Exploring genetic association of allergic disease with cardiovascular disease: A bidirectional Mendelian randomization study

doi:10.21203/rs.3.rs-2463442/v1

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Exploring genetic association of allergic disease with cardiovascular disease: A bidirectional Mendelian randomization study

https://doi.org/10.21203/rs.3.rs-2463442/v1

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Background: In observational and experimental studies, allergic diseases have been reported to be associated with some types of cardiovascular diseases. They share a typical pathophysiological process, including inflammatory and metabolism disorders. However, the direction of the causal association between them remains unclear. This Mendelian randomization (MR) study aims to examine the bidirectional causality between allergic diseases and cardiovascular diseases.

Methods:We used publicly available GWAS summary statistics data only, including European participants from UK Biobank or on the IEU Open GWAS database. We identified genetic variants associated with allergic diseases, asthma, or cardiovascular diseases as instrumental variables to investigate the genetically causal association between allergic diseases and asthma and the risk of 12 kinds of cardiovascular diseases. MR was performed using analytical methods including the inverse variance weighted (IVW), MR-Egger and, weighted median. Sensitivity tests were also performed in the MR to assess the validity of the casualty.

Results: Genetically predicted allergic diseases was associated with essential hypertension [odds ratio (OR)=0.9987, 95% confidence interval (CI): 0.9976-0.9998, P=0.024], and asthma was associated with atherosclerosis (OR=1.0006, 95% CI: 1.0001-1.0012, P=0.02) in the MR analysis with the IVW method. In the reverse MR analyses, we found that essential hypertension was associated with allergic diseases (OR=8.16E-03, 95% CI: 7.55E-05 - 8,82E-01, P=0.044) and asthma (OR=8.16E-03, 95% CI: 7.55E-05 - 8,82E-01, P=0.044), and stroke was associated with allergic diseases (OR=3.59E-02, 95% CI: 1.34E-03 - 9.62E-01, P=0.047). However, no causal effect has been detected bidirectionally after the Bonferroni correction.

Conclusion: The MR study found that patients with AD or asthma might have a decreased risk of essential hypertension and an increased risk of atherosclerosis in European individuals. In reverse analysis, essential hypertension, AD, and asthma are negatively correlated, and stroke may decrease the risk of AD. However, after a Bonferroni correction, our evidence did not suggest a significant causal between them, which means that the evidence is weak. Whether AD exerts effects on CVD needs further investigation.

Allergic disease

Cardiovascular disease

Asthma

Mendelian randomization

The global prevalence of allergic diseases (AD) has increased dramatically constituting a considerable burden on global health[1]. In some countries, even one-fourth of individuals approximately have AD[2]. Many epidemiology studies have concluded that the risk factors attributed to some cardiovascular diseases (CVD) include inflammatory and immune responses, which are the primary pathophysiological processes of AD[3, 4]. As a part of immune dysfunction, AD have emerged as potential risk factors in the development of CVD[4–10]. Many experimental and observational studies have concluded accumulating evidence on the association between AD such as asthma[5–7], atopic dermatitis[5, 8], rhinitis[5, 9, 10], and CVD including atrial fibrillation[5], atherosclerosis[4], heart attack[8], heart failure[8], hypertension[9, 10], stroke[6], coronary heart disease[11], and others. These studies came to controversial conclusions. AD may be associated with an increased risk of cardiovascular disease[4–10]. However, a decreased risk has been found in other studies[11].

Although many observational studies have studied the knowledge of the links between AD and CVD, the inevitable confounding factors and the ambiguous causal direction concluded are biased. To reduce the effects of confounding factors and reverse causality, the Mendelian randomization (MR) method was introduced. In MR, the causal effects of the exposure on the outcome are assessed by instrumental variables (IVs). Since the genetic variants are randomly distributed during meiosis and cannot be modified after conception, genetic variants are generally used as IVs to increase the reliability of the results. In order to obtain unbiased estimates, genetic variants can be used as IVs only when they meet the conditions as follows[12]. Firstly, the variants should be highly associated with exposure. Secondly, the variants should be independent of confounding factors of the exposure-outcome association. Lastly, the variants affect the outcome only via the exposure pathway and not through other biological pathways. Besides, based on the available publicly genetic data, MR can be applied widely.

