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The Causal Effects of Primary Biliary Cholangitis on Thyroid Dysfunction: A Two-Sample Mendelian Randomization Study.

ABSTRACT: Background: Primary biliary cholangitis (PBC) is an autoimmune disease and is often accompanied by thyroid dysfunction. Understanding the potential causal relationship between PBC and thyroid dysfunction is helpful to explore the pathogenesis of PBC and to develop strategies for the prevention and treatment of PBC and its complications. Methods: We used a two-sample Mendelian randomization (MR) method to estimate the potential causal effect of PBC on the risk of autoimmune thyroid disease (AITD), thyroid-stimulating hormone (TSH) and free thyroxine (FT4), hyperthyroidism, hypothyroidism, and thyroid cancer (TC) in the European population. We collected seven datasets of PBC and related traits to perform a series MR analysis and performed extensive sensitivity analyses to ensure the reliability of our results. Results: Using a sensitivity analysis, we found that PBC was a risk factor for AITD, TSH, hypothyroidism, and TC with odds ratio (OR) of 1.002 (95% CI: 1.000-1.005, p = 0.042), 1.016 (95% CI: 1.006-1.027, p = 0.002), 1.068 (95% CI: 1.022-1.115, p = 0.003), and 1.106 (95% CI: 1.019-1.120, p = 0.042), respectively. Interestingly, using reverse-direction MR analysis, we also found that AITD had a significant potential causal association with PBC with an OR of 0.021 (p = 5.10E-4) and that the other two had no significant causal relation on PBC. Conclusion: PBC causes thyroid dysfunction, specifically as AITD, mild hypothyroidism, and TC. The potential causal relationship between PBC and thyroid dysfunction provides a new direction for the etiology of PBC.

SUBMITTER: Huang P

PROVIDER: S-EPMC8703001 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The correlation between obesity and primary open-angle glaucoma (POAG) has not yet been fully established. The aim of this study was to investigate the causal relationship between obesity and POAG by a two-sample Mendelian randomization (MR) study. In this study, body mass index (BMI), an index to evaluate general obesity, and waist and hip circumference, indices to evaluate abdominal obesity, were selected as exposures in MR analysis. Single-nucleotide polymorphisms (SNPs) were chosen as instrumental variables (IVs). Summary data from genome-wide association studies (GWASs) based on a European ancestry by Locke et al., with regard to BMI, and Shungin et al., with regard to waist and hip circumference, were used. Genetic predictors of POAG were obtained from public GWAS summary data. To assess the causal effect of obesity on POAG, the inverse variance-weighted (IVW) method was used as the primary method, and other methods, such as MR-Egger, weighted median, simple mode, and weighted mode, were also used as complementary analyses. Finally, we performed Cochran's Q statistic to assess heterogeneity, and sensitivity analysis was performed to evaluate the reliability and stability of the MR results. MR analysis showed that BMI has a positive effect on the risk of POAG, with 1 standard deviation (SD) increase in BMI; the risk of POAG increases by approximately 90.9% [OR = 1.909; 95% CI= (1.225, 2.975); p = 0.0042)] (analyzed by IVW); there were no heterogeneity and pleiotropy in the result; and waist circumference also had a positive effect on the risk of POAG [OR = 2.319; 95% CI= (1.071, 5.018); p = 0.033)] analyzed by weighted median. As hip circumference increases, with 1 SD increase in hip circumference, the risk of POAG increases by approximately 119% [OR = 2.199; 95% CI= (1.306, 3.703); p = 0.00305)] estimated by IVW, there were not heterogeneity and pleiotropy as for the result. Our study for the first time confirms that obesity might increase the risk of POAG using two-sample MR analysis. These results might provide guidance on the prevention and treatment of POAG.

Project description:BackgroundThe role of thyroid hormones in cancers has been discussed in observational studies; however, the causal relationship between them remains controversial.MethodsThe SNPs associated with hypothyroidism and hyperthyroidism were selected from a FinnGen biobank of 342,499 (190,879 females and 151,620 males) Finnish adult subjects. Data from the Thyroidomics Consortium on 72,167 individuals were used to assess genetically determined thyroid-stimulating hormone (TSH) and free thyroxine (FT4). Lung cancer, lung adenocarcinoma and squamous cell lung cancer GWAS data from the International Lung Cancer Consortium(ILCCO). Six different Mendelian randomization (MR) Methods, including Inverse variance weighted (IVW), MR-Egger, Simple mode, MR-Pleiotropy Residual Sum and Outlier methods (MR-PRESSO), Weighted mode and Weighted median were used to Two-Sample MR analysis. IVW was used as the primary estimate. Sensitivity analyses were examined via four aspects (Cochran's Q-test, MR Egger intercept analysis, Funnel plot and Leave-one-out sensitivity test).ResultsThe OR of hypothyroidism on lung cancer was 0.918 (95% CI, 0.859-0.982; p = 0.013) in MR analysis with IVW method. No evidence for effects of hyperthyroidism, TSH and FT4 on lung cancer risk was found via six MR methods. Meanwhile, there was no evidence for effects of lung cancer on hypothyroidism through six MR methods. Lung adenocarcinoma and squamous cell lung carcinoma were further analyzed on the basis of lung cancer. The OR of hypothyroidism on lung adenocarcinoma was 0.893(95% CI, 0.813-0.981; p = 0.019), the OR of hypothyroidism on squamous cell lung cancer was 0.888(95%CI,0.797-0.990, p = 0.032) in MR analysis with IVW method.ConclusionIn summary, hypothyroidism genetically had a protective causal association with lung cancer. Furthermore, hypothyroidism had protective effects both on lung adenocarcinoma and squamous cell lung cancer. Further work is needed to elucidate the potential mechanisms.

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The Causal Effects of Primary Biliary Cholangitis on Thyroid Dysfunction: A Two-Sample Mendelian Randomization Study.

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