Mendelian randomization study to investigate the causal relationship between plasma homocysteine and chronic obstructive pulmonary disease

doi:10.21203/rs.3.rs-2455061/v1

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Mendelian randomization study to investigate the causal relationship between plasma homocysteine and chronic obstructive pulmonary disease

https://doi.org/10.21203/rs.3.rs-2455061/v1

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Background

Several studies have shown an association between plasma homocysteine levels and chronic obstructive pulmonary disease (COPD). It is not clear whether there is a causal association. A two-sample Mendelian randomization (MR) based method was used to further explore the causal association between plasma homocysteine and COPD.

Methods

Several studies have shown an association between plasma homocysteine levels and COPD. It is not clear whether there is a causal association.we performed a second data analysis using pooled data from published genome-wide association studies (GWASs) .we used genome-wide meta-analysis (n = 44147) to obtain genome-wide single nucleotide polypeptides (SNPs) associated with plasma homocysteine levels as instrumental variables. We used two-sample MR to study plasma homocysteine and COPD and COPD related diseases. MR analysis was performed by the random effects inverse variance weighting method and heterogeneity tests and pleiotropy tests were performed to evaluate the robustness of our findings.

Results

By two-sample MR analysis, We did not find causal associations between genetically predicted plasma homocysteine levels and COPD and COPD related diseases. In COPD hospital admissions,(OR = 1.06,95%CI 0.91–1.24,P = 0.42),asthma/COPD,(OR = 0.97,95%CI 0.89–1.06, P = 0.55),COPD related to chronic (opportunist) infection(OR = 1.50,95%CI 0.57–3.99,P = 0.41),COPD/asthma/ILD-related pneumonia or pneumonia-derived (OR = 0.93,95%CI 0.86–1.02,P = 0.13),COPD-related respiratory insufficiency(OR = 1.00,95%CI 0.7–1.44,P = 0.99), no heterogeneity and horizontal pleiotropy werefound.

Conclusions

Our study shows that genetically predicted plasma homocysteine levels are not causally associated with COPD, contrary to previous observational findings.As homocysteine is known to have deleterious effects on endothelial function and vascular homeostasis, further studies are needed to investigate whether additional factors mediate the association between homocysteine and COPD.

Homocysteine

Chronic Obstructive Pulmonary Disease

Mendelian Randomization

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the respiratory system .That is characterized by persistent airflow obstruction, accelerated loss of lung function, and irreversible lung damage.With global climate and residential changes, mortality from chronic obstructive pulmonary disease is increasing year by year and COPD is projected to be the seventh leading cause of disability-adjusted life years lost globally in 2030.Second, there is a direct relationship between the severity of COPD and medical expenses.COPD has become a global public health problem because it is often accompanied by a huge economic burden^[1].With the increasing burden of chronic obstructive pulmonary disease (COPD), there is an urgent need to study the current independent risk factors and establish new prevention strategies.Observational studies have shown that plasma homocysteine levels are protective factors for COPD.Homocysteine (Hcy) is an amino acid containing a sulfhydryl group that is an important product in the metabolism of methionine and cysteine ^[2].It leads to a decline in the vital capacity of COPD patients and is related to the severity of COPD symptoms which has predictive value for the occurrence and acute progression of COPD ^[3].However, the causal relationship between plasma homocysteine levels and COPD remains unclear.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the lungs that is known to have systemic features.The main pathogenic mechanism of homocysteine (Hcy) involves mediating the expression of inflammatory substances and cytokines, increasing the number of inflammatory cells and enhancing the oxidative stress response, and imbalance of oxidants and antioxidants ^[1].

Traditional observational studies suffer from methodological limitations such as confounding factors, reverse causality, and the effects of examination offsets.Based on observational studies alone, the evidence for their correlation is challenging.In the absence of large-scale randomized clinical trials, new approaches are needed to avoid distractors.Mendelian randomization (MR) is a new method to assess the causal effect between risk factors and disease.It uses genetic variants associated with exposure, usually single nucleotide polymorphisms (SNPs), as instrumental variables to infer causal associations between exposure and disease.Compared with observational studies, MR uses genetic variation as an instrumental variable to simulate random assignment of randomized controlled trials, so it can reduce the bias of confounding factors and avoid reverse causality and the influence of confounding factors ^[4].Therefore, we conducted a two-sample MR analysis genome-wide association study (GWASs) to investigate the causal association between plasma homocysteine levels and COPD and other pulmonary diseases from the perspective of genetic polymorphisms.