Here, a bidirectional MR analysis was performed to investigate the causal link between AD and CVD, in which we used the summary statistics available publicly.

Study design overview

The design of the MR study is shown in Figure 1. In brief, the causal effects of AD on CVD were estimated first, then the causal effects of CVD on AD were evaluated. Genetic variants should strictly meet the three assumptions[12]. We utilized summary statistic datasets from recent genome-wide association studies (GWAS) of allergic and CVD.

Data sources and SNP selection of genetic instruments for AD

The AD includes asthma, hay fever, and eczema, which share many genetic variants that dysregulate the expression of immune-related genes and often coexist in the same individuals. The summary statistics for the AD were obtained from the GWAS catalog (https://www.ebi.ac.uk/gwas/downloads/summary-statistics) or the IEU OpenGWAS project (https://gwas.mrcieu.ac.uk/), conducted by Ferreira MA et al. [13]. This study included 360,838 European individuals (180,129 cases vs 180,709 controls). Since many observational studies paid attention to asthma[5-7], but not all of the three AD and the three coexist in the same individuals partly, the causal effects of asthma on CVD were also estimated. The summary statistics for asthma were obtained from the GWAS catalog or the IEU OpenGWAS project as well, conducted by Valette K et al., including 408,442 individuals with European ancestry (56,167 cases vs 352,255 controls)[14]. Detailed information on conduction procedures and diagnostic criteria is described in the original publications. The sample characteristics of the study population are described in Additional file 1 Table S1.

Genetic variants associated with AD and asthma, respectively, at genome-wide significance (P＜5×10^-8), were reported by the GWAS. In the meantime, to clump SNPs for independence, a linkage disequilibrium (LD) test was performed between SNPs. The criteria for LD were defined as SNPs with r²＞0.001 and physical distance kb＜10,000. SNPs with the lowest p values were retained. Then we searched all 74 and 80 remained SNPs associated with AD and asthma respectively, in, the Phenoscanner database (http://www.phenoscanner.medschl.cam.ac.uk/) to identify whether these SNPs associated with confounding factors or directly affected the outcome[15] (P＜5×10^-8). We found 10 SNPs correlated with AD associated with confounders (rs56375023, rs7406234 were associated with coronary artery disease; rs11168245 were associated with hypertension; rs6011033 were associated with diastolic blood pressure; rs1419675 were associated with type 1 diabetes; rs301802, rs5758343 were associated with body fat percentage; rs2854001, rs1689510 were associated with body mass index and rs7224129 were associated with HDL cholesterol). As for SNPs of asthma, 7 SNPs associated with confounders (rs10477741、rs56375023 were associated with coronary artery disease; rs112267124、rs2412099 were associated with self-reported hypertension; rs11042902 were associated with blood pressure; rs4480384 were associated with body fat percentage and rs1689510 were associated with body mass index). After removing 10 SNPs and 7 SNPs in AD and asthma GWAS separately to avoid possible pleiotropic effects, we used the remaining SNPs as the IVs in the bidirectional MR analysis (see Additional file 1 Table S2, S3). After removing the SNPs whose proxy SNPs were not available in the outcome GWAS, we harmonized the exposure and outcome data before estimating the association between AD or asthma and CVD.

Data sources and SNP selection of genetic instruments for CVD

Summary statistics on CVD, including heart arrhythmia, atrial fibrillation, supraventricular tachycardia, atherosclerosis, aortic aneurysm and dissection, stroke, peripheral vascular disease, cardiomyopathy, heart valve problem, heart failure, cardiac arrest, and essential hypertension, were obtained from the second round of GWASs results of the UK Biobank (UKB) (http://www.nealelab.is/uk-biobank). The UKB study is a prospective cohort study that collected and offered genetic and other information on more than 500,000 participants living in the UK[16]. These diseases were defined by the UKB study by self-reported status or ICD10 codes. Additional file 1 Table S1 summarizes of the detailed information on these different traits, including sample size, the number of SNPs, phenotype code, and others.

