Causal Association of Thyroid Signaling with C-Reactive Protein: A Bidirectional Mendelian Randomization

Abstract

Context. Existing literature demonstrated that thyroid-stimulating hormone (TSH) and free thyroid hormone (fT4) were associated with the C-reactive protein (CRP), an inflammatory risk factor of cardiovascular diseases (CVD), but the causal relationship between them remained unclear. Methods. Based on the latest genome-wide association study summary data, bidirectional two-sample Mendelian randomization (MR) was employed to detect the causal relationship and effect direction between TSH, fT4, and CRP. Furthermore, in view of obesity being an important risk factor of CVD, obesity trait waist-hip ratio (WHR) and body mass index (BMI) were treated as the research objects in MR analyses for exploring the causal effects of TSH and fT4 on them, respectively. Results. Genetically increased CRP was associated with increased TSH ( $\beta =-0.02$ , $P=0.011$ ) and with increased fT4 ( $\beta =0.043$ , $P=0.001$ ), respectively, but there was no evidence that TSH or fT4 could affect CRP. In further analyses, genetically increased TSH was associated with decreased WHR ( $\beta =-0.02$ , $P=3.99e-4$ ). Genetically increased WHR was associated with decreased fT4 ( $\beta =-0.081$ , $P=0.002$ ). Genetically increased BMI was associated with increased TSH ( $\beta =0.03$ , $P=0.028$ ) and with decreased fT4 ( $\beta =-0.078$ , $P=1.05e-4$ ). Causal associations of WHR and BMI with thyroid signaling were not supported by weighted median analysis in sensitivity analyses. Conclusion. TSH and fT4 were increased due to the higher genetically predicted CRP. WHR was decreased due to the higher genetically predicted TSH. These findings will provide reference for the prevention and treatment of inflammation and metabolic syndrome.