Relationship between Thyroid Hormones and Metabolic Syndrome in a Normal Thyroid Function Population in Western China: A Cross-Sectional Study Based on Both Epidemiological and Genetic Analysis
Metabolic syndrome (MetS) is a cluster of metabolic disorders that includes abdominal obesity, hyperglycemia, hypertension, and dyslipidemia. Thyroid hormones, which are essential for cellular energy homeostasis and regulation, have been extensively studied in relation to MetS. However, the findings have been inconsistent, with some studies suggesting a positive association between thyrotropin (TSH) levels and MetS, while others found no such correlation. Similarly, free thyroxine (FT4) levels have been reported to have both inverse and positive associations with unfavorable metabolic parameters. These discrepancies may arise from differences in study design, population characteristics, and methodologies. This study aimed to evaluate the association and causal relationship between thyroid hormones and MetS in a population with normal thyroid function in Western China, using both epidemiological and Mendelian randomization analyses.
Study Design and Population
This cross-sectional study was conducted in Shaanxi Province as part of the China National Diabetes and Metabolic Disorders Study (CNDMDS) from June 2007 to May 2008. The study adhered to ethical standards and was approved by the Xijing Hospital Ethical Committee. A total of 394 individuals were excluded due to thyroid dysfunction, age under 20 years, diabetes diagnosis with medication use, or missing data for key variables such as waist circumference (WC), blood pressure, fasting blood glucose, serum-free triiodothyronine (FT3), FT4, TSH, triglycerides, or high-density lipoprotein cholesterol (HDL-C). The final cohort included 2903 individuals (1190 men) with normal thyroid function and complete data.
Data Collection and Measurements
Data on demographic characteristics, lifestyle risk factors, personal medical history, and family history of diseases were collected using a standardized questionnaire. Key measurements included body weight, height, body mass index (BMI), WC, hip circumference, waist/hip ratio, blood pressure, body fat rate, fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and the area under the curve (AUC) for glucose (AUCglu) and insulin (AUCins). Serum levels of TSH, FT4, and FT3 were measured using electrochemiluminescence immunoassays. Genomic DNA was extracted from whole blood, and single-nucleotide polymorphisms (SNPs) associated with TSH (NR3C2 rs10032216, PDE10A rs753760, CAPZB rs10799824, PDE8B rs2046045) and FT3/FT4 (DIO1 rs2235544) were genotyped using Sequenom MassARRAY RS1000.
Statistical Analysis
Parametric continuous variables were compared using unpaired Student’s t-test, and categorical variables were assessed using the Chi-squared test. Univariate and multivariate linear regression analyses were used to evaluate the correlation between thyroid hormones and metabolic parameters. Multivariate logistic regression identified SNPs independently associated with MetS. Significant SNPs were then integrated into univariate linear regression to assess their association with thyroid hormones. Mendelian randomization analysis was conducted using the inverse variance-weighted method to evaluate the causal relationship between thyroid hormones and MetS.
Results
Demographic and Metabolic Differences
Significant differences in demographic and metabolic indexes were observed between genders. Female subjects had higher body fat percentage, heart rate, TSH levels, and HDL-C levels compared to males, while other indicators were lower in females.
Correlation Between Thyroid Hormones and Metabolic Parameters
After adjusting for age, sex, smoking, and alcohol history, serum FT3, FT4, and log-TSH levels were negatively correlated with HDL-C levels. FT3 and FT4 were positively correlated with BMI, WC, systolic blood pressure (SBP), and various blood glucose-related indexes, while TSH was negatively correlated with blood glucose-related indexes. The FT3/FT4 ratio was negatively correlated with most metabolic parameters.
Incidence of MetS and Thyroid Hormones
The incidence of MetS was positively correlated with FT3 and TSH levels but negatively correlated with the FT3/FT4 ratio. SNPs rs10799824 G-G, rs10799824 G-A, rs2235544 C-C, and rs2235544 C-A were independently related to MetS. Among these, rs2235544 C-C was the only SNP independently related to thyroid hormones (FT3/FT4).
Mendelian Randomization Analysis
Mendelian randomization analysis indicated a causal relationship between the FT3/FT4 ratio and MetS. The regression coefficients of rs2235544 C-C and MetS, and rs2235544 C-C and FT3/FT4, were included in the analysis, suggesting that the FT3/FT4 ratio has a causal effect on MetS.
Genetic Association with Thyroid Hormones and MetS
The FT4 level was higher in C/A and A/A genotypes of rs2235544 compared to the C/C genotype, while the FT3/FT4 ratio was lower. Subjects with C/A or A/A genotypes had a higher prevalence of MetS compared to those with the C/C genotype. In the co-dominant model, genotypes C/A and A/A increased MetS risk by 1.46 and 1.40 times, respectively. In the dominant model, genotype C/A-A/A increased MetS risk by 1.44 times. These findings suggest that the rs2235544 C-C genotype is positively correlated with the FT3/FT4 ratio but negatively correlated with MetS, indirectly supporting the negative correlation between the FT3/FT4 ratio and MetS risk.
Discussion
This study highlights the negative association between the FT3/FT4 ratio and MetS risk in a euthyroid Chinese population. The findings are consistent with several Korean studies but differ from others, possibly due to genetic differences in study populations. The use of genetic association analysis and Mendelian randomization provided robust evidence for the causal relationship between the FT3/FT4 ratio and MetS. The balance of FT3 and FT4 appears to be more critical than previously recognized in the context of metabolic health.
Conclusion
The study demonstrates that the FT3/FT4 ratio is negatively associated with MetS risk in a euthyroid population in Western China. Genetic analysis and Mendelian randomization support the causal relationship between the FT3/FT4 ratio and MetS, emphasizing the importance of thyroid hormone balance in metabolic health. These findings contribute to a better understanding of the complex relationship between thyroid function and metabolic syndrome, highlighting the need for further research in diverse populations.
doi.org/10.1097/CM9.0000000000001553
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