We obtained the variants associated with these CVD at genome-wide significance (P＜5×10^-6) and independence (r²＜0.001, kb＞10,000) levels, respectively. Similarly, we checked all SNPs using the Phenoscanner database, and none were associated with confounding factors or directly affected the outcome. Details of SNPs used as IVs are listed in Additional file 1 Tables S4-S15. Then the SNPs not available in the outcome GWAS were removed before estimating the causal effects between the 12 kinds of CVD and AD or asthma, respectively.

MR analysis

We conducted bidirectional MR analysis using by TwoSampleMR package[17] with R software (version 4.2.2). The inverse variance weighted (IVW) method was used as our primary analysis approach, which is the most efficient and widely-used method. The Wald ratio method is used to calculate the effect of each SNP, and a meta-analysis of the individual effect of each SNP was conducted by IVW to generate the concluding beta estimate (beta _outcome/beta _exposure). Since the outcome was binary[18], we transformed it into the odds ratio (OR). To detect possible violations of IVs assumptions because of directional horizontal pleiotropy, namely the third assumption of SNP, we applied MR-Egger since it can test the null causal hypothesis effectively, which is the base method of horizontal pleiotropy in our analysis[19]. The IVW method relies on the assumption that all SNPs are valid IVs, which can be made up of a weighted median (WM) model providing a consistent effect even if half of the SNPs are pleiotropic[18].

Cochran Q statistics and I² statistics are used to quantify heterogeneity based on IVW and MR-Egger methods[20]. We used MR pleiotropy residual sum and outlier (MR-PRESSO) test[21] to detect outlier SNPs (Nb Distribution = 10000, Significant Threshold = 0.05), which was conducted by the package “MR-PRESSO”, and the results are shown in Additional file 1 Table S16. Besides, a “leave-one-out” analysis was performed to detect if there is any single SNP too sensitive to be disproportionately responsible for the result. Finally, F statistics were used to evaluate the strength of SNPs to satisfy the first assumption[17]. We calculated the F statistic with the formula:

$$F=(N-k-1)/N\times {R}^{2}/(1-{R}^{2})$$

(N = sample size of the exposure, k = the number of selected SNPs, and R² represents the phenotype variance induced by the SNPs.) When R² is not available, we used the formula:

$${R}^{2}=2\times MAF\times (1-MAF)\times {(\beta /SD)}^{2}$$

(β = the effect value of the genetic variant of the exposure, MAF = the effect allele frequency of selected SNPs, $SD=SE\times \surd N$, SE = the standard error of the genetic variant of the exposure, N = sample size of the exposure). All instruments had an F-statistics above the standard cutoff (༞10), indicating sufficient powerful instruments[22]. Each R² and F are shown in Additional file 1 Table S16.

Given the multiple testing, a p-value below 0.002 (0.05/24) was considered robust significance after a Bonferroni correction. The p-value between 0.002–0.05 was considered suggestive significance, and the p-value above 0.05 was considered no significance. All statistical analyses were two-sided.

The causal effect of AD and asthma on CVD

64 and 73 LD-independent genetic variants were taken as IVs for AD and asthma, respectively, after P value selection and LD clumping (see Additional file 1 Table S2, S3). After excluding the SNPs not available in the outcome GWAS and distortion SNPs detected by MR-PRESSO and the “leave-one-out” test, the remaining SNPs were taken as IVs for AD and asthma. The “leave-one-out” test results of final SNPs are shown in Additional file 2 Figure S1, S2. F-statistics for IVs of AD and asthma indicated that the IVs were robust instruments reducing the bias of IVs estimates.

We mainly used the IVW method to investigate the genetic correlation between AD or asthma and CVD. Genetically predicted AD was associated with essential hypertension [odds ratio (OR)=0.9987, 95% confidence interval (CI): 0.9976-0.9998, P=0.024], which may be a protective factor. Asthma suggested to be a risk factor of atherosclerosis (OR=1.0006, 95% CI: 1.0001-1.0012, P=0.02). However, after the Bonferroni correction, we found that AD and asthma did not have robust association with any cardiovascular disease we included as shown in Figure 2. The results of the other two models were consistent with IVW (see Additional file 1 Table S17). Sensitivity analyses were performed by detecting the presence of horizontal pleiotropy to verify the reliability of IVW results, which did not suggest any horizontal pleiotropy, as shown in Additional file 1 Table S18. Cochran’s Q test did not detect any heterogeneity according to IVW and MR-Egger tests, as shown in Additional file 1 Table S19. The result of reporting bias tested by MR-Egger and IVW is shown in funnel plots (see Additional file 2 Figure S3, S4), and the effect of confounding factors on outcomes is shown in scatter plots (see Additional file 2 Figure S5, S6). The forest plots of each pair of associations for casualty are presented in Additional file 2 Figures S7 and S8.

