We read with interest the recent report by Zheng et al which reported the first and largest genome-wide association study (GWAS) with haemorrhoidal disease (HEM), and these data offered us a resource for understanding the genetic risk factors for HEM.1 However, the aetiology of HEM, as well as its molecular mechanism, remains primarily unclear.2 In addition, the identification of proteins with therapeutic effects needs to be conducted. In recent years, by incorporating protein quantitative trait loci (pQTLs) into Mendelian randomisation (MR) analysis, such an approach has been successfully used to prioritise drug targets.3 4 Here, using a two-sample bidirectional MR analysis, we estimated the causal effects of 4907 plasma proteins on HEM outcomes, and investigated the effects of plasma proteins that may mediate the impact of risk factors on HEM.

As stated in the online supplemental methods, 4907 proteins (cis-pQTLs) were used as instrumental variables for exposure and HEM as the outcome to estimate the causal effect of plasma protein levels on HEM in a proteome-wide context using MR analysis.5–8 Our study revealed five potential causative proteins at the Bonferroni-corrected threshold of p<1.01e-05, including three negative and two positive associations (figure 1A,B). MR analysis, for example, revealed that genetically predicted ERLEC1 levels were linked to an increased risk of HEM (p=5.18e-07). To determine whether the identified relationships of the …