2.1. Study design

Two-sample Mendelian randomization analysis was used in this study.To explore the relationship between plasma homocysteine levels and COPD hospital admissions, asthma/COPD, COPD-related to chronic (Opportunistic) infections, and COPD/asthma/interstitial lung disease (ILD),the cause-effect association of pneumonia or pneumonia-derived septicaemia, COPD-related respiratory insufficiency and the reliability of the results were evaluated.Cochran's Q-test was used to evaluate the heterogeneity of MR results and MR‒Egger regression was used to detect horizontal pleiotropy.

2.2. Data source

In this study, homocysteine (HCY) GWAS data published by Van Meurs et al. 2013 were used as instrumental variable.The data contained data from 10 independent cohorts of European ancestry, with a total of 44,147 individuals ^[5].(see Table 1 for specific information)The outcome variables were COPD hospital admissions, asthma/COPD, COPD Related to chronic (opportunist) Infections,COPD/asthma/ILD-related The pneumonia or pneumonia-derived septicaemia, COPD-related respiratory insufficiency.Variable data was obtained through IEU Open GWAS. Project, a public database (https://gwas.mrcieu.ac.uk/).We limited our analysis to studies that included individuals of European ancestry to minimize potential bias due to population stratification.

(see Table 2 for specific information)

LC-MS/MS, liquid chromatography–tandem mass spectrometry; LC-MS, liquid chromatography–mass spectrometry; HPLC,high-performance liquid chromatography.

Table 2

Descriptive characteristics of the GWAS meta-analysis used in the outcomes.
group	year	Population	N-snp	N-case	N-control
COPD, hospital admissions	2021	European	16380466	6500	212292
Asthma/COPD	2021	European	16380423	21444	186723
COPD related to chronic (opportunist) infections	2021	European	16380363	234	186723
COPD/asthma/ILD related pneumonia or pneumonia derived septichaemia	2021	European	16380352	27715	159867
COPD-related respiratory insufficiency	2021	European	16380365	1031	186723

2.3. Statistical analysis

In the MR method, single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) to meet three assumptions, as shown in Fig. 1. First IVs were closely related to exposure factors (Hcy). Second, IVs should not be associated with confounding factors. Third, IVs affect outcomes (COPD) only through Hcy and not through other pathways.

2.4. Selection of the tool variables

We used the results of a previous GWAS aggregation analysis.18 SNPs associated with plasma Hcy levels were selected from the whole genome of 44,147 individuals of European ancestry (31,400 cases and 92,927 controls) (P < 5.0 × 10 − 8).In addition, we used the PLINK clustering method with r² < 0.001to prune SNPs in linkage disequilibrium.To ensure that the selected SNPs were independent ^[6].we calculated F-statistics for 18 SNPs to detect the strength of instrumental variables F > 10 is usually recommended in MR analysis; and the F statistic can be calculated as F = R² \(\frac{n-1-k}{\left(1-{R}^{2}\right)K}\), where n is the sample size, k is the number of IVs, and R² is the percent of variation explained by the SNP ^[7].

2.5. Statistical methods

In this study, inverse variance weighting (IVW) was used as the primary causal effect estimation.The inverse variance weighting (IVW) method is a relatively ideal estimation, which is an effective analysis under the assumption that all genetic variants are valid instrumental variables and has a strong ability to detect causality.However, the inverse variance weighting (IVW) method requires that genetic variants affect the target outcome only through the exposure in the study.Although known confounding SNPs were excluded as far as possible in this study, there are still many unknown confounding factors that can cause pleiotropy and bias the estimate of effect size.Therefore, we used another four methods to test the reliability and stability of the results namely,MR‒Egger regression, the weighted median method (WME), a simple estimator based on mode, and a weighted estimator based on mode.MR analysis of different types of COPD was performed sequentially. If the above five different MR models produced similar estimates of causal effects, we considered that the causal relationship between homocysteine and COPD was stable and reliable.All results were expressed as ORs and 95% confidence intervals, and P < 0.05 was considered statistically significant.In the test results, if the P value is greater than 0.05, it is considered that there is no heterogeneity or pleiotropy in the included instrumental variables and the influence of heterogeneity on causal effect estimation can be ignored.

