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. 2023 Oct 12;23(1):162.
doi: 10.1186/s12894-023-01332-4.

Causal effects of inflammatory bowel diseases on the risk of kidney stone disease: a two-sample bidirectional mendelian randomization

Huayang Zhang #  1 , Yong Huang #  2 , Junyong Zhang  1 , Huiyi Su  3 , Chengguo Ge  4
Affiliations

Causal effects of inflammatory bowel diseases on the risk of kidney stone disease: a two-sample bidirectional mendelian randomization

Huayang Zhang et al. BMC Urol. .

Abstract

Background: Existing epidemiological observational studies have suggested interesting but inconsistent clinical correlations between inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), and kidney stone disease (KSD). Herein, we implemented a two-sample bidirectional Mendelian randomization (MR) to investigate the causal relationship between IBD and KSD.

Methods: Data on IBD and KSD were obtained from Genome-Wide Association Studies (GWAS) summary statistics and the FinnGen consortium, respectively. Strict selection steps were used to screen for eligible instrumental SNPs. We applied inverse variance weighting (IVW) with the fix-effects model as the major method. Several sensitivity analyses were used to evaluate pleiotropy and heterogeneity. Causal relationships between IBD and KSD were explored in two opposite directions. Furthermore, we carried out multivariable MR (MVMR) to obtain the direct causal effects of IBD on KSD.

Results: Our results demonstrated that CD could increase the risk of KSD (IVW: OR = 1.06, 95% CI = 1.03-1.10, p < 0.001). Similar results were found in the validation group (IVW: OR = 1.05, 95% CI = 1.01-1.08, p = 0.013) and in the MVMR analysis. Meanwhile, no evidence of a causal association between UC and KSD was identified. The reverse MR analysis detected no causal association.

Conclusions: This MR study verified that CD plays a critical role in developing kidney stones and that the effect of UC on KSD needs to be further explored.

Keywords: Bidirectional mendelian randomization; Crohn’s disease; Inflammatory bowel disease; Kidney stone disease; Ulcerative colitis.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Study design overview. Notes: MR analysis follows 3 key assumptions: (I) Genetic variants applied as IVs should be robustly correlated with exposure; (II) Genetic variants applied are supposed not to link to any confounders; (III) Genetic variants selected should affect the risk of KSD only via IBD rather than other pathways. The orange line represents a Mendelian analysis of the genetic correlation between IBD (including CD and UC) and KSD; The blue line represents a Mendelian analysis of the genetic correlation between KSD and IBD (including CD and UC). Abbreviations: FinnGen, FinnGen Consortium; IBD, inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis
Fig. 2
Fig. 2
Flow chart on how to perform MR analysis step by step. Abbreviations: SNPs, single-nucleotide polymorphisms; MR-PRESSO, MR-Pleiotropy Sum and Outlier method; val, validation; IBD, inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis; KSD, kidney stone disease
Fig. 3
Fig. 3
Forest plots of causal estimates for the effect of IBD, CD and UC on KSD using fix-effects IVW method. (A) Forest plots of causal estimates for the effect of IBD on KSD. (B) Forest plots of causal estimates for the effect of CD on KSD. (C) Forest plots of causal estimates for the effect of UC on KSD. ORs for KSD were scaled to genetically predicted IBD, CD and UC. Abbreviations: OR, odds ratio; CI, confidence interval; IBD, inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis; val, validation
Fig. 4
Fig. 4
Comparison of Mendelian randomization estimates of IBD, CD and UC on KSD after removing pleiotropic genetic variants. Abbreviations: IBD, inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis; val, validation; IVW-FE, inverse variance weighted with fixed effects model; OR, odds ratio; *Pleiotropic SNPs excluded
Fig. 5
Fig. 5
Causal estimates of IBD, CD and UC on KSD in MVMR. Abbreviations: IBD, inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; TG: Triglycerides; BMI: Body mass index; OR, odds ratio
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