Association Analysis of Single Nucleotide Polymorphisms in C1QTNF6, RAC2, and an Intergenic Region at 14q32.2 with Graves' Disease in Chinese Han Population.

BACKGROUND: Variation within the C1QTNF6 gene at 22q12.3, the RAC2 gene at 22q13.1, and an intergenic region at 14q32.2 were found to be associated with risk to Graves' disease (GD) in a recent study. We aimed to validate these associations with GD in an independent sample set of Han Chinese population. METHODS: We investigated these associations by genotyping the most significantly associated single nucleotide polymorphisms (SNPs) located in these three regions. Rs1456988 within the intergenic region at 14q32.2, rs229527 within C1QTNF6 at 22q12.3, and rs2284038 within RAC2 at 22q13.1 were selected for genotyping. These three SNPs were genotyped using a case-control study that included 2382 GD patients and 3092 unrelated healthy controls from Northern Han Chinese ancestry. The genotyping was performed using TaqMan assays on the ABI7900 platform. RESULTS: We found both the rs229527 allele within C1QTNF6 (odds ratio [OR] = 1.23, confidence interval [95% CI]: 1.12-1.33, pAllelic = 4.60 × 10-6) and the rs2284038 allele within RAC2 (OR = 1.10, 95% CI: 1.01-0.19, pAllelic = 3.00 × 10-2) showed significant associations with GD susceptibility. However, rs1456988 located in 14q32.2 (OR = 1.08, 95% CI: 0.99-1.16, pAllelic = 7.01 × 10-2) showed no association. Analysis of models of inheritance suggested that both the dominant and recessive models showed significant associations for rs229527 (OR = 1.24, 95% CI: 1.13-1.38, pDominant = 9.90 × 10-5; OR = 1.49, 95% CI: 1.19-1.86, pRecessive = 3.90 × 10-4), with the dominant model being preferred. For rs2284038, the recessive model was preferred (OR = 1.18, 95% CI: 1.00-1.40, pRecessive = 4.76 × 10-2), whereas analysis of dominant model showed no association (OR = 1.10, 95% CI: 0.98-1.22, pDominant = 0.10). CONCLUSIONS: Our findings confirmed that chromosome 22q12.3 and 22q13.1 variants are associated with GD in an independent Han Chinese population; however, 14q32.2 showed no association with GD.

Association of 4p14 and 6q27 variation with Graves disease: a case-control study and a meta-analysis of available evidence.

BACKGROUND: The etiology of the Graves' disease (GD) is largely unknown. However, genetic factors are believed to play a major role. A recent genome-wide association study in a Han Chinese sample collection revealed two new Graves' disease (GD) risk loci within chromosome band 4p14 and 6q27. In this study, we aimed to investigate these associations with Weifang Han Chinese population of Shandong province and perform a meta-analysis of associations with GD. METHODS: A case-control study was conducted to investigate association of variation within 4p14 and 6q27 to GD susceptibility in Weifang Han Chinese population of Shandong province. SNP rs6832151 at chromosome 4p14 and SNP rs9355610 at chromosome 6q27 was selected for genotyping in 2,382 GD patients and 3,092 unrelated controls. SNP genotyping was performed using TaqMan Real-time PCR technique assays on ABI7900 platform. A meta-analysis was performed with the data obtained in the current sample-set and those available from prior studies. RESULTS: Association analysis revealed both rs6832151 located in 4p14 (odds ratio (OR) = 1.27, P Allelic = 1.48 × 10-9) and rs9355610 located in 6q27 (OR = 1.10, P Allelic = 1.04 × 10-2) was associated with GD susceptibility. By model of inheritance analysis, we found the recessive model should be preferred (P Recessive = 2.75 × 10-11) for rs6832151. The dominant model should be preferred (P Dominant = 7.15 × 10-3) for rs9355610, whereas analysis of recessive model showed no significant association (P Recessive = 0.13). Meta-analysis with the data of 10,781 cases and 16,304 controls obtained from present sample-set and those available from prior studies confirmed association of rs6832151 at 4p14 with GD susceptibility using a fixed model (OR = 1.27, 95% CI: 1.22 to 1.32; I2 = 0%). Meta-analysis with the data of 11,306 cases and 12,756 controls confirmed association of rs9355610 at 6q27 with GD susceptibility using a fixed model (OR = 1.18, 95% CI: 1.13 to 1.22; I2 = 41.2%). CONCLUSIONS: Our findings showed that chromosome 4p14 and 6q27 variants were associated with Graves' disease in Weifang Han Chinese population of Shandong province.

Predicting relapse of Graves' disease following treatment with antithyroid drugs.

The aim of the present study was to monitor long term antithyroid drug treatments and to identify prognostic factors for Graves' disease (GD). A total of 306 patients with GD who were referred to the Endocrinology Clinic at Weifang People's Hospital (Weifang, China) between August 2005 and June 2009 and treated with methimazole were included in the present study. Following treatment, patients were divided into non-remission, including recurrence and constant treatment subgroups, and remission groups. Various prognosis factors were analyzed and compared, including: Patient age, gender, size of thyroid prior to and following treatment, thyroid hormone levels, disease relapse, hypothyroidism and drug side-effects, and states of thyrotropin suppression were observed at 3, 6 and 12 months post-treatment. Sixty-five patients (21.2%) were male, and 241 patients (78.8%) were female. The mean age was 42±11 years, and the follow-up was 31.5±6.8 months. Following long-term treatment, 141 patients (46%) demonstrated remission of hyperthyroidism with a mean duration of 18.7±1.9 months. The average age at diagnosis was 45.6±10.3 years in the remission group, as compared with 36.4±8.8 years in the non-remission group (t=3.152; P=0.002). Free thyroxine (FT)3 levels were demonstrated to be 25.2±8.9 and 18.7±9.4 pmol/l in the non-remission and remission groups, respectively (t=3.326, P=0.001). The FT3/FT4 ratio and thyrotrophin receptor antibody (TRAb) levels were both significantly higher in the non-remission group (t=3.331, 3.389, P=0.001), as compared with the remission group. Logistic regression analysis demonstrated that elevated thyroid size, FT3/FT4 ratio and TRAb at diagnosis were associated with poor outcomes. The ratio of continued thyrotropin suppression in the recurrent subgroup was significantly increased, as compared with the remission group (P=0.001), as thyroid function reached euthyroid state at 3, 6 and 12 months post-treatment. Patients with GD exhibiting large thyroids, high pre-mediation TRAb levels and elevated FT3/FT4 ratios responded less markedly to antithyroid drug treatments, as compared with patients not exhibiting these prognostic factors. Furthermore, patients with large thyroids, post-medication ophthalmopathy and continued thyrotropin suppression demonstrated higher rates of recurrence.