Causal relationship of familial hypercholesterolemia with risk of intestinal vascular disorders: A mendelian randomization study

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The causal relationship between the familial hypercholesterolemia (FH) and intestinal vascular diseases was unnoticed. This study aims to investigate the cause-and-effect relationship of FH with risk of intestinal vascular diseases in human. A Mendelian randomization (MR) analysis was performed by extracting summary-level datasets for FH or FH concurrently with ischemic heart disease (IHD) and intestinal vascular diseases from the FinnGen study including 329,115, 316,290 and 350,505 individuals. The inverse-variance weighted (IVW) method and the weighted median method were applied to analyze the causal relationships between FH or FH concurrently with IHD and the risk of intestinal vascular diseases. Cochran's Q statistic method and MR-Egger regression were used to assess heterogeneity and pleiotropy. The IVW method demonstrated that FH was significantly associated with higher odds of intestinal vascular diseases [OR (95%CI): 1.22 (1.03, 1.45)] ( P = 0.02) without significant heterogeneity ( P = 0.54) and horizontal pleiotropy ( P = 0.43). Rs7575840 in 6.5kda upstream of ApoB gene, rs11591147 in PCSK9 gene and rs9644862 in the CDKN2B-AS1 (or named ANRIL; p15AS ; PCAT12 ; CDKN2BAS ; CDKN2B-AS ; NCRNA00089 ) gene were illustrated to mostly influence the risk of intestinal vascular diseases. However, no significant causal relationship between FH concurrently with IHD and intestinal vascular diseases was observed. In conclusion, FH was causally positive-associated with the increased risk of intestinal vascular diseases, revealing a potential unfortunate outcome for FH. Therefore, patients with FH should pay closely attention to the risk of intestinal vascular diseases. Our study may provide evidence for new diagnostic and therapeutic strategies in clinical practices. • FH was significantly associated with higher odds of intestinal vascular diseases. • The causal link of FH and intestinal vascular disease was solid without significant heterogeneity and horizontal pleiotropy. • The risk of intestinal vascular disease was associated with ApoB , PCSK9 and CDKN2B-AS1 . • No significant causal relationship was found between FH coupled with IHD and intestinal vascular diseases.

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