A study on the correlation between microRNA and liver cirrhosis

doi:10.21203/rs.3.rs-4808493/v1

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A study on the correlation between microRNA and liver cirrhosis

https://doi.org/10.21203/rs.3.rs-4808493/v1

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Background: MicroRNAs (miRNAs) occupy a pivotal position in the intricate machinery of gene regulation. However, the potential causal linkage between miRNA and cirrhosis remains unexplored. This study attempts to investigate this causal relationship in depth through various methods such as Mendelian randomization (MR).

Methods: This study uncovered the causal relationship between miRNA and cirrhosis through the utilization of pertinent data. Employing a two-sample MR design, the investigation was conducted utilizing five different methods: the inverse variance weighted (IVW) method, the MR Egger method, the weighted median method, the simple mode method, and the weighted mode method. To ensure the robustness of our findings, we conducted a thorough sensitivity analysis encompassing Cochran's Q test, the MR Egger intercept test, MR-PRESSO, and leave-one-out analysis. Furthermore, to strengthen the validation of the causal effects, we performed meta-analysis on data gathered from diverse platforms. Ultimately, we delved into potential mechanisms of action by predicting the target genes of corresponding miRNAs and analyzing their functional enrichment.

Results: A total of seven miRNAs were identified as being associated with the risk of cirrhosis. Notably, the instrumental variables (IVs) employed in this study exhibited no significant heterogeneity or horizontal pleiotropy. The results of the meta-analysis further confirmed that hsa-miR-27b-3p was a risk factor for liver cirrhosis, while hsa-miR-1303 had a protective effect. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the target genes corresponding to hsa-miR-27b-3p were significantly enriched in pathways such as cell cycle, oxidative stress, and cell fibrosis, while the target genes corresponding to hsa-miR-1303 were mainly enriched in pathways such as amino acid metabolism.

Conclusion: Our research findings not only identified potential miRNA biomarkers that could significantly contribute to the diagnosis and treatment of cirrhosis, but also paved new avenues for future study in this domain.

Cirrhosis

miRNAs

Mendelian randomization

meta-analysis

biomarker

Cirrhosis, a chronic and relentlessly advancing liver malady, primarily stems from widespread liver cell necrosis. Characterized by the extensive proliferation of fibrous tissue, it engenders nodules and pseudolobules, ultimately disrupting the liver's anatomical integrity and blood supply. The etiology encompasses a multitude of factors, with viral hepatitis (hepatitis B and C foremost), chronic alcohol abuse, nonalcoholic fatty liver disease (NAFLD), prolonged cholestasis, exposure to drugs or toxins, circulatory disturbances within the liver, genetic and metabolic disorders, immune imbalances, and parasitic infections topping the list [1].

Globally, cirrhosis stands as a formidable cause of liver-related mortality, claiming millions of lives annually. Statistics reveal it ranks as the 11th most prevalent cause of death worldwide, underscoring its dire impact on public health [2]. Despite remarkable advancements in cirrhosis diagnosis, treatment modalities, and management strategies in recent times, clinical interventions often fall short in offering substantial long-term survival benefits to certain patients. Consequently, intensifying efforts towards cirrhosis prevention, early detection, and effective treatment holds paramount significance in mitigating its global burden.

As a type of short (approximately 22 nucleotides) non-coding RNA, miRNAs occupy a pivotal position in the regulation of gene expression. They play indispensable roles in diverse biological processes, ranging from the determination of cell fate and embryonic development to the modulation of cell proliferation, differentiation, and apoptosis [3, 4]. Even more noteworthy is the fact that miRNAs have emerged as exceptionally valuable biomarkers in the context of certain diseases [5, 6]. Furthermore, as research progresses, mounting evidence indicates that extracellular circulating miRNAs can be detected in biological fluids such as blood, urine, serum, plasma, and cerebrospinal fluid [7, 8]. These miRNAs exhibit remarkable chemical stability, thereby offering novel perspectives and avenues for the diagnosis and treatment of a wide range of diseases [9].