Due to the differences in analysis platforms, experimental conditions, selected populations and SNPs, the MR analysis of the two samples may be heterogeneous, resulting in bias in the estimation of causal effects.Cochran's Q-test was used to evaluate the heterogeneity of MR results, and MR‒Egger regression was used to detect horizontal pleiotropy.In the test results, P < 0.05 was considered to be no heterogeneity or pleiotropy in the included instrumental variables.The influence of heterogeneity on causal effect estimation can be ignored.Heterogeneity between IVs was assessed using the Cochranʼ S Q statistic, which can be controlled by the random effects model IVW (MRE-IVW).MR‒Egger regression analysis was used to evaluate pleiotropy. If the P value was less than 0.05, the leave-one-out method was used to conduct sensitivity analysis. All relevant SNPs were removed one by one, and the pooled effect of the remaining SNPs was calculated to evaluate the influence of each SNP on the outcome.All statistical analyses were performed with R (version 4.1.1) using the Two Sample MR and MR-PRESSO software packages.Ethical approval was not required because the study used only publicly available data.

MR analysis showed no significant association between plasma homocysteine levels and COPD.In this study, the F-statistics for all variables are much greater than 10, indicating that the possibility of weak instrumental bias is quite small.The IVW result is displayed for COPD hospital admissions, each SD increase in Hcy level OR = 1.06 95%CI (0.91–1.24) P = 0.42;asthma/COPD,each SD increase in Hcy level OR = 0.97 95%CI (0.89–1.06) P = 0.55; COPD related to chronic (opportunist) infections, Each SD increase in Hcy level OR = 1.5 95%CI (0.57–3.99) P = 0.41; COPD/asthma/ILD related pneumonia or pneumonia-derived septicaemia, each SD increase in Hcy level OR = 0.93 95%CI (0.86–1.02) P = 0.13; COPD-related respiratory insufficiency, each SD increase in Hcy level OR = 1 95%CI (0.7–1.44) P = 0.99.The results of groups were consistent in sensitivity analysis and repeated analysis, without heterogeneity or horizontal pleiotropy (Fig. 2, Table 3)

Table 3

Results of heterogeneity and directional pleiotropy analysis.
group	SNP	Q	P-value for heterogeneity	MR-Egger intercept	P-value for directional pleiotropy
COPD, hospital admissions	14	9.19	0.82	-0.06	0.81
Asthma/COPD	14	11.18	0.67	-0.01	0.21
COPD related to chronic (opportunist) infections	14	11.17	0.34	-0.01	0.54
COPD/asthma/ILD related pneumonia or pneumonia derived septichaemia	14	18.07	0.2	-0.01	0.11
COPD-related respiratory insufficiency	14	10.07	0.76	-0.02	0.5

This is the first study to explore causation between plasma homocysteine levels and COPD using MR studies using a large sample in the MR GWAS summary data, we found no gene prediction of plasma homocysteine levels associated with COPD or causal evidence.These MR results were analysed by five methods. The P values of heterogeneity and pleiotropy tests were all greater than 0.05,and the F-statistics of all variables were far greater than 10, indicating robust results. There was no evidence in this study to support a causal association between genetically-associated plasma homocysteine levels and COPD; the reason for the lack of an association is unclear. This is contrary to the results of most previous observational studies.

