Dataset Information

Systemic Lupus Erythematosus and Cardiovascular Disease: A Mendelian Randomization Study.

ABSTRACT:

Background

Previous studies have shown that patients with systemic lupus erythematosus (SLE) tend to have a higher risk of cardiovascular disease (CVD), but the potential causal relationship between genetic susceptibility to SLE and CVD risk is not clear. This study systematically investigated the potential association between genetically determined SLE and the risk of CVD.

Methods

The genetic tools were obtained from genome-wide association studies of SLE and CVD, with no overlap between their participating populations. Mendelian randomization (MR) analysis was performed using inverse variance weighting as the primary method. Simultaneously, a series of repeated analyses, sensitivity analyses, and instrumental variable strength evaluations were performed to verify the reliability of our results.

Results

MR analysis showed that genetic susceptibility to SLE was associated with a higher risk of heart failure (OR=1.025, 95% CI [1.009-1.041], P=0.002), ischemic stroke (OR=1.020, 95% CI [1.005-1.034], P=0.009), and venous thromboembolism (OR=1.001, 95% CI [1.000-1.002], P=0.014). However, genetic susceptibility to SLE was negatively correlated with the risk of type 2 diabetes (OR=0.968, 95% CI [0.947-0.990], P=0.004). Sensitivity analysis found no evidence of horizontal pleiotropy or heterogeneity.

Conclusion

Our MR study explored the causal role of SLE in the etiology of CVD, which would help improve our understanding of the basic disease mechanisms of SLE and provide comprehensive CVD assessment and treatment for SLE patients.

SUBMITTER: Gao N

PROVIDER: S-EPMC9207262 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Systemic Lupus Erythematosus and Cardiovascular Disease: A Mendelian Randomization Study.

Gao Ning N Kong Minjian M Li Xuebiao X Wei Dongdong D Zhu Xian X Hong Ze Z Ni Ming M Wang Yifan Y Dong Aiqiang A

Frontiers in immunology 20220606

<h4>Background</h4>Previous studies have shown that patients with systemic lupus erythematosus (SLE) tend to have a higher risk of cardiovascular disease (CVD), but the potential causal relationship between genetic susceptibility to SLE and CVD risk is not clear. This study systematically investigated the potential association between genetically determined SLE and the risk of CVD.<h4>Methods</h4>The genetic tools were obtained from genome-wide association studies of SLE and CVD, with no overlap ...[more]

PMID: 35734181

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Project description:ObjectiveNumerous observational studies have found a relationship between systemic lupus erythematosus (SLE) and epilepsy; however, their causal relationship remains unclear. This study aimed to investigate the causal role of SLE in epilepsy or any of its subtypes using a two-sample Mendelian randomization (MR) analysis.MethodsSingle nucleotide polymorphisms (SNPs) linked to SLE were utilized as instrumental variables in MR analysis to assess their causal impact on epilepsy. The primary MR findings were derived using the inverse variance weighted (IVW) method, which was further supported by the weighted median and MR-Egger regression techniques. Additionally, sensitivity analyses, including Cochran's Q test and pleiotropy tests, were conducted to evaluate the influence of these SNPs on epilepsy, particularly looking for signs of horizontal pleiotropy and heterogeneity.ResultsWe selected 43 SNPs that reached genome-wide significance from genome-wide association studies (GWASs) on SLE to serve as instrumental variables in this study. The IVW method showed no evidence to support a causal association between SLE and epilepsy (all epilepsy: odds ratio (OR) = 1.006, 95% confidence interval (CI) = 0.994-1.018; focal epilepsy: OR = 1.006, 95% CI = 0.994-1.019; generalized epilepsy: OR = 1.015, 95% CI = 0.996-1.035). Other MR complementary methods revealed consistent results. Furthermore, there was no evidence indicating heterogeneity or horizontal pleiotropy.SignificanceThe findings of MR analysis did not support a genetically predicted causal relationship between SLE and epilepsy, but emphasized the need for further research on shared pathophysiological mechanisms, particularly the role of immune system abnormalities and potential influences such as chronic inflammation and therapeutic interventions.Plain language summaryThe etiology of epilepsy is complex and diverse, including immune factors. Through a Mendelian randomization analysis, we did not find evidence of a genetic causal relationship between systemic lupus erythematosus and epilepsy. However, this does not invalidate epidemiological evidence, and further exploration is needed to investigate factors influencing the relationship between the two.