Recognizing the significant role of miRNAs in physiological and pathological processes, numerous research teams have embarked on exploring the potential link between miRNA and cirrhosis [10]. Nevertheless, traditional research designs face challenges in disentangling reverse causal relationships and confounding factors, potentially introducing bias into the findings. Additionally, previous studies have primarily concentrated on uncovering correlations between miRNA and cirrhosis, with limited focus on causal relationships, thereby limiting the potential and reliability of miRNA as biomarkers for cirrhosis to a certain extent [11].

MR is a highly influential research methodology that ingeniously harnesses genetic variations as IVs to precisely estimate the causal effect of exposure factors on outcomes [12]. In MR studies, confounding bias is greatly diminished, as genetic variations are randomly assigned at birth, thus ensuring the objectivity and accuracy of research findings [13]. Additionally, as genetic variations are established prior to disease progression, the likelihood of reverse causality is effectively negated. Owing to its distinctive advantages, the MR method has been extensively employed to delve into the causal relationship between miRNAs and various diseases, including but not limited to COVID-19 [14], inflammatory bowel disease [15], amyotrophic lateral sclerosis [16], Parkinson's disease [17], and lung cancer [18]. This approach has furnished novel insights and methodologies for disease research, clinical diagnosis, and treatment.

Utilizing methods such as MR and meta-analysis, this study comprehensively examined the potential causal relationship between miRNA and cirrhosis from multiple perspectives. The findings uncovered potential association mechanisms, thereby offering novel directions and theoretical frameworks for the diagnosis and treatment of cirrhosis.

Study design

To delve into the potential causal link between miRNA and cirrhosis, we acquired ample and diverse relevant data from various platforms and conducted a two-sample MR study. In constructing our MR model, we grounded it on three fundamental assumptions: (1) a strong correlation existed between genetic variation and exposure data; (2) genetic variation was uncorrelated with potential confounding factors; and (3) the effect of genetic variation on outcomes was solely mediated through the specific exposure factors under investigation [19, 20]. In this study, we employed multiple methods for MR and sensitivity analysis to ensure the robustness and credibility of our findings. Meta-analysis was utilized to scrutinize data across various platforms, while four databases served as the foundation for predicting potential target genes. Additionally, enrichment analysis was conducted on these target genes, leveraging two databases.

Exposure data

Drawing upon previous high-quality research, our study successfully procured pivotal data on miRNA expression quantitative loci (eQTLs) [21]. During the data processing and analysis phase, we rigorously corrected and adjusted for potential confounding factors, including gender, age, the top ten principal components, and genotype batches, to ensure the precision and reliability of our results.

Outcome data

In order to comprehensively study the causal relationship between miRNA and cirrhosis, we collected GWAS summary statistical data of four cirrhosis-related phenotypes, including bbj-a-105 and ebi-a-GCST90018826 from the IEU OpenGWAS project database, as well as finngen_R10_CIRRHOSIS_BROAD and finngen_R10_CHIRHEP_NAS from the FinnGen database.

Selection criteria of instrumental variables

Adhering strictly to the three cornerstone assumptions outlined in the study's design, rigorous quality control measures were implemented for single nucleotide polymorphisms (SNPs), ensuring the robustness of our findings. In line with prevailing practices in contemporary MR studies, we employed a genome-wide significance threshold of p < 5×10 − 8 to rigorously screen and filter SNPs. To maintain the independence among instrumental variables (IVs), we employed linkage disequilibrium clumping with a 10MB window and an R2 threshold of less than 0.001. Furthermore, to mitigate potential bias resulting from suboptimal instruments, we calculated F-statistics for each SNP as a measure of statistical robustness. As a result, only SNPs with robust instrumental variables, defined as F-statistics exceeding 10, for each exposure were retained. Additionally, ambiguous and palindromic SNPs, whose effects could not be accurately harmonized, were rigorously excluded from our analysis. Given the propensity of MR to generate false positives in the context of genetic correlations between traits, we rigorously excluded SNPs exhibiting associations with the outcome variable (cirrhosis) [22, 23]. As we all know, the causes of cirrhosis are multifarious, encompassing viral hepatitis (particularly hepatitis B and C), chronic alcoholism, NAFLD, persistent cholestasis, exposure to drugs or toxins, liver blood flow abnormalities, genetic and metabolic conditions, immune system disorders, and parasitic infections [24, 25]. Consequently, in this study, we have rigorously excluded instrumental variables (IVs) that showed significant associations with these confounding factors.