The causal effect of CVD on AD and asthma

After LD clumping and searching in the Phenoscanner database, the remaining SNPs were shown in Additional file 1 Tables S4-S15. After excluding distortion SNPs, we used the remaining SNPs as final IVs to estimate the causal effect of CVD on AD and asthma. The results of the “leave-one-out” test and F-statistics are shown in Additional file 2 Figures S9, S10, and Additional file 1 Table S16. According to the IVW model, we found that essential hypertension was suggested to be a protected factor against AD (OR=8.16E-03, 95% CI: 7.55E-05 - 8,82E-01, P=0.044) and asthma (OR=8.16E-03, 95% CI: 7.55E-05 - 8,82E-01, P=0.044). Stroke may be a protective factor of AD (OR=3.59E-02, 95% CI: 1.34E-03 - 9.62E-01, P=0.047). However, no robust causal effect has been detected between all 12 CVD and AD or asthma after the Bonferroni correction (Figure 3). The results of the other two models were consistent with IVW. No horizontal pleiotropy or heterogeneity was suggested, shown in Additional file 1 Tables S18 and S19. Additionally, the funnel plots, scatter plots, and forest plots of each pair of associations for casualty are presented in Additional file 2 Figure S11-S16.

This bidirectional MR analysis provides evidence of the suggestive association of AD and asthma with essential hypertension and atherosclerosis. AD may be a protective factor against essential hypertension, and asthma is suggested to be a risk factor for atherosclerosis. In the opposite direction, essential hypertension may decrease the risk of AD and asthma, and stroke plays a similar role in asthma. However, there is no robustly causal after a Bonferroni correction, which suggests weak evidence between them.

To the best of our knowledge, this is the first MR study to identify the bidirectional causal relationship between AD and CVD. A previous MR study has identified that asthma and atopic dermatitis are causal risk factors of heart failure (P = 0.03 and 0.01)[23]. The study could not illustrate the causal association between them after a Bonferroni correction. Previous observational studies have drawn controversial conclusions. The presence of AD may be associated with an increased risk of CVD, including atrial fibrillation[5], atherosclerosis[4], heart attack[8], heart failure[8], hypertension[9, 10], stroke[6], and others. Furthermore, the co-existence of allergic and CVD may increase the mortality of both diseases[6, 7]. However, there is also a decreased risk of CVD, and all-cause mortality in individuals with allergic rhinitis has been reported compared with people without allergic rhinitis[11]. Our finding of no causal effects of AD on CVD is partly inconsistent with these observational studies. The observational study is typically affected by reverse causality or confounding factors, which could be avoided by an MR study.

As for the possible mechanism of these two kinds of diseases, according to experimental studies, inflammatory and immune responses could be powerful mechanisms[3, 4]. AD such as asthma, atopic dermatitis, and rheumatic arthritic can induce chronic inflammation, which is associated with CVD[4–10]. IgE and IgG are the fundamental molecules of allergic reactions[24] associated with atherosclerosis[4]. IgE-induced M1 macrophage polarization, foam cell formation, and vascular cell apoptosis to promote plaque progression[24]. The anti-IgE may be a protective factor for atherosclerotic, and the treatment with an anti-IgE-neutralizing antibody could accelerate the formation of the atherosclerotic lesion[25]. High serum concentrations of IgG have been detected in ApoE-/- mice[26], and oxLDL-specific IgG has been observed in human plaques[27], using the antibodies which may hinder the rapid regression of atherosclerotic lesions[28]. Th2 cell is the center of late-phase allergic inflammation, and a high Th2 cell frequency in circulation is associated with a reduced risk of myocardial infarction and stroke[29]. Th2-related cytokine interleukin (IL)-4 may be a principal cytokine in the progression of early atherosclerosis[30], but IL-13 showed a protective effect[31]. The active mast cell could induce matrix degradation and apoptosis and recruit inflammatory cells to promote the progression of CVD[32–34]. Except for the pathophysiological processes of immunological system, other conditions such as metabolism disorders[35, 36], central obesity[37], and the typical lifestyle[38] could also be the potential mechanism of the association between the two diseases. Some observational cohort studies identified the clinical relevance between asthma and dyslipidemia, a significant risk factor for CVD[35, 36]. Adults with eczema were more likely to have sleep disturbances and smoke[38]. However, based on five different MR test methods, we found no causality of AD with CVD. There may be a gap between the hypothesis, experimental studies and the actual human situation.

