Height and risk of liver fibrosis progression: A multivariable Mendelian randomization study

doi:10.21203/rs.3.rs-3096688/v1

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Height and risk of liver fibrosis progression: A multivariable Mendelian randomization study

https://doi.org/10.21203/rs.3.rs-3096688/v1

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The relationship between liver fibrosis, cirrhosis, and height has been an immensely controversial topic that is unclear. To accurately identify the causal relationship, Mendelian randomization research (MR) has been conducted. For the first time, we employed genome-wide significance (p < 5×10 − 8) levels of genetic variance for Standing height, and Sitting height (exposure) with liver fibrosis, and cirrhosis (outcome). A two-sample MR analysis of standing height, liver fibrosis, and cirrhosis was performed. We discovered that single nucleotide polymorphisms (SNPs) associated with standing and sitting height were both negatively causally related to liver fibrosis and cirrhosis. The ratio (OR) of 0.71 (p = 0.005^**) was employed to determine the causal effect of elevated standing height level (per 1-SD) on the probability of liver fibrosis progression. A ratio (OR) of 0.70 (p = 0.012^*) was calculated to represent the causative influence of elevated sitting height level (per 1-SD) on the probability of liver fibrosis progression. Our MR study hypothesized that the shorter the height, the higher the risk of liver fibrosis progression. These findings suggest early identification of short-stature populations and health education to prevent further development of liver fibrosis in patients with chronic liver disease.

Biological sciences/Genetics/Genetic association study

Health sciences/Gastroenterology/Hepatology/Liver diseases

Liver fibrosis

Liver cirrhosis

Standing height

Sitting height

Mendelian randomization study

Hepatic fibrosis, a medical disorder that results in the formation of scar tissue and changes in the extracellular matrix deposition, may be attributed to chronic liver damage of numerous different etiologies¹. Removal or elimination of the pathogen (e.g., control or cure of viral infection) indicates that liver fibrosis is reversible². However, to prevent life-threatening complications, reversals frequently occur excessively slowly or infrequently, especially in advanced fibrosis and cirrhosis ^{3, 4}. Cirrhosis is widely prevalent worldwide and is the 11th leading cause of death as well as the 15th leading cause of morbidity worldwide⁵. Numerous factors, including individual factors (physical traits like height, heavy alcohol consumption), liver diseases (autoimmune diseases, cholestatic diseases), etc., can lead to cirrhosis, which manifests as the deformation of the liver's structural elements and the formation of regenerative nodules⁶. Consequently, the struggle against hepatic fibrosis in chronic liver disease has continuously served a crucial role.

It continues to be highly debatable whether liver fibrosis and cirrhosis correlate with fundamental biological traits, particularly height, which has received less attention from researchers as an independent variable. In the previous literature, when compared to weight, height is considerably more challenging in research which associates it with liver illness (particularly in people who are obese)^7,8. The current research suggests that certain researchers believe that taller people tend to be at a higher risk of liver disease⁹. However, another partial finding revealed that the relationship between it and liver disease had not been that significant¹⁰. Furthermore, there are even studies that indicated that height has a directionally opposite relationship with the risk of chronic liver disease causes^11–14. For instance, "small" liver transplant candidates tend to possess a higher mortality rate and lower transplant rates as compared with their "taller" counterparts^{15, 16}.

Height is a crucial fundamental biological trait that receives special consideration in epidemiological investigations, especially when integrating controls in clinical studies. However, a causal relationship between height and risk of liver fibrosis progression cannot be concluded due to the residual confounding of observational studies (e.g., age, obesity, heavy alcohol consumption, etc.) as well as the inherent challenges of potential reverse causality. Nevertheless, the application of MR methods may be able to effectively address these issues.

Mendelian randomization (MR), a type of statistical method employed in RCT research to identify causal correlations, is based on whole genome sequencing data. By converting phenotype-to-phenotype causal investigations into genotype studies, MR leverages genetic variants as instrumental variables (IVs) to represent specific exposures to infer a causal relationship between exposures and outcomes. Hence, this method may be able to minimize bias driven by confounding variables or reverse causality¹⁷. Similarly, previous MR studies have also examined the risk factors for liver fibrosis and cirrhosis¹⁸ a relationship between height and other diseases had been discovered by the MR studies¹⁹. However, there has been a lack of Mendelian randomization studies on these two aspects.