At present, case‒control studies have shown that homocysteine is correlated with the risk of COPD ^[8–11] and is related to the severity of COPD ^[12]. A meta-analysis involving four case‒control trials involving 145 COPD subjects and 107 healthy controls also confirmed that elevated serum homocysteine concentration would lead to an increased risk of COPD, but the significance level of 5% was not reached so the overall efficacy of the study was limited ^[13]. In addition, a retrospective study tested patients with COPD in nonacute exacerbation and acute exacerbation stages; the results showed that homocysteine levels were positively correlated with the severity of COPD, which had predictive value for the occurrence and acute progression of COPD ^[3]. From a mechanistic point of view, the main symptom of COPD is persistent airflow limitation, which leads to increased oxygen consumption for breathing. At the molecular level, there is evidence of systemic inflammation in patients with COPD. Circulating cytokines such as IL-6, TNF-α, IL1-β, chemokines and CRP, monocytes,neutrophils, lymphocytes and NK cells, are abnormal in COPD patients ^[14]. This chronic inflammatory response may induce parenchymal tissue destruction (leading to emphysema) and disrupt normal repair and defence mechanisms. During lung tissue repair, DNA, RNA and methylation of different proteins generate a large amount of S-adenosine-Hcy and Hcy in lung tissue and plasma respectively. Although the above studies adjusted for some confounding factors,it seems impossible to completely control the unmeasured risk factors due to the characteristics of observational studies. This may also account for the association found between homocysteine and COPD in observational studies.

Second, as COPD is a systemic disease, the disease process requires a large amount of energy ,which easily leads to a negative energy balance. Therefore,malnutrition has become a common phenomenon in patients with advanced COPD, resulting in a reduction in folate and vitamin B content ^[15]. Folic acid is essential in processing one carbon unit of metabolism, affects epigenetic regulation through the synthesis of nucleic acids ^[16] and a variety of biological molecules needed for methylation intermediates ^[17] Vitamin B12 is methyl malonyl coa mutase and methionine synthase coenzyme is the indispensable metabolic connection between these two kinds of vitamin B complexes .Folic acid is one of the cofactors of methionine synthase which is also necessary for the removal of homocysteine by methylation ^[18]. Insufficient folic acid levels hinder homocysteine clearance and increase its concentration;deficiency of either vitamin slows the response and leads to insufficient DNA synthesis, leading to hyperhomocysteinemia ^[19].Therefore, previous observational studies have found that the increased plasma homocysteine concentration in patients with COPD may be due to the increased energy consumption in patients with COPD,which leads to insufficient folate and vitamin B, affecting methylation and leading to increased plasma homocysteine concentrations. Acute administration of homocysteine to rats has been reported to result in increased concentrations of inflammatory cytokines in blood and brain cells. This suggests that hyperhomocysteinemia may be partly responsible for the systemic inflammation observed in COPD patients ^[20].Our results show that genetically predicted homocysteine has a weak protective effect against COPD, suggesting that homocysteine is a risk marker for folate and vitamin B deficiency rather than a causal risk factor for COPDand confirming the results of a case‒control study ^[21].Second, COPD is a complex disease whose development is influenced by environmental factors. Smoking is considered a major environmental risk factor in the development of COPD,and the results indicated that smokers have higher levels of plasma homocysteine, folic acid, and vitamin B, than nonsmokers. Based on the limitation of research methods, observational studies cannot control for confounding factors, which may result in bias in observational studies on COPD patients and healthy people.

COPD often coexists with other diseases that may have a significant impact on prognosis ^[22]. Previous studies have shown that almost all patients have ≥ 1 comorbidity and half of them have ≥ 4 comorbidities. Some comorbidities are independent of COPD, while others are causally related to COPD either by sharing risk factors with COPD (e.g., age, smoking, systemic inflammation) or by having one disease that increases the risk severity of another.Common comorbidities include bronchiectasis, CVD, chronic kidney disease, dyslipidaemia, diabetes mellitus, hypertension, lung cancer, mental disorders, osteoporosis, obstructive sleep apnoea syndrome and skeletal muscle dysfunction ^[23].At present, a number of MR analyses have shown that plasma homocysteine levels are causally associated with (small vessel stroke) SVS^[24], cerebral small vessel disease ^[25], metabolic syndrome ^[26], sleep apnoea syndrome^[27], estimated glomerular filtration rate^[28], and Immunoglobin A^[29]. Second, factors leading to hyperhomocysteinemia may also include gender differences ^[30], body mass index ^[31], vitamin B deficiency ^[32], hyperlipidaemia ^[33], hypertension ^[34], diabetic nephropathy ^[35], smoking ^[36] and other factors. Therefore, determining the primary cause of elevated plasma homocysteine levels in individual subjects is complex. The case‒control retrospective study was also unable to control confounding factors, such as smoking, different metabolic disorders/situations, and neuroendocrine effects on the results. The influence of such factors could be why our MR found no causal relationship between gene prediction of plasma homocysteine levels and the cause of chronic obstructive pulmonary disease. Therefore,the possible pathogenic mechanism of elevated homocysteine concentration in COPD needs to be further explored.

