Human haemorrhoidal disease (HEM) is a common anorectal pathology. However, being one of the diseases that affect a wide range of people, the etiology of HEM, as well as its molecular mechanism, remains primarily unclear. In this study, we applied a two-sample bi-direction Mendelian randomization (MR) framework to estimate the causal effects of 4677 plasma proteins on HEM outcomes and investigated the mediating impacts of plasma proteins on HEM risk factors to uncover potential HEM treatment targets by integrating GWASs statistics of HEM and plasma protein levels. Following MR analysis, our study identified 13 probable causal proteins associated with HEM. Particularly, genetically predicted OLFM1 levels were linked to an increased risk of HEM. In addition, it was discovered that a genetically greater risk of myxoedema, diverticular disease, and ulcerative colitis was linked to an elevated risk of HEM (FDR<0.05). However, there was no evidence that dorsalgia, hernia, and ankylosing spondylitis were causally associated with HEM. Interestingly, a higher risk of myxoedema was associated with higher genetically predicted OLFM1 levels. Finally, mediation analysis suggested that the effect of myxoedema on HEM via OLFM1 might explain 32.8% of the mediation effect. Overall, this study identified some causal associations of circulating proteins and risk factors with HEM by integrating the largest-to-date plasma proteome and GWASs of HEM. The findings could provide further insight into understanding biological mechanisms for HEM.

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