| Thyroid hormones(THs) are essential for the cellular energy homeostasis and regulation, and also have pleiotropic effects on glucose and lipid metabolism, blood pressure and body composition. Therefore, it is very important to keep the euthyroid status. There are many factors that influence the thyroid hormone levels, in which iodine intake and genetic factors play an important role. Recently, with the application of the approach of genome-wide association study(GWAS) in the research of various diseases and human functions, we have obtained growing knowledge for the genetic factors which are involved in regulating thyroid hormones. Moreover, substantial single nucleotide polymorphisms(SNP) affecting THs have drawn attention for the scientists.Metabolic syndrome(MS) is defined as a cluster of cardiovascular risk factors. Insulin resistance is assumed to be the key feature of the MS. Considering the critical role of THs in regulating energy homeostasis, the levels of THs exhibit correlation with the metabolic profiles. Numerous studies have investigated the relationship between thyroid function disorder and MS components, which proved that both hyperthyroidism and hypothyroidism were positively correlated with insulin resistance. During the past decade, several surveys have investigated the association between thyroid hormones with MS and its components within euthyroid subjects, whereas inconsistent results still existed within these studies. Moreover, due to the impact of genetic factors on thyroid functions, many studies have also focused on the relationship between TH-associated SNPs and clinical symptoms and disorders. However, these results differed among different populations.Because of the vast territory and large population in China, the population genetic background may have huge difference with the distinct geographical environment. Thus, the present study was performed based on the epidemiology survey in Shaanxi province for further identifying the relationship between THs and MS together with its components, and also analyzing the influence of SNPs on THs and MS. The whole thesis is divided into the following five parts.Section 1: The establishment of reference intervals(RIs) of THs in the population of Xi’anObjective: To establish the RIs of THs in Xi’an, a previously iodine-deficient area but presently more than iodine-adequate area of Western China, and also to investigate the factors which affect thyroid function.Methods: The subjects in this study were selected from the database of the epidemical survey which was performed in Xi’an from the year of 2012 to 2013. A total of 1286 subjects were involved in this study, in which 717 subjects were selected as the reference population. Thyrotropin(TSH), total triiodothyronine(T3), free triiodothyronine(FT3), total thyroxine(T4), free thyroxine(FT4), thyroperoxidase antibody(TPO-Ab) and thyroglobulin antibody(Tg-Ab) were measured. Thyroid ultrasound examination was also performed.Results: The present study established the new RIs of serum TSH(0.43-5.51 m IU/L), FT4(11.0-20.4 pmol/L), FT3(3.63-5.73 pmol/L), T4(67.8-157 mmol/L) and T3(1.08-2.20 mmol/L), which were different from the data provided by the manufacturers. Significant differences among all the age groups were observed in FT3, but neither in TSH nor in FT4. The TSH levels in adults with pathologic ultrasonography results or positive thyroid autoantibody were significantly higher than those in reference adults.Conclusion: Our present results provide valuable references for the diagnosis of thyroid diseases in the population of Western China. Considering that most inland areas of China have faced the challenge of the transition from iodine deficiency to adequacy or more than adequacy, we recommend physicians utilize our RIs to determine thyroid diseases in the similar areas with Xi’an in China.Section 2: The cross-sectional study for the relationship between the thyroid function and MS in euthyroid subjects of Shaanxi provinceObjective: To analyze the correlation between the levels of THs and MS together with its components in euthyroid population via the cross-sectional study.Methods: This cross-sectional survey in Shaanxi province, as part of the China National Diabetes and Metabolic disorders Study(CNDMS), was conducted from June 2007 to May 2008. All individuals were subjected to the physical examination, body fat percentage measurement and ECG. The OGTT or steamed bun test, serum lipid, glucose, insulin and TH measurements were also performed. All subjects also filled out the standardized questionnaire. First, we compared the differences of MS and its components between the subclinical thyroid dysfunction groups and the euthyroid group. Then, the differences of MS and its components between the FT4 tertile groups in euthyroid populations were compared. Finally, we performed multiple linear regression and logistic regression analyses to quantify the relationship between THs and MS(THs as the dependent variables, and MS as the independent variables).Results: A total of 2991 subjects were involved in this study, including 76 subclinical hyperthyroid and 121 subclinical hypothyroid patients. No significant difference in the MS incidence was observed between the subclinical thyroid dysfunction groups and the euthyroid group(P>0.05). The values of SBP, DBP, FBG, FINS, AUCglu, AUCins, HOMAIR, TC, LDL-C and TG were increased with the FT4 value in euthyroid populations(P<0.01), whereas HDL-C was reduced with the increase of FT4 value(P<0.01). Moreover, we observed significant increase of MS levels as well as the incidence of abdominal obesity, hyperglycemia, hypertension, high TG and low HDL-C with the increase of the FT4 value(P<0.01). The logistic regression results demonstrate that MS showed higher risks in the highest FT3 and FT4 tertiles(ORFT4:2.48, 95%CI FT4: 1.93-3.17; ORFT3:1.94, 95%CI FT3: 1.45-2.58) and lower risks in FT3/FT4 tertiles as compared with the lowest tertiles(OR: 0.52, 95% CI: 0.41-0.66). Furthermore, the MS risk had increased tendency in the highest TSH tertile, but showed no statistically significant difference(OR: 1.26, 95% CI: 0.99-1.59).Conclusion: The cross-sectional study demonstrates that subclinical thyroid dysfunctions exhibited no significant impacts on the MS incidence. MS and its components showed positive correlation with the FT4 and FT3 levels and negative correlation with the FT3/FT4 ratio in the euthyroid populations, whereas MS and its components