Assessing causality between inflammatory bowel diseases with frailty index and sarcopenia: a bidirectional Mendelian randomization study

Abstract

Background: Previous studies have found that frailty and sarcopenia are commonly diagnosed in inflammatory bowel disease (IBD) patients, indicating an association between these conditions. Nonetheless, the cause‒effect connection between IBD, frailty, and sarcopenia remains unclear.

Methods: We sourced the genetic variants for the exposures and outcomes from publicly accessible, extensive genome-wide association studies (GWAS). Specifically, we obtained IBD data from the International IBD Genetics Consortium, frailty index (FI) data from the United Kingdom Biobank and Swedish TwinGene, and sarcopenia data from a recent GWAS meta-analysis. Five methods, including inverse variance weighted (IVW), simple mode, MR-Egger, weighted mode, and the weighted median, were used to proceed with MR estimates. We also performed heterogeneity and horizontal pleiotropy tests.

Results: Our results indicated a positive causal relationship between ulcerative colitis (UC) (IVW: β = 0.014, 95% CI, 0.006 to 0.021, p = 0.001) and Crohn's disease (CD) (IVW: β = 0.012; 95% CI, 0.006 to 0.018, p = 2e-04) with the FI. However, we uncovered no proof of a cause-and-effect relationship between UC (IVW: β = 0.001, 95% CI, -0.015 to 0.017, p = 0.344) or CD (IVW: β = 0.003, 95% CI, -0.009 to 0.015, p = 0.214) and sarcopenia. Additionally, in the inverse order, we also discovered no cause-and-effect connection between FI or sarcopenia on UC or CD in this study.

Conclusion: The MR analysis showed a positive causal association between IBD and FI, indicating that IBD patients may exhibit aging-related characteristics. Therefore, frailty assessments should be conducted as early as possible in IBD patients.

Keywords: Frailty; Inflammatory bowel disease; Mendelian randomization; Sarcopenia.

Fig. 1

The methodology of implementing a bidirectional Mendelian randomization (MR) examination. The sign " × " suggests that genomic changes are disconnected from confounding elements or do not directly affect the outcome. Rather, they wield their impact via the exposure pathway. A persistent line is indicative of a substantial link, while a discontinuous line shows no interrelation between the variables. SNP: single nucleotide polymorphism; UC, ulcerative colitis; CD, Crohn’s disease

Fig. 2

Point diagrams and a funnel illustration were used to portray the causative impact of UC and CD on the frailty index. Research focusing on the influence of UC (A, B) on the frailty index and the impact of CD (C, D) on the frailty index was performed. These studies implemented conventional IVW, simple mode, MR Egger, weighted median and weighted mode methods. The inclination of each line served to compute the MR influence per approach. A funnel chart was adopted for the analysis of variance in the data. The azure line characterizes the IVW prediction, while the deep blue line exhibits the MR-Egger prediction

Fig. 3

Point diagrams and a funnel chart were utilized to demonstrate the causative relationship of UC and CD with sarcopenia. This encompassed studies on the impact of UC on sarcopenia (A, B) and the influence of CD on sarcopenia (C, D). Analyses were performed employing traditional IVW, simple mode, MR Egger, weighted median, and weighted mode methods. The slope of each line represents the estimated MR impact per technique. A funnel chart was used to assess the dispersion or heterogeneity of the data. The azure line characterizes the IVW prediction, while the deep blue line exhibits the MR-Egger prediction

Fig. 4

Point diagrams and a funnel illustration were used to portray the causative impact of the frailty index on UC and CD. This encompassed an examination of how the frailty index affects UC (A, B) and its role in CD (C, D). The analyses were performed using the standard IVW, simple mode, MR Egger, weighted median, and weighted mode methods. The inclination of each line represents the estimated MR influence per method. A funnel chart was deployed to assess the diversity or dispersion in the data. The azure line characterizes the IVW prediction, while the deep blue line exhibits the MR-Egger prediction

Fig. 5

Scatter diagrams and a funnel chart were deployed to depict the cause-and-effect link of sarcopenia on UC and CD. This included an exploration of the impact of sarcopenia on UC (A, B) and its effect on CD (C, D). The research was conducted using conventional IVW, simple mode, weighted median, MR Egger, and weighted mode strategies. The gradient of each line symbolizes the approximated MR effect per technique. A funnel chart was selected to gauge the heterogeneity in the data. The azure line characterizes the IVW prediction, while the deep blue line exhibits the MR-Egger prediction