Mendelian randomization analyses

To evaluate the causal relationships between miRNA and cirrhosis, we employed five distinct MR methods: IVW, MR Egger, weighted median, simple mode, and weighted mode. Of these, the IVW method served as the primary analytical tool [26]. The IVW method simulates the randomization process, effectively bypassing potential collinearity issues between genetic variations and confounding factors. This approach not only strengthens the reliability of causal inference but also enables a more precise assessment of genes' contributions to specific traits or diseases [27]. Moreover, the inverse variance weight is calculated by considering the estimated effect variance of each genetic variation, giving higher weights to those with lower variances, thus minimizing estimation errors [28]. It is worth noting that in the IVW analysis, confounding factors are rigorously controlled, and sensitivity analysis is conducted, distinguishing it from other MR methods [29].

Sensitivity analysis

A rigorous sensitivity analysis has been conducted to identify and mitigate the potential impact of pleiotropy and heterogeneity on MR estimates. Utilizing Cochran's Q test, we found no significant heterogeneity among the data when the p-value exceeded 0.05 [30]. To preliminarily assess pleiotropy, we examined the intercept of the MR Egger regression, considering a p-value less than 0.05 as an indication of potential pleiotropic effects among the instrumental variables [31]. Furthermore, we employed the MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) techniques to evaluate and correct for horizontal pleiotropy [32]. Additionally, a Leave-one-out analysis was performed to determine if the MR estimate was influenced or biased by any individual SNP.

Statistical analysis

To minimize the influence of multiple testing in our primary analyses, we implemented a false discovery rate (FDR) correction utilizing the q-value procedure, setting a threshold of q-value less than 0.1 [33]. miRNA and cirrhosis were considered to exhibit a nominal association if the p-value fell below 0.05 but the q-value remained greater than or equal to 0.1. All these analyses were conducted using the Two-Sample MR package (version 0.5.6) and the qvalue package (version 2.15.0) within the R programming environment (version 4.3.3), ensuring the rigor and reproducibility of our findings.

Meta analysis and miRNA target prediction

To validate the potential causal relationship between miRNA and cirrhosis across diverse platforms, we conducted meta-analysis, thereby strengthening the credibility of our findings. To gain further insights into the potential functions of these miRNAs, we harnessed four databases: miranda, mirdb, pictar, and targetscan [34], to predict their corresponding target genes. Ultimately, we performed an in-depth enrichment analysis on the predicted target genes, leveraging GO and KEGG databases, to explore their enrichment in specific biological processes and elucidate the potential regulatory mechanisms of certain miRNAs on cirrhosis.

Based on the selection criteria for IVs, the F-statistics of the genetic instruments employed in this study surpassed the commonly adopted threshold of 10, indicating their robustness and minimal potential for adverse effects on the research outcomes. To comprehensively assess the potential causal relationship between miRNA and cirrhosis, we executed a MR analysis employing five distinct MR methods. IVW analysis revealed that seven miRNAs (hsa-miR-27b-3p, hsa-miR-30a-3p, hsa-miR-100-5p, hsa-miR-151a-5p, hsa-miR-183-3p, hsa-miR-494, and hsa-miR-1303) were closely correlated with cirrhosis (Fig. 1). While the research findings primarily relied on the IVW method, the integration of five distinct MR techniques and the consistency in results across each approach further strengthened the credibility of our research outcomes.

To evaluate the robustness of our previous findings, we conducted a comprehensive series of sensitivity analyses, including Cochran's Q test, the MR Egger intercept test, and the MR-PRESSO global test. Notably, all resulting p-values surpassed the 0.05 threshold, indicating no significant heterogeneity or horizontal pleiotropy. Additionally, to detect any potential bias stemming from high-influence SNPs skewing the MR outcomes, we performed leave-one-out analysis. This analysis confirmed that no single SNP independently influenced the results, further enhancing the credibility and reliability of our findings (Fig. 2).