Project description:BackgroundPrevious observational studies have suggested that the causal role of systemic lupus erythematosus (SLE) in the risk of cardiovascular diseases (CVDs) remained inconsistent. In this study, we aimed to investigate the causal relationship between SLE and CVDs by two-sample Mendelian randomization (MR) analysis.MethodsGenetic instruments for SLE were obtained from a public genome-wide association study (GWAS) with 4,036 patients with SLE and 6,959 controls. Summary statistical data for CVDs, including coronary artery disease (CAD), myocardial infarction (MI), atrial fibrillation (AF), ischemic stroke (IS), and its subtypes, were identified from other available GWAS meta-analyses. The inverse-variance weighted (IVW) method was used as the primary method to estimate the causal effect. The simple- and weighted-median method, MR-Egger method, and MR pleiotropy residual sum and outlier (MR-PRESSO) were provided as a supplement to the IVW method. Besides, we performed sensitivity analyses, including Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis, to evaluate the robustness of the results.ResultsA total of 15 single-nucleotide polymorphisms (SNPs) were identified after excluding linkage disequilibrium (LD) and potential confounding factors. According to the IVW results, our MR study indicated that genetically predicted SLE was not causally connected with the risk of CVDs [CAD: odds ratio (OR) = 1.005, 95% confidence interval (CI) = 0.986-1.024, p-value = 0.619; MI: OR = 1.002, 95% CI = 0.982-1.023, p-value = 0.854; AF: OR = 0.998, 95% CI = 0.982-1.014, p-value = 0.795; IS: OR = 1.006, 95% CI = 0.984-1.028, p-value = 0.621; cardioembolic stroke (CES): OR = 0.992, 95% CI = 0.949-1.036, p-value = 0.707; small vessel stroke (SVS): OR = 1.014, 95% CI = 0.964-1.067, p-value = 0.589; large artery stroke (LAS): OR = 1.030, 95% CI = 0.968-1.096, p-value = 0.352]. Analogical findings could be observed in supplementary MR methods. Sensitivity analyses suggested that the causal estimates were robust.ConclusionOur two-sample MR analysis provided no evidence that genetically determined SLE was causally associated with the risk of CVDs.

Project description:BackgroundThe relationship between systemic lupus erythematosus (SLE) and thyroid diseases is still controversial. Due to confounders and reverse causation, previous studies were not convincing. We aimed to investigate the relationship between SLE and hyperthyroidism or hypothyroidism by Mendelian randomization (MR) analysis.MethodsWe performed a two-step analysis using bidirectional two-sample univariable and multivariable MR (MVMR) to explore the causality of SLE and hyperthyroidism or hypothyroidism in three genome-wide association studies (GWAS) datasets, including 402,195 samples and 39,831,813 single-nucleotide polymorphisms (SNPs). In the first step analysis, with SLE as exposure and thyroid diseases as outcomes, 38 and 37 independent SNPs strongly (P < 5*10-8) associated with SLE on hyperthyroidism or SLE on hypothyroidism were extracted as valid instrumental variables (IVs). In the second step analysis, with thyroid diseases as exposures and SLE as outcome, 5 and 37 independent SNPs strongly associated with hyperthyroidism on SLE or hypothyroidism on SLE were extracted as valid IVs. In addition, MVMR analysis was performed in the second step analysis to eliminate the interference of SNPs that were strongly associated with both hyperthyroidism and hypothyroidism. 2 and 35 valid IVs for hyperthyroidism on SLE and hypothyroidism on SLE were obtained in MVMR analysis. MR results of two steps analysis were estimated respectively by multiplicative random effects-inverse variance weighted (MRE-IVW), simple mode (SM), weighted median (WME) and MR-Egger regression methods. Sensitivity analysis and visualization of MR results were performed by heterogeneity test, pleiotropy test, leave-one-out test, scatter plots, forest plots and funnel plots.ResultsThe MRE-IVW method in the first step of MR analysis revealed that SLE was causally associated with hypothyroidism (OR = 1.049, 95% CI = 1.020-1.079, P < 0.001), but not causally associated with hyperthyroidism (OR = 1.045, 95% CI = 0.987-1.107, P = 0.130). In the inverse MR analysis, the MRE-IVW method revealed that both hyperthyroidism (OR = 1.920, 95% CI = 1.310-2.814, P < 0.001) and hypothyroidism (OR = 1.630, 95% CI = 1.125-2.362, P = 0.010) were causally associated with SLE. Results from other MR methods were consistent with MRE-IVW. However, when MVMR analysis was performed, there was no longer a causal relationship of hyperthyroidism on SLE (OR = 1.395, 95% CI = 0.984-1.978, P = 0.061), nor was there a causal relationship of hypothyroidism on SLE (OR = 1.290, 95% CI = 0.823-2.022, P = 0.266). The stability and reliability of the results were confirmed by sensitivity analysis and visualization.ConclusionsOur univariable and multivariable MR analysis revealed that systemic lupus erythematosus was causally associated with hypothyroidism, but did not provided evidence to support a causal relationship of hypothyroidism on SLE or between SLE and hyperthyroidism.

Dataset Information

Systemic Lupus Erythematosus and Cardiovascular Disease: A Mendelian Randomization Study.

Background

Methods

Results

Conclusion

Publications

Systemic Lupus Erythematosus and Cardiovascular Disease: A Mendelian Randomization Study.

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