Intensive but quite chaotic and decentralized candidate gene studies on susceptibility to Graves' disease ( GD ) carried out in small size population in the past half century have provided a quantity of inconsistent data,which,however,resulted in finding of a proven association of GD with the MHC class Ⅱ region that exerts a major effect on the genetics of GD.Using low-resolution microsatellite-based human genome-wide linkage analysis,several regions of linkage harboring putative susceptibility variants but no gene susceptibility to GD were identified.Further,high throughput genotyping of large population cohorts with help of high dense panels of single nucleotide polymorphisms (SNPs) and application of advanced tools for analysis of extended blocks of linkage disequilibrium within a candidate gene ( tagging SNP,etc.) have found several genes susceptible to GD,including immune-related genes such as MHC,CTLA4,SCGB3A2/UGRP1,FCRL3,and thyroid specific genes ( such as TSHR,etc.).Less consistent results have been obtained in cases of PTPN22 and thyroglobulin.In the nearest future,implementation of even more robust technology such as genome-whole associated analysis (GWAS) and whole-genome re-sequencing are expected to catch more genes susceptibilities to GD.

Gene chips, recently developed techniques, are widely used in many different fields including clinical and basic endocrine research. However, there still exist some problems in the application of gene chips, such as how to collect and process the samples and how to analyze the results etc. This article is focusing on analyzing the possible problems and limitations in applying gene chips and trying to further explore appropriate solutions.

Graves' disease is a common autoimmune disease triggered by the susceptibility genes and environmental factors.Among the 9 risk genes related to Graves' disease,SCGB3A2 is the first Graves' disease-predisposing gene identified by our group using tagSNPs,strategy of candidate genes,and positional clones.The association between SCGB3A2 and Graves' disease has been confirmed by two independent cohorts from UK and Russia.So far,the geneticists on Graves' disease regard SCGB3A2 as a validated susceptibility gene of that disease.

Thyroid hormones play major roles in the regulation of a wide range of metabolie and physiologic processes.Serum thyroid-stimulating hormone( TSH ) concentration,a sensitive barometer of thyroid function,shows significant individual difference in which genetic variation is a major factor.After using traditional genetic linkage studies and candidate gene association studies to explore the suseeptibility genes of serum TSH,many progresses have been made and new susceptibility genes have been identified by genome-wide association study (GWAS).In this review,we focus on the susceptibility genes of serum TSH levels and also the future prospect that may be obtained from these studies.

Objective To investigate the relationship between the polymorphisms of collagen type Ⅰ alpha 1 (COLIA1) gene and bone mineral density of postmenopausal women in Shanghai. Methods The polymorphisms of Sp1 binding site in COLIA1 gene were observed in 205 postmenopausal women by PCR, digested with MscⅠ restriction endonuclease and separated by 12% polyacrylamide gel electrophoresis. The capital letter S represents for the absence of the restriction endonuclease site, while the small letter s for the presence of the restriction endonuclease site. Bone mineral density at lumbar spine and femoral neck, etc. were measured by DEXA. Results Neither Ss nor ss genotypes of COLIA1 gene was found in our sample, all were SS genotype. Conclusion The contribution of Sp1 site variation of COLIA1 gene to bone mass might have a strong ethnic difference. The restriction fragment length polymorphisms of COLIA1 gene do not show relationship with the bone mass of postmenopausal women in Shanghai. The significance of this genetic marker of osteoporosis needs to be further explored in larger samples and in different areas.

Objective The aim of this article is to discuss the relation between serum uric acid and prehypertension, and to evaluate the influence of age, obesity, fasting plasma glucose (FPG) and lipids in Chinese adults. Methods All the 14 451 non-hypertensive samples were analyzed for blood pressure, body mass index (BMI), FPG, lipids and serum uric acid. Results The serum uric acid levels were stratified by quintiles, after adjustment for relevant factors, OR values of prehypertcnsion increased with the elevated uric acid levels. Serum uric acid level was 200-380 μmol/L, it had a linear relationship with the risk of prehypertension, 200 μmol/L as a turning point for this linear relationship, FPG could affect their correlation (P ＜ 0.0001 ). Conclusions Serum uric acid was associated with prehypertension, independent of metabolic risk factors. The associations were not significant in old individuals. FPG may modify the associations.

The interactions between genetic variations and dietary factors in type 2 diabetes mellitus have attracted some attention. Several studies revealed that dietary carbohydrate quality and quantity and increased dietary fat intake might interact with genetic variations of type 2 diabetes mellitus and increase risk of this disease. Genome-wide association studies suggest that genetic variance may modulate the association between dietary pattern and type 2 diabetes mellitus.

Objective To obtain more information concerning polymorphism of the thyrotropin (TSHR) in Graves diseases(GD). Methods (1)A family of GD was studied (including 3 patients and 9 healthy family members)to examine SNPs of TSHR through direct sequencing of all 10 exons and part of introns. (2)In the current case-control study, 30 patients with familiar GD, 48 sporadic patients and 96 healthy control individuals were used to assess whether SNP of TSHR was associated with GD. Genomic DNA was extracted from peripheral leukocytes isolated from ACD-anticoagulated blood. Ten exons were amplified by PCR, using primers designed by ourselves. After purifying, the products were sequenced. Results Eight polymorphisms were found. There was a novel polymorphism in exon 8. There were no significant differences between patients and controls. Conclusions These findings suggested that the novel and other polymorphisms of the TSHR gene may not be responsible for GD. There are racial differences in the distribution of polymorphisms of TSHR gene.

Objective To explore the correlation of the gene polymorphism of the two single nucleotide polymorphisms(SNPs)rs1443434andrs925489onforkheadboxEl(FOXE1)withthehighnormalthyroidstimulating hormone ( TSH) level in Chinese Han population. Methods 1 400 subjects with normal serum TSH and thyroid peroxidase antibody(TPOAb) levels were included. According to TSH or TPOAb levels, the subjects were divided into high normal TSH group(H-TSH group,n=195) and normal TSH control group(TSH control group,n=1 205) or high normal TPOAb group ( H-TPOAb group, n=711 ) and low normal TPOAb group ( L-TPOAb group, n=689 ) , respectively. The genotypes on the two SNPs of all the subjects were performed by whole-genome genotyping chips. Results There were significant differences in rs925489 genotypic distributions and allele frequencies between H-TSH group and TSH control group(both P<0. 05). The genotype TT and allele T in H-TSH group were significantly higher than those in TSH control group(89. 75% vs 83. 15%, 94. 62% vs 91. 29%). The normal TSH levels were positively associated with rs925489 genotypic distributions after adjustment for sex, age, and high density lipoprotein cholesterol(P<0. 01). There were no significant differences in rs1443434 genotypic distributions and allele frequencies between two TSH groups or two TPOAb groups. Conclusion FOXE1 rs925489 gene polymorphism may be correlated with the high normal TSH level in Chinese Han population.

[Summary] The genotypes of rs6832151 in the 4p14 were genotyped by Taqman probe technique on FluidigmEPl platform in 617 patients with Graves′disease( GD) and 4 915 health control subjects. The result showed thatRs6832151 Gin4p14wasstronglyassociatedwithGD(OR=1.39,P<0.01),withstatisticalsignificancefor three genetic models according to the locus genotyping ( additive model,dominant model,and recessive model,all P<0.01). There was no statistically significant difference in the sizes of goiter between the genotype subgroups(P>0. 05). The result suggests that rs6832151 G in 4p14 is the susceptibility genes of Graves′ disease in Bengbu population, and is related to the high risk of GD.