5.Limitations

In summary, MR can overcome the limitations of observational studies with unmeasured confounders and reverse causality and minimize confounding by environmental factors, thereby minimizing the possibility of bias. However, there are limitations to our study.First, a major limitation of MR is bias due to pleiotropy, which indicates that one genetic variant affects various phenotypes. In addition, it is difficult to rule out that all SNPs in our study might affect COPD risk through mechanisms other than affecting plasma Hcy levels. Although we did not find any evidence of pleiotropy for the other groupings in the MR‒Egger intercept analysis and the groupings with pleiotropy were controlled by leave one out, this result may have been hampered by the relatively small number of SNPs; the small number of SNPs may have overestimated the effect of exposure on the results. Therefore, more studies with larger sample sizes and higher resolution are needed to identify factors associated with plasma Hcy levels and exposure. Second, to control for bias due to population stratification, we reduced this possible bias by limiting the study population to individuals of European ancestry. However, this population limitation limits the general applicability of our findings to other populations.

Our Mendelian randomization study showed no causal relationship between plasma homocysteine levels and chronic obstructive pulmonary disease.contrary to previous observational findings.As homocysteine is known to have deleterious effects on endothelial function and vascular homeostasis, further studies are needed to investigate whether additional factors mediate the association between homocysteine and COPD.

COPD: Chronic obstructive pulmonary disease;Hcy:homocysteine;MR: Mendelian randomization; GWAS: Genomic-wide association study; SNP: Single-nucleotide polymorphism; IV: Instrumental variable; IVW: Inverse variance-weighted; MR-Egger: Mendelian randomization-Egger regression; WME: Weighted median estimator; OR: Odds ratio; SD: Standard deviation; TNF-α: Tumor necrosis factor-alpha. CRP:C-reactive protein;IL-6:Interleukin-6.

Availability of data and materials

The datasets analysed during the current study are available in the IEU Open GWAS

(https://gwas.mrcieu.ac.uk/). Additional data can be requested from the corresponding author.

Acknowledgments

We thank all the authors of the studies included in our bibliometrics analysis.

Authors’ contributions

CZL, SJY, YLH, QL,JZ,CHZ and JTW conceived and designed the study. YLH and JTW drafted the manuscript,YLH,JTW, QL, ZJ,CHZ,SJY,YLH and CZL revised the manuscript. All authors contributed substantially to its critical revision and final approval.

Funding

This study was supported by Hainan Provincial Natural Science Foundation of China (821RC557, 2019RC232), National Natural Science Foundation of China (81871611, 82160647), Finance Science and Technology Program of Sichuan Province (2022YFS0602).

Competing interests

The authors declare that they have no competing interests

consent for publication

All the authors approved the publication

Ethics approval and consent to participate

This research was based on publicly available data. Ethical approval was obtained by the original study authors.

Data availability statement

Data used in this study were from publicly available summary statistics of genome-wide association studies.

Conflicts of interest statement

The authors declare that they have no conflicts of interest.

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No competing interests reported.

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Mendelian randomization study to investigate the causal relationship between plasma homocysteine and chronic obstructive pulmonary disease

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Abstract

Background

Methods

Results

Conclusions

Figures

Introduction

Methods

2.1. Study design

2.2. Data source

2.3. Statistical analysis

2.4. Selection of the tool variables

2.5. Statistical methods

Results

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

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