In order to better comprehend the causal relationship between height and liver fibrosis and cirrhosis, we performed the first multivariate MR analysis in this study. To slow or reverse the progression of liver fibrosis as much as possible in people at high risk for liver disease and who are shorter in stature, we recommend increased screening efforts and disease prevention campaigns.

Study Design

This is a bidirectional two-sample MR and MVMR study. An overview of the study design has been presented in Fig. 1.

GWAS Data Source

Based on the whole gene study and the association statistics obtained from the databases, we selected the UK Biobank (https://www.nealelab.is/uk-biobank) and FinnGen (https://www.finngen.fi/en/node/17) database data. At the same time, two variables, liver fibrosis, and cirrhosis, as well as standing height, had been selected for the construction of genetic factors, the data were of European origin, and the initial GWAS had been approved by the relevant institutional review board.

Exposed GWAS data

Specifically, we selected the standing height component, which was derived from the standing height data in the UK Biobank database body measurements panel, as one of the exposure factors.

As one of the genetic instrumental variables for height, we utilized Ben Elsworth's study on standing height to identify 461,950 participants who utilized the Seca 202 equipment to measure their standing height, which ranged from 75 to 209 cm with a mean of 168.4 cm. subsequently, as one of the exposure factors, we opted for the sit-to-stand height section, which was obtained from the sit-to-stand height data in the UK Biobank database body size measurement panel. Additionally, we employed Ben Elsworth's sitting height study to select 461536 individuals who had measured their sitting height using the Seca 202 instrument. Depending on their standing height, the participants sat on a box with varying seat boxes of 30 cm, 40 cm, and 50 cm. When seated, participants measured the distance between their rump and their crown. The final measured sitting height, one of the genetic instrumental variables for height, ranged from 20 to 124 cm, with a mean of 89.1 cm.

Ending GWAS data

Outcomes included cirrhosis and hepatic fibrosis. The information was retrieved from the FinnGen database by employing the code "K11_FIBROCHIRLIV" for 214,403 European patients with liver fibrosis and cirrhosis, including those with primary biliary cirrhosis, secondary biliary cirrhosis, biliary cirrhosis, other and unspecified cirrhosis, as well as biliary cirrhosis. The final screening report served as a significant genetic variable for cirrhosis and liver fibrosis.

Selection of genetic factors

According to the three predominant assumptions of MR, first, to satisfy the association hypothesis, genetic variants (outcomes) must be strongly associated with exposure (P < 5e-08) LD refers to non-random (nonrandom) associations between alleles (alleles) of different loci (loci), measured using two parameters r² and kb. We set the window to 10,000 kb and r² < 0.01 to ensure the independence of the selected genetic variants. Second, by employing the Phenoscan website, we eliminated confounding sociodemographic and disease state factors, comprising age, obesity, excessive consumption of alcohol, non-alcoholic fatty liver disease, hepatitis B or C infection, autoimmune disease, cholestatic disease, iron or copper overload, that may contribute to liver fibrosis and even cirrhosis⁶. No SNP had been discovered to be associated with confounding factors. Finally, SNPs associated with outcomes were excluded and P2 > 5 × 10 − 5 was set to satisfy the exclusivity assumption. In addition, F-value calculation was performed and SNPs with F < 10 were excluded.

MR analysis method

The initial evaluation of the causal relationship between standing height and liver fibrosis and cirrhosis utilized the inverse variance weighting (IVW) method. Typically employed to aggregate the findings of separate research, it is a method of aggregating two or more random variables to minimize the sum variance, where the weight of each random variable in the sum is inversely proportional to its variance. Since the IVW approach requires that all instrumental variables satisfy the MR assumption, we adopted five methods (MR-Egger, weighted median method²⁰, simple median method, MR-presso²¹, and maximum likelihood) as well as the "IVW" Q statistic for additional sensitivity analysis. We take into account the intercept term's inclusion in the MR-Egger hypothesis and utilize it to evaluate multi-effectiveness. The weighted median approach, or WME, yields consistent effect estimates even when the proportion of invalid instrumental variables is as high as 50% and the precision of the estimates varies significantly between instrumental variables²². The weighted empirical density function of the ratio estimates is what is meant by the term "weighted median approach"¹⁸. The sample median offers evidence for pleiotropy as well, albeit being less reliable than IVW. A popular technique for evaluating horizontal multi-effectiveness is Mr-presso. Therefore, in order to filter out anomalous SNPs (outliers) and estimate the corrected results, we applied the MR-PRESSO global test, MR-PRESSO outlier test, and MR-PRESSO distortion test. Similar to IVW, the maximum likelihood (ML) technique makes the assumption that there is neither horizontal multiplicity of effects nor heterogeneity. The results will be objective and the standard error will be less than IVW if the assumptions are true²³. The Cochran Q statistic is a frequently employed test for heterogeneity²⁴. The Cochran Q statistic is a standardized weighted sum of squares of the variances across studies, and a smaller P value (usually at the level of α < 0.10) indicates the presence of heterogeneity. The Q statistic usually exhibits a high statistical power when the number of included studies is large. Finally, we consider the absence of heterogeneity and pleiotropic effects.