This study has several limitations. First, the wide confidence interval around the effect estimate in the reverse study remains compatible with noninferiority and limits conclusions about the causal association between two diseases. Second, we used P༜5×10^− 6 as the standard of genome-wide significance to select the variants related to the 12 kinds of CVD, which might make the SNPs less specific. Moreover, the number of SNPs involved is relatively small. Third, we did not detect the association between other AD and CVD since the limitation of public genetic data. Fourth, we did not stratify the causal association between allergic and CVD by gender, age, BMI, and other factors. However, some studies suggested that these factors may affect the causality. Besides, only participants of European descent are included in our MR study, and instruments identified in European populations are not necessarily suitable for non-European populations. What’s more, since the SNPs identified have a minor variance, the effect of most of them is moderate[39], which means a more reliable instrument and more samples are needed for more precise results.

Nevertheless, the MR study has several advantages. First, we included the variants across the phenotypes of AD and asthma from a recent meta-analysis. We extracted the IVs of the 12 kinds of CVD from the largest GWAS. Second, the bidirectional MR method reduces potential bias from confounding factors and reverses causality, which means a clear causal direction in our analysis. Third, the association between AD and a wide range of CVD was assessed, most of which were not previously examined based on genetic instruments. Fourth, to prevent the overlap of the study population, we selected samples from two different databases. Besides, it is easy to obtain abundant genetic data from the public genetic dataset using the MR method. The summary statistics can also be applied to individual-level data in terms of statistical power[40].

In summary, there may be a suggestive association between AD and asthma and essential hypertension or atherosclerosis, indicating that patients with AD or asthma might have a decreased risk of essential hypertension and an increased risk of atherosclerosis in European individuals. In reverse analysis, essential hypertension, AD, and asthma are negatively correlated, and stroke may decrease the risk of AD. However, after a Bonferroni correction, our evidence did not suggest a significant causal between them, which means that the evidence is weak. Whether AD exerts effects on CVD needs further investigation.

AD: Allergic diseases

CVD: Cardiovascular diseases

MR: Mendelian randomization

GWAS: Genome-wide association studies

Ethics approval and consent to participate: Not applicable.
Consent for publication: Not applicable.
Availability of data and materials: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Competing interests: Not applicable.
Funding: Our study was supported by the National Natural Science Foundation of China (81974048).
Authors' contributions: SLW chose the topic. ZWW and PYH identified genetic variants associated with exposure. SLW, HL, and PWY completed the subsequent data analysis and article writing. SC, JHX, and PY provided guidance and assistance throughout the process. All authors read and approved the final manuscript.
Acknowledgements: Not applicable.

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No competing interests reported.

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1 Additional file 1: supplementary tables (.xlsx) contain supplementary tables S1-S20 mentioned in the manuscript.
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2 Additional file 2: supplementary figures (.pdf) contain supplementary figures S1-S16 mentioned in the manuscript.

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Exploring genetic association of allergic disease with cardiovascular disease: A bidirectional Mendelian randomization study

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Abstract

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Introduction

Methods

Study design overview

Data sources and SNP selection of genetic instruments for AD

Data sources and SNP selection of genetic instruments for CVD

MR analysis

Results

The causal effect of AD and asthma on CVD

The causal effect of CVD on AD and asthma

Discussion

Conclusions

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