To mitigate potential biases arising from diverse data sources, we conducted rigorous meta-analysis of the results across different database sources, aiming to clarify the effect of certain miRNA on cirrhosis. Research had found that in all four sets of data from two platforms, hsa-miR-27b-3p was indeed a risk factor for liver cirrhosis, while hsa-miR-1303 had the opposite effect (Fig. 3). To further investigate the potential role of hsa-miR-27b-3p and hsa-miR-1303 in cirrhosis, we employed four databases: miranda, mirdb, pictar, and targetscan, to predict the potential regulatory target genes. Our analysis yielded a total of 75 unique genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the target genes corresponding to hsa-miR-27b-3p were significantly enriched in pathways such as cell cycle, oxidative stress, and cell fibrosis, while the target genes corresponding to hsa-miR-1303 were mainly enriched in pathways such as amino acid metabolism (Fig. 4,5).

In this study, we performed a genome-wide MR analysis to elucidate the causal association between miRNA and cirrhosis. Among the seven miRNAs identified as potentially related to cirrhosis, hsa-miR-27b-3p was indeed a risk factor for liver cirrhosis, while hsa-miR-1303 had the opposite effect. Our findings demonstrated that the target genes of hsa-miR-27b-3p exhibited marked enrichment in vital pathways, encompassing cell cycle regulation, oxidative stress response, and cellular fibrosis, implying their intricate involvement in the onset and progression of liver cirrhosis. Additionally, the target protein of hsa-miR-1303 was predominantly enriched in amino acid metabolism pathways, particularly those involving arginine, glutamine, and ornithine, which underscored its potential therapeutic and rehabilitative significance for liver cirrhosis. These discoveries not only reinforced the pivotal role of these two miRNAs in liver cirrhosis but also shed light on potential underlying mechanisms of action, fostering new avenues for research and therapeutic intervention.

Cirrhosis represents an advanced pathological stage stemming from the prolonged evolution of various chronic liver ailments. It is distinguished by chronic inflammation within the liver, widespread fibrosis, the formation of pseudolobules, and the proliferation of blood vessels both within and surrounding the organ. This intricate process disrupts the liver's normal architecture and blood flow, ultimately impairing its vital functions. Among the primary culprits driving the development of cirrhosis are viral hepatitis (notably hepatitis B and C), chronic alcohol abuse, non-alcoholic fatty liver disease, liver damage induced by medications or chemical toxins, circulatory disturbances within the liver, genetic and metabolic disorders, immune system irregularities, and parasitic infections. To arrive at a cirrhosis diagnosis, a comprehensive appraisal of the patient's medical background, symptomatic presentation, and liver function tests is essential. Once confirmed, the therapeutic approach encompasses drug regimens, surgical interventions, and other modalities tailored to the individual's unique circumstances.

