Causal Relationship Between Cataracts and Gastrointestinal Diseases: A Two-Sample Mendelian Randomization Study

Cataracts, a leading cause of blindness, have been linked to systemic conditions. Previous studies showing associations between cataracts and gastrointestinal diseases have not determined causal relationships. We aimed to investigate the causal relationship between cataracts and 23 gastrointestinal diseases through Mendelian randomization (MR).

We obtained genome-wide association study (GWAS) datasets for 23 gastrointestinal diseases and cataracts in European populations from the IEU OpenGWAS project. Multivariable MR was performed to account for lipid-related confounders. A two-step MR analysis was conducted to investigate the potential mediating role of 1400 plasma metabolites.

After Bonferroni correction and validation using additional cataract GWAS datasets, gastroesophageal reflux disease (GERD; odds ratio [OR] = 1.131, P = 5.85e-5) and celiac disease (OR = 1.012, P = 0.002) were found to be associated with increased risks of cataracts. Subgroup analyses revealed that GERD was specifically associated with senile cataract, whereas celiac disease showed suggestive causal relationships with senile cataract, drug-induced cataract, and other cataract types. RNF5 was downregulated in both celiac disease and lens injury models and was identified as a significant protective factor for senile and other cataracts. Furthermore, the causal effects of GERD and celiac disease on cataracts remained robust after adjusting for lipid profiles, suggesting independence from lipid-related pathways. Notably, 1-linoleoyl-GPE (18:2) was identified as a potential mediator of the causal pathway between GERD and cataract risk (β = 0.008, P = 0.035).

These findings reveal causal effects between cataracts and gastrointestinal diseases, providing new insights into their potential biological links.

This study revealed a possible association between cataracts and gastrointestinal diseases, supporting the need for targeted screening and early intervention strategies in at-risk populations to improve cataract prevention and comorbidity care.