The statistical program R (version 5.0.4) has been employed to analyze all of the aforementioned statistical analyses. The weighted median method, weighted mode method, as well as the IVW method are all implemented in the TwoSampleMR R package. The MR Egger analysis is executed by the MendelianRandomizationR program. Concurrently, the MRPRESSO analysis is conducted through the MR-PRESSO R package.

Statistical analysis

This research has been conducted using consortia providing publicly available summary statistics. All original studies have been approved by the corresponding ethical review board, and the participants have provided informed consent. In addition, no individual-level data were used in this study. Therefore, no new ethical review board approval was required.

	Inverse variance weighted		Egger		MR PRESSO
	Q	Q P	intercept	P	P
Standing height	659.488	0.912	0.002	0.573	0.911
Sitting height	553.575	0.604	-0.002	0.721	0.609

Tbl 1. Trilinear table of standing height, sitting height, and liver fibrosis and cirrhosis levels multivalence and heterogeneity analysis.

Standing height and liver fibrosis, cirrhosis

Without the influence of linkage disequilibrium reaching genome-wide significance levels (p༜5×10 − 8), we acquired 711 IVs (LD, r2 0.001) from standing height GWAS (Supplementary File Table 2). The final included SNPs exhibited F values ranging from 11.7 to 784.6, and they were all strongly associated.

The Mendelian randomization analysis's IVW results revealed that the causal effect of elevated standing height levels (per 1-SD) on the risk of liver fibrosis progression was estimated as a ratio (OR) of 0.71, which was a statistically significant difference (Fig. 2), i.e., the IVW OR: 0.71, 95% Cl: 0.56–0.9, P = 0.005^**. Furthermore, MR Egger OR: 0.63, 95% Cl: 0.38–1.02, P = 0.063, and P = 0.207; weighted median OR: 0.77; 95% Cl: 0.51–1.16; P = 0.747, Weighted mean OR: 0.89 0.89, 95% Cl: 0.43–1.83 Simple median OR was 0.73, 95% Cl was 0.48 to 1.1, and P was 0.14. Maximum likelihood OR was 0.71, 95% confidence interval was 0.56 to 0.9, and the overall OR was 0.74. Second, the scatter plot (Fig. 3) revealed that the six lines of the "Inverse variance weighted," "MR Egger," "Weighted median," "Weighted mode," "Simple mode," and "Maximum likelihood" analyses all displayed consistent slope beta values, and the P values of IVW and Maximum likelihood were coordinated. The combined analysis revealed that height had a significant impact on liver fibrosis and cirrhosis and that they all satisfied the negative relationship. It reveals that standing height is adversely connected with liver fibrosis and cirrhosis, i.e., the higher the risk of liver fibrosis advancement, the shorter the standing height. The funnel plot (Fig. 4) was subsequently observed, and all samples were evenly dispersed and exhibited excellent symmetry on both sides. Additionally, the "MR_PRESSO" global test possesses a P-value of 0.91 which is higher than 0.05. Following our analysis, we discovered that Cochran's Q statistic value was 659.49, which equals a P-value of 0.91 (Tbl 1), which is likewise greater than 0.05 and indicates above that there is no horizontal multiplicity and heterogeneity. Additionally, none of the other significant risk factors were associated with each other.

Sitting height and liver fibrosis, cirrhosis

From a GWAS of sit-stand height, we obtained 565 IVs (LD, r2 0.001) without the effect of linkage disequilibrium reaching genome-wide significance levels (p5 10 − 8) (Supplementary File Table 3). subsequently, we eliminated SNPs (rs118115924) with significant outliers based on the scatter plot (Fig. 3) and funnel plot (Fig. 4). With a total of 564 SNPs taken into account, their F values ranged from 29.9 to 1625.4, and they were all significantly associated.