Cirrhosis is a grave liver condition, and its prognosis hinges on factors such as disease severity and the timeliness and efficacy of treatment. Consequently, for individuals at risk of liver disease, regular health check-ups and screening measures are paramount for early identification and intervention to manage cirrhosis and its associated complications. The overarching goal of this study was to unravel the causal nexus between miRNA and cirrhosis, aiming to pave the way for novel therapeutic avenues. Recent pertinent research report had highlighted the significant overexpression of hsa-miR-27b-3p within endothelial cells, underscoring its pivotal role in mitigating mitochondrial oxidative stress and inflammation [35]. A separate investigation has pointed towards a possible association between hsa-miR-27b-3p, along with its regulated target genes, and the phenomenon of premature aging [36]. hsa-miR-27b-3p has also been definitively implicated in the regulation of target genes that were integral to the tumor necrosis factor alpha signaling pathway [37]. Comprehensive bioinformatics analysis has confirmed that the target genes modulated by hsa-miR-27b-3p exhibited a marked enrichment in pathways pertaining to cell cycle regulation, transcription, cell proliferation, as well as the gonadotropin-releasing hormone signaling cascade [38]. Utilizing RT-qPCR methodology, it was further validated that compared to normal gastric tissue, has-miR-27b-3p exhibited significant aberrant expression levels in GC (gastric cancer) tissue [39]. The invasive nature of liver biopsy posed challenges to the histopathological diagnosis of non-alcoholic fatty liver disease (NAFLD), resulting in suboptimal diagnostic performance. However, hsa-miR-27b-3p emerged as a promising novel diagnostic biomarker for NAFLD, offering an alternative approach [40]. Investigations have revealed that hsa-miR-1303 participated in protein binding as well as in various cellular components, thereby contributing to diverse biological processes [41]. Comprehensive expression correlation studies coupled with luciferase-based target validation have conclusively demonstrated that hsa-miR-1303 exerted regulatory control over cholesterol biosynthesis by targeting and modulating key genes within this metabolic pathway [42]. hsa-miR-1303 also held significant potential as a biomarker, facilitating the exploration of underlying pathogenesis and the development of targeted treatment strategies for various liver diseases [43]. Both hsa-miR-100-5p and hsa-miR-494 have been identified as microRNAs that exhibited a notable association with liver diseases, highlighting their potential involvement in disease pathogenesis [44, 45]. In summary, the findings of this study aligned with those of prior research endeavors, paving the way for future endeavors to delve deeper into the intricate relationship between the pertinent miRNAs and the development of liver cirrhosis.

This study boasts several noteworthy strengths. Foremost, by utilizing MR analysis, we have emulated the rigor of randomized controlled trials within an observational framework, a methodology widely recognized for its causal inference capabilities. This approach significantly mitigated the potential for reverse causation and confounding factors that often plagued traditional observational studies. Furthermore, our rigorous sensitivity analyses revealed no significant heterogeneity or pleiotropy, indicating the robustness of our findings. Our work marked the inaugural attempt to leverage MR analysis to explore the causal nexus between miRNA and cirrhosis, offering novel biomarkers that hold promising potential for the prevention and treatment of cirrhosis.

In this study, we conducted a comprehensive MR analysis, identifying multiple miRNAs that might be implicated in cirrhosis. However, it was noteworthy that our study was not without limitations. Firstly, the sample size of the miRNA eQTL data was relatively modest. Secondly, the diverse racial backgrounds of our study cohort might constrain the generalizability of our research findings to other racial groups. Lastly, our work offered only a partial glimpse into the intricate relationship between specific miRNA and cirrhosis, in the future, rigorous in vitro and in vivo experiments could be undertaken to rigorously validate and deepen our understanding of the intricate relationship between the pertinent target genes and the pathogenesis of liver cirrhosis.

In this study, we have pinpointed two miRNAs that held promise in exerting influence on cirrhosis. The aim of this study was to identify biomarker that was beneficial for the diagnosis and treatment of cirrhosis, opening up new directions for future research.

Ethics approval and consent to participate

Not Applicable.

Consent for publication

All authors have approved the final manuscript and submission to the journal.

Availability of data and materials

Publicly available datasets were analyzed in this study. This data can be found here:

IEU OpenGWAS project (https://gwas.mrcieu.ac.uk/)

FinnGen (https://www.finngen.fi/en)

Author Contributions

Conceptualization: SY. Methodology: DZ and JY. Writing: JY. Review and editing: SY. All authors contributed to the article and approved the submitted version.

Conflict of interest

The authors declared that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Fund

There was no funding project support for this study.

Acknowledgments

We gratefully acknowledged the IEU OpenGWAS project and FinnGen for making their GWAS summary-level statistics publicly available.

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No competing interests reported.

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Editorial decision: Revision requested
29 Jul, 2024
Editor assigned by journal
28 Jul, 2024
Submission checks completed at journal
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First submitted to journal
26 Jul, 2024

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A study on the correlation between microRNA and liver cirrhosis

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Abstract

Figures

Introduction

Materials and methods

Study design

Exposure data

Outcome data

Selection criteria of instrumental variables

Mendelian randomization analyses

Sensitivity analysis

Statistical analysis

Meta analysis and miRNA target prediction

Results

Discussion

Conclusion

Declarations

References

Additional Declarations

Status:

Version 1