Causal association between hyperthyroidism and risk of gastroesophageal reflux or esophageal cancer: a bidirectional Mendelian randomization investigation.

Background: Emerging observational studies indicated an association between hyperthyroidism and gastrointestinal disorders. However, it remains unclear whether this association is causal, particularly in the case of gastroesophageal reflux (GERD) and esophageal cancer. Methods: To assess the potential causal relationship between hyperthyroidism and GERD or esophageal cancer, we conducted a bidirectional 2-sample Mendelian randomization study. Independent genetic instruments for hyperthyroidism from the UK Biobank (N case=3,545 and N control=459,388) and public genome-wide association study (GWAS) dataset (N case=3,731 and N control=480,867) were used to investigate the association with esophageal cancer in the UK Biobank study (N case=740 and N control=372,016) and GERD in the public GWAS database (N case=20,381 and N control=464,217). Four different approaches (inverse variance weighted (IVW), weighted mode, MR-Egger, and weighted median regression) were used to ensure that our results more reliable. Additional sensitivity analyses were also performed to validate our results. Results: When hyperthyroidism was considered as the exposure factor, it appeared to act as a protective factor for GERD (ORIVW = 0.88, 95% CI, 0.79-0.99, P = 0.039), while as a risk factor for esophageal cancer (ORIVW = 1.03, 95% CI, 1.01-1.06, P = 0.003). However, there is no evidence supporting a reverse causal relationship between genetic susceptibility to hyperthyroidism and GERD or esophageal cancer. Conclusion: Our findings provided genetic evidence supporting bidirectional causal relationships between hyperthyroidism and GERD or esophageal cancer. These results substantiate certain discoveries from previous observational studies on a causal level and provide insight into relevant genetic susceptibility factors.

Deciphering the circulating immunological landscape of thoracic aortic aneurysm: Insights from a two-sample Mendelian randomization study.

Background: Thoracic Aortic Aneurysm (TAA) poses significant health risks due to aortic dilation. Recent evidence suggests a pivotal role for the immune-inflammatory response in the mechanism of aortic aneurysm formation. In this study, we aim to investigate the causal relationship between circulating immune cells and TAA. Methods: This study employs a two-sample Mendelian Randomization (MR) approach, utilizing genome-wide association study (GWAS) summary statistics for 731 immune cell types and two TAA data from large-scale studies. Causal effects of both peripheral immune cells on TAA and TAA on peripheral immune cells are explored. To ensure more accurate results, we intersected the findings from two TAA data from large-scale studies, excluding results where the direction of the odds ratio (OR) was inconsistent. Findings: The study identifies specific immune cells associated with TAA. Notably, CD45+ NKT cell (OR: 0.95, 95CI%: 0.90-0.99 in FinnGen study; OR: 0.91, 95CI%: 0.84-0.99 in CHIP + MGI study) and CD45+ HLA-DR + CD8+ T cells (OR: 0.95, 95CI%: 0.90-0.99 in FinnGen study; OR: 0.90, 95CI%: 0.82-0.99 in CHIP + MGI study) demonstrate a protective role against TAA. In addition, CD28+ CD45RA- CD8+ T cells (relative cell counts and absolute cell counts) and HVEM + CM + CD8+ T cells are adversely affected by TAA. Interpretation: The findings indicate that the potential protective influence exerted by specific subsets of peripheral NKT cells and CD8+ T cells in mitigating the development of TAA, while simultaneously highlighting the reciprocal effects of TAA on peripheral Treg cells subsets and T cell subsets. The complex interaction between immune cells and TAA could provide valuable clues for earlier detection and more efficacious treatment strategies for TAA.