Miaozhi Yu, Yuan Shang, Lingling Han, Xi Yu

Department of General Surgery, Xinhua Hospital Affiliated to Dalian University, Dalian, 116011, People’s Republic of China

Correspondence: Xi Yu, Tel +86 411-84323794, Email 3813538751@qq.com

Purpose: Hemorrhoids (HEM) are the most common perianal disease, but current observational studies have yielded inconsistent results in investigating the risk factors. Our further exploration of the risk factors will help prevent the disease.
Patients and Methods: We conducted a two-sample bidirectional Mendelian randomization (MR) analysis using publicly available genome-wide association studies (GWAS) statistics from multiple consortia. The inverse-variance weighted (IVW) method was used for the primary analysis. We applied four complementary methods, including weighted median, weighted mode, MR-Egger regression, and Cochrane’s Q value, to detect and correct the effects of horizontal pleiotropy.
Results: Genetically determined constipation (OR = 0.97, 95% CI: 0.91– 1.03, P = 0.28) and diarrhea (OR = 1.00, 95% CI: 0.99– 1.01, P = 0.90) did not have a causal effect on HEM but stool frequency (OR = 1.28, 95% CI: 1.05– 1.55, P = 0.01), waist-to-hip ratio adjusted for BMI (OR = 1.11, 95% CI: 1.06– 1.64, P = 1.59× 10-5), and order Burkholderiales (OR = 1.09, 95% CI = 1.04– 1.14, p = 1.63× 10-4) had a causal effect on. Furthermore, we found a significant causal effect of constipation on HEM in the reverse MR analysis (OR = 1.21, 95% CI: 1.13– 1.28, P = 3.72× 10-9). The results of MR-Egger regression, Weighted Median, and Weighted Mode methods were consistent with those of the IVW method. Horizontal pleiotropy was unlikely to distort the causal estimates, as indicated by the sensitivity analysis.
Conclusion: Our MR analysis reveals a causal association between stool frequency and waist-to-hip ratio with HEM, despite variations in results reported by observational studies. Unexpectedly, we found a relationship between the order Burkholderiales in the gut flora and HEM, although the mechanism is unclear.

Keywords: hemorrhoids, HEM, gut microbiota, GM, constipation, diarrhea, stool frequency, waist-to-Hip ratio