The IVW results of the Mendelian randomization analysis indicated that the risk of liver fibrosis progression was causally influenced by elevated sit-to-stand body level (per 1-SD) and was estimated as a ratio (OR) of 0.70, which was a statistically significant difference (Tbl 1). In addition, MR Egger OR: 0.78, 95% Cl: 0.41–1.46, P = 0.437, Weighted median OR: 0.78, 95% Cl: 0.49–1.23, P = 0.277, Weighted mode OR: 0.96, 95% Cl: 0.44–2.08, P = 0.919, Simple median OR: 0.74, 95% Cl: 0.47–1.14, P = 0.169, Maximum likelihood OR: 0.71, 95% Cl: 0.54–0.93, P = 0.015^*, and the total OR was 0.78. Second, the scatter plot (Fig. 3) revealed that the six lines of the "Inverse variance weighted," "MR Egger," "Weighted median," "Weighted mode," "Simple mode," and "Maximum likelihood" analyses all displayed consistent slope beta values, and the P values for IVW and Maximum likelihood were coordinated. The combined analysis revealed that sitting and standing height had significant differences in liver fibrosis and cirrhosis, and all of them satisfied the negative relationship. It reveals that sitting height and liver fibrosis and cirrhosis are inversely associated, implying that the higher the risk of liver fibrosis progression, the shorter the sitting height. The funnel plot (Fig. 4) demonstrated that all samples were dispersed equally and symmetrically on both sides. The global test for "MR_PRESSO" has a P-value of 0.61, which is higher than 0.05. Following the completion of our analysis, we demonstrated that Cochran's Q-statistic value was 553.58, which corresponds to a P-value of 0.6 (Tbl 1), which is once again greater than 0.05, and the foregoing illustrates that there is no horizontal multiplicity or heterogeneity. Additionally, none of the other significant risk factors were associated with each other.

Based on the entire GWAS database of standing height, sitting height (exposure), liver fibrosis and cirrhosis (outcome), we conducted the first two-sample MR analysis of exposure (standing height, sitting height) and liver fibrosis progression (liver fibrosis, cirrhosis). This study illustrates the potential value of height profile in liver fibrosis as it revealed a negative causal association between height and the advancement of liver fibrosis.

There has always been a relationship between height and disease, and being short or tall will inevitably have certain impact on health^25,26. For example, being too short can result in complications such as type 2 diabetes²⁷ and psychosocial disorders²⁸ in addition to the dwarfism we know about. Correspondingly, being too tall may also increase the risk of cancer²⁹. A relatively small percentage of studies have examined specifically the relationship between height and cirrhosis and liver fibrosis to date. Leg length was discovered to be negatively correlated with adult liver enzyme levels in previous observational studies of the effects of height on chronic liver disease, and it was discovered that the relationship between torso length and liver enzymes would become less significant when adult lifestyle factors (such as smoking, physical activity, and alcohol consumption) were taken into account. Additionally, adult height had a negative association with the incidence of non-alcoholic fatty liver disease (NAFLD) in both men and women. A 2018 Italian National Survey study analyzed an RR of 0.62 for height and cirrhosis³⁰. According to the results obtained from the present research, one of the few studies on chronic liver illness supported our hypothesis that liver fibrosis progression is more likely to occur in people with shorter birth heights.

Furthermore, in other studies analyzed in previous studies of liver fibrosis and cirrhosis, liver volume (LV) had been positively correlated with height, and the mean caudate lobe volume in patients with Child-Pugh class A was 36.83 +/- 22.11 cm3, which was significantly greater than the values in patients with Child-Pugh class B and C³¹. Patients with liver fibrosis and cirrhosis had significantly reduced the liver volume^32,33. However, there are relatively few studies in healthy populations with susceptibility to progressive liver fibrosis, or even cirrhosis as observational studies, even when confounding factors are taken into account, may be subject to biases that undermine validity (e.g., residual confounding). As a result, the ability to answer questions of causality has been at an impasse. Simultaneously, randomized controlled trials (considered the gold standard for testing hypotheses) are confronted with more challenges to overcome as they will involve objective factors such as excessive study time and easy subject dislodgement. In this case, we adopted the MR analysis to identify the association between height and liver fibrosis and cirrhosis, excluding confounding factors of sociodemographic and disease status that could lead to liver fibrosis and cirrhosis, as well as excluding SNPs associated with outcomes to ensure that they were all strongly associated genetic factors with F > 10, which were finally evaluated with multiple analyses. This approach of MR will be able to provide critical information on causal relationships of public health importance so as to inform guidelines and health guidance.

