suggested that common genetic polymorphisms at IL2 RA do not exert a significant genetic effect on the development of GD in the Chinese Han population. Previously reported associations between CD25/ IL2 RA and autoimmune diseases including GD in Caucasians again imply that heterogeneity exists in different ethnic populations. [ABSTRACT FROM AUTHOR]

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 (Pcombined = 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. [ABSTRACT FROM AUTHOR]

The crystal structure of the title compound, named [2,2′-bi-1H-indene]-1,1′-dione-3,3′-dihydroxyl-3,3′-dicyclohexyl (I), has been determined by X-ray crystallographic techniques. The photoinduced radical and photochromic behavior of I has also been investigated in the single crystalline phase. However, we failed to identify the magnetic interaction of the photogenerated isomer for the reason of the weak signal on the magnetometer. This may be related to the distance of the intermolecular carbonyl groups in the crystal structure. [ABSTRACT FROM AUTHOR]

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.

The cover image is based on the Original Article A dense mapping study of six European AITD susceptibility regions in a large Chinese Han Cohort of Graves' disease by Wei Liu et al., DOI: 10.1111/cen.13847. Design Credit: Qianyue Zhang. [ABSTRACT FROM AUTHOR]

Importance: Thyrotoxic periodic paralysis (TPP) is a potentially lethal complication of hyperthyroidism. However, only 1 specific susceptibility locus for TPP has been identified. Additional genetic determinants should be detected so that a prediction model can be constructed., Objective: To investigate the genetic architecture of TPP and distinguish TPP from Graves disease cohorts., Design, Setting, and Participants: This population-based case-control study used a 2-stage genome-wide association study to investigate the risk loci of TPP and weighted genetic risk score to construct a TPP prediction model with data from a Chinese Han population recruited in hospitals in China from March 2003 to December 2015. The analysis was conducted from November 2014 to August 2016., Main Outcomes and Measures: Loci specifically associated with TPP risk and those shared with Graves disease and prediction model of joint effects of TPP-specific loci., Results: A total of 537 patients with TPP (mean [SD] age, 35 [11] years; 458 male) 1519 patients with Graves disease and no history of TPP (mean [SD] age, 38 [13] years; 366 male), and 3249 healthy participants (mean [SD] age, 46 [10] years; 1648 male) were recruited from the Han population by hospitals throughout China. Two new TPP-specific susceptibility loci were identified: DCHS2 on 4q31.3 (rs1352714: odds ratio [OR], 1.58; 95% CI, 1.35-1.85; P = 1.24 × 10-8) and C11orf67 on 11q14.1 (rs2186564: OR, 1.50; 95% CI, 1.29-1.74; P = 2.80 × 10-7). One previously reported specific locus was confirmed on 17q24.3 near KCNJ2 (rs312729: OR, 2.08; 95% CI, 1.83-2.38; P = 8.02 × 10-29). Meanwhile, 2 risk loci (MHC and Xq21.1) were shared by Graves disease and TPP. After 2 years of treatment, the ratio of persistent thyrotropin receptor antibody positivity was higher in patients with TPP than in patients with Graves disease and no history of TPP (OR, 3.82; 95% CI, 2.04-7.16; P = 7.05 × 10-6). The prediction model using a weighted genetic risk score and 11 candidate TPP-specific single-nucleotide polymorphisms had an area under the curve of 0.80., Conclusions and Relevance: These findings provide evidence that TPP is a novel molecular subtype of Graves disease. The newly identified loci, along with other previously reported loci, demonstrate the growing complexity of the heritable contribution to TPP pathogenesis. A complete genetic architecture will be helpful to understand the pathophysiology of TPP, and a useful prediction model could prevent the onset of TPP.

Objective: To explore the correlations of the polymorphisms of phosphodiesterase 8B (PDE8B) gene with Hyperthyroxinemia in Chinese Han population., Methods: A case-control study of genotype 657366 SNPs was performed by Illumina Human660-Quad BeadChips in 98 Hyperthyroxinemia patients and 1300 controls. And 25 SNPs within PDE8B gene intron 1 were used for association analyses., Results: Allele frequencies of 5 SNPS in PDE8B gene intron 1 showed significant differences between the case and control groups (P < 0.05). In comparison with the control group, the genotypic distributions of rs7714529 (χ(2) = 6.430, P = 0.040), rs12514694 (χ(2) = 7.191, P = 0.027) and rs10066802 (χ(2) = 9.213, P = 0.010) in H-TSH group had significant differences. Haplotype AGTAG (rs7702192/rs7714529/rs251421/rs12514694/rs10066802) was over-represented in hyperthyrotropinemia cases versus the control group., Conclusion: PDE8B gene polymorphisms may be correlated with Hyperthyroxinemia in Chinese Han population. And it may provide new concepts for the treatment of thyroid dysfunction.

Graves' disease is a common autoimmune disorder characterized by thyroid stimulating hormone receptor autoantibodies (TRAb) and hyperthyroidism. To investigate the genetic architecture of Graves' disease, we conducted a genome-wide association study in 1,536 individuals with Graves' disease (cases) and 1,516 controls. We further evaluated a group of associated SNPs in a second set of 3,994 cases and 3,510 controls. We confirmed four previously reported loci (in the major histocompatibility complex, TSHR, CTLA4 and FCRL3) and identified two new susceptibility loci (the RNASET2-FGFR1OP-CCR6 region at 6q27 (P(combined) = 6.85 × 10(-10) for rs9355610) and an intergenic region at 4p14 (P(combined) = 1.08 × 10(-13) for rs6832151)). These newly associated SNPs were correlated with the expression levels of RNASET2 at 6q27, of CHRNA9 and of a previously uncharacterized gene at 4p14, respectively. Moreover, we identified strong associations of TSHR and major histocompatibility complex class II variants with persistently TRAb-positive Graves' disease.

Objective: To evaluate the surgical therapeutic strategy and prognostic factors for non-small cell lung cancer (NSCLC) with mediastinal lymph node metastasis (N2)., Methods: The survival rate of 117 patients with N2 NSCLC treated surgically from January 1999 to May 2003 were analyzed. There were 88 male cases and 29 female cases, aged from 29 to 79 years. The procedure of operation (lobectomy, pneumonectomy and palliative resection), histological classification (squamous cell carcinoma, adenocarcinoma, mixed carcinoma, and large cell carcinoma and others), T primary tumor status, and adjuvant therapy were analyzed to determine their impact on the 5-year survival rate., Results: The median survival time was 22 months, and the over-all 3- and 5-year survival rate was 28.1% and 19.0%. Survival was higher in patients with lobectomy than with palliative resection, with T1 and T2 than with T4. The 5-year survival rate had no deference in age, sex and different histological classification. The 5-year survival rates of lobectomy and pneumonectomy (22.2% and 25.0% respectively) was higher than palliative resection (9.1%)., Conclusions: Surgical procedures (especially lobectomy) is the best choice for N2 NSCLC patients with T1 or T2. But it can not prolong T4 patients' life significantly.