had no obvious correlation with the TSH level.Section 3: The follow-up study for the relationship between the thyroid function and MS in euthyroid subjects of Shaanxi provinceObjective: To analyze the correlation between the thyroid functions and MS components in euthyroid populations via the follow-up study.Methods: The baseline subjects in this follow-up survey were the populations in the Shaanxi province part of the CNDMS program conducted from June 2007 to May 2008. We performed a 5-year follow-up survey for these subjects from the year of 2012 to 2013. In these follow-up investigations, all individuals were subjected to the physical examination, body fat percentage measurement and ECG test. The OGTT or steamed bun test, serum lipid, glucose, insulin and TH measurements were also performed. All subjects also filled out the standardized questionnaire. Then, we performed multiple linear regression analyses to quantify the relationship between the changes of metabolic parameters and THs(the metabolic parameters as the dependent variables, and THs as the independent variables).Results: A total of qualified 668 subjects were involved in this follow-up study. The multiple linear regression analysis results showed that the changes of the waistline, body fat percentage, BMI and LDL-C levels exhibited positive correlation with the change of the FT3 value(P<0.05). The change of the body fat percentage, SBP, DBP, TC, LDL-C and FBG exhibited positive correlation with the change of the FT4 level. The change of the waistline and BMI showed positive correlation with the change of the FT3/FT4 ratio(P<0.05). The change of the body fat percentage, SBP, LDL-C and FBG had negative correlation with the change of the FT3/FT4 ratio(P<0.05). However, no significant difference was found between the changes of the metabolic parameters and the change of the TSH value(P>0.05). We also found that the change of the waistline, SBP and DBP showed significant positive correlation with the change of the T3 value(P<0.05). The change of BMI, TC and TG exhibited negative correlation with the change of T4(P<0.05).Conclusion: This follow-up study indicates that the changes of several metabolic parameters showed association with the FT3, FT4, FT3/FT4 ratio, T3 and T4 levels, but had no obvious correlation with the TSH value.Section 4: Study for the association between thyroid-related SNPs and thyroid functions in the population of Shaanxi province.Objective: To evaluate the association between thyroid-related SNPs and thyroid functions in the population of Shaanxi province.Methods: The subjects in this section were the populations in the Shaanxi province part of the CNDMS program conducted from June 2007 to May 2008. The Mass ARRAY technique was employed to determine the genotype of thyroid-related SNPs in this population, including rs10032216, rs753760, rs10799824, rs2046045 and rs2235544. Then, we compared the difference of THs and TSH levels between distinct genotypes. The multiple linear regression analyses were used to analyze the association between the alleles and the levels of THs and TSH(the alleles as the dependent variables, and the levels of THs and TSH as the independent variables).Results: A total of qualified 2486 subjects were involved in this study. The FT4 and T4 levels in the carrier of minor allele A in rs2235544(DIO1) were increased with the occurrence of allele A(P<0.05). The levels of FT3 and FT3/FT4 ratio were decreased with the occurrence of allele A(P<0.05). The TSH level was decreased with the occurrence of minor alleles in rs10032216(NR3C2), rs2046045(PDE8B) and rs753760(PDE10A)(P<0.05). However, the levels of FT3, FT4, FT3/FT4, T3 and T4 exhibited no significant difference within the genotypes of the above locus(P>0.05). Moreover, the levels of TSH, FT3, FT4, FT3/FT4, T3 and T4 showed no significant difference among the different genotypes of rs10799824(CAPZB)(P>0.05).Conclusion: In the population of Han Chinese in Shaanxi province, the polymorphism of rs2235544(DIO1) was associated with the levels of FT3 and FT4. The polymorphism of rs10032216(NR3C2), rs2046045(PDE8B) and rs753760(PDE10A) showed significant correlation with the serum TSH level, whereas the polymorphism of rs10799824(CAPZB) was not associated with the THs and TSH levels.Section 5: The association between the DIO1 polymorphism and MS in the population of Shaanxi province.Objective: To investigate the association between the DIO1 polymorphism and MS in the population of Shaanxi province.Methods: The subjects in this section were the populations in the Shaanxi province part of the CNDMS program conducted from June 2007 to May 2008. The genotype of rs2235544 in this population was measured by using the Mass ARRAY technique. We performed a casecontrol study to compare the differences of genotype distributions between the MS group and Control group. Firstly, the Pearson Chi-square test was employed to analyze the differences of genotype frequencies between the two groups. Secondly, we used logistic regression to analyze the association between the polymorphism of rs2235544 and MS together with its components. Thirdly, the covariance analysis was used to compare the metabolic parameters between distinct genotypes. Finally, the multiple linear regression was utilized to analyze the association between the polymorphism of rs2235544 and metabolic parameters.Results: The prevalence of the minor allele A in rs2235544(DIO1) was higher in the MS group than the Control group(P<0.01). The results of logistic regression demonstrate that dominant model C/A-A/A exhibited significant correlation with the incidence of MS(OR=1.38, P=0.039). The results of the covariance analysis reveal that all the parameters except TG did not show statistically significant differences between the distinct genotypes(P>0.05). The multiple linear regression results for the addictive model of rs2235544 indicate that FINS and HOMA-IR showed positive correlation with the allele A after the adjustment of gender and age(P<0.05). However, the statistical difference disappeared after the adjustment of BMI and HOMA-IR(P>0.05).Conclusion: In the population of Shaanxi province, the polymorphism of rs2235544(DIO1) exhibited obvious association with the increased MS risk. The underlying mechanism may be related with the increased insulin resistance. However, this association still needs to be further identified in other populations. |
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