🙏 Grateful acknowledgments:
This work was a true collaboration with my co-authors
Xuemin Wang and @drtracy.bsky.social @qimrb.bsky.social
Science advances through teamwork and shared expertise. 12/x

Our research opens several important questions:

Are their specific immune pathways linking thyroid dysfunction to cancer protection?

How can we translate these insights into clinical applications? 11/x

🔬 Supporting evidence for autoimmunity protection: Sjögren's syndrome also reduces EC risk (e.g. pubmed.ncbi.nlm.nih.gov/40406544/), suggesting enhanced immune surveillance - a promising avenue for understanding cancer prevention mechanisms. 10/x

🧪 The protective effect of Hashimoto's thyroiditis (i.e. autoimmune hypothyroidism) points to potential immune-mediated mechanisms that could inform new approaches for endometrial cancer prevention or treatment. 9/x

This study doesn't mean hypothyroidism is "good" - it causes many health problems. But it suggests:

Thyroid hormone pathways may influence cancer biology, although we found no evidence of this our study.

Immune mechanisms (especially in Hashimoto's) warrant investigation. 8/x

Notably, we found that both body mass index (as a proxy for obesity) and hypothyroidism independently influence EC risk. 7/x

Observational studies had suggested hypothyroidism increases EC risk, but these might have been confounded by obesity, a major EC risk factor that is also associated with hypothyroidism. 6/x

Hashimoto's disease (an autoimmune disorder that results in hypothyroidism) had a similar protective effect on EC risk and risk of the common endometrioid EC subtype was also reduced by hypothyroidism. 5/x

However, we found hypothyroidism was causally associated with 7% DECREASED EC risk:

Overall EC: (OR = 0.93, 95% CI: 0.89-0.97) 4/x

🔬 Why is this important? Traditional observational studies suggested hypothyroidism might INCREASE EC risk, but these could be confounded by other risk factors such as obesity. 3/x

What is Mendelian randomization (MR)? Think of it as "nature's randomized trial." We use genetic variants as instruments to study causal relationships between exposures and diseases, avoiding confounding that plagues observational studies. 2/x

These findings offer vital insights into CRC molecular mechanisms & support promising therapeutic avenues. They pave the way for more tailored approaches to CRC prevention & treatment. Your thoughts & questions are welcome. #OpenScience #Research 7/7

Our approach also uncovered sex- & anatomical subsite-specific associations. We identified a female-specific link for CCM2 expression with CRC risk, & LAMC1 with rectal cancer risk. This highlights CRC's inherent heterogeneity, paving the way for more tailored strategies. 💡 6/7

Causal genes with cancer cell dependency show elevated expression linked to risk, suggesting therapeutic potential. SEMA4D, a protein targeted by investigational CRC therapy, emerged as a key risk gene not found at known CRC GWAS loci. 🎯 #DrugDiscovery #Oncology 5/7

Our study revealed 37 genes with robust causal links to #CRC risk using 3 different TWAS approaches. 10 of these genes are novel findings not previously reported by TWAS. This significantly expands our understanding of CRC's genetic susceptibility. 🧬 #GeneDiscovery 4/7

How? Large-scale TWAS across 6 relevant tissues, integrating expression & splicing data with Mendelian randomisation & colocalisation. Data from 52,775 CRC cases & 45,940 controls powered our findings. 🔬 #TWAS #Epidemiology #Splicing 3/7

While GWAS has highlighted candidate CRC risk genes, their causality & therapeutic potential were unclear. Our
@NatureComms
paper (doi.org/10.1038/s414...) was designed to identify causal genes for CRC risk and prioritise genes with therapeutic potential. 2/7