Height differences are related to multiple factors such as the pituitary-growth hormone axis (growth hormone ^34–36, etc.), genes^37,38, society, and environment³⁹, while liver stiffness is positively correlated with visceral fat and ALT, γ-GT and AST, and fat mass⁴⁰. We hypothesize that this height disparity affects the liver in a variety of ways, which comprises size, nutritional status⁴¹, blood supply, and susceptibility to external factors that damage the liver, resulting in changes to the liver's texture (fatty changes, fibrous changes, etc.), ultimately promoting the development of liver fibrosis and cirrhosis disease processes.

This early identification may be able to effectively allow individuals to alter their lifestyle such that people with short stature can compensate for the lack of height by achieving equilibrium in other ways (increased nutrition^42–44, physical activity^45–47, etc.) to prevent further development of liver fibrosis in chronic liver disease. At the same time, We propose that health education may be utilized to achieve disease prevention before illness in individuals who are shorter, which has consequences for clinical and public health for both the present and the future. Likewise, future research is essential to comprehensively understand the processes behind the association between height and the risk of cirrhosis and liver fibrosis.

Strengths of the study

For the first time, we performed Mendelian randomization research to examine the causal relationship between height and liver fibrosis and cirrhosis. These analyses of Mendelian randomization offer an array of benefits. At the outset, we were able to mitigate the potential effects of confounding variables and reverse causality observed in observational studies by employing randomly assigned variants as instrumental variables. In addition, to enhance the accuracy of the estimates, we incorporated estimates from studies with greater sample sizes (standing height, up to 461950; sitting height, up to 461536; and liver fibrosis, cirrhosis, up to 214403). Furthermore, bioinformatics possesses the capacity to measure genetic variation with high precision, which significantly minimizes estimation bias that is brought on by measurement errors and strengthens the validity of study outcomes. Following that, our analysis integrated databases with results from more current studies. Ultimately, several methods (MR-Egger, Cochran Q, MR-PRESSO, weighted median method, simple median method, maximum likelihood method, and exclusion of outlier pleiotropic SNPs) have been employed to successfully identify and correct for potential pleiotropy bias.

Limitations

Initially, as genetic information was not available, we were merely able to perform analyses of European ethnicity for height, liver fibrosis, and cirrhosis. Hence, the genetic diversity renders it challenging to draw conclusions about the causes of racial differences, thus a multiracial sample is recommended. Subsequently, as we were unable to differentiate the results into how much the specific influence of height is under both sexes due to the fact that we failed to gather separate height data for men and women. As such, we must acquire more height data for both genders to boost the accuracy of the results.

Our MR study hypothesized that the shorter the height, the higher the risk of liver fibrosis progression. Hence, we recommend that health promotion can be adopted to effectively achieve the goal of prevention before the disease and prevention of both diseases in people of shorter height. However, future studies are still necessary in order to comprehensively elucidate the mechanisms underlying the association between height and the risk of liver fibrosis progression.

ACKNOWLEDGMENTS

The authors would like to express their appreciation to the participants and researchers of the FinnGen study and the UK Biobank database.

Disclosure

The authors declare that they have no competing interests.

Data availability statement format guidelines

The datasets generated during and/or analysed during the current study are available in the FinnGen study and the UK Biobank repository.

Author Contributions and Guarantor Statement

HUO, G.Y. and GAO, Y.Q. were involved in the conception, design, and conduct of the study and the analysis and interpretation of the results. HUO, G.Y. wrote the first draft of the manuscript, and all authors edited, reviewed, and approved the final version of the manuscript. GAO, Y.Q. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding

This work was supported by the shanghai university of traditional chinese medicine(2021KJ03-12); Shanghai Municipal Health Commission (ZY(2021-2023)-0302, ZY(2021-2023)-0103, shslczdzk01201).

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No competing interests reported.

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Height and risk of liver fibrosis progression: A multivariable Mendelian randomization study

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Abstract

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INTRODUCTION

Methods

Study Design

GWAS Data Source

Exposed GWAS data

Ending GWAS data

MR analysis method

Statistical analysis

Result

Standing height and liver fibrosis, cirrhosis

Sitting height and liver fibrosis, cirrhosis

Discussion

Strengths of the study

Limitations

Conclusions

Declarations

References

Additional Declarations

Supplementary Files

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