Mendelian randomization analysis revealed potential causal factors for systemic lupus erythematosus

Objectives To appraise the causal effect of systemic lupus erythematosus (SLE) for risk of Coronary heart disease (CHD). Methods We selected single nucleotide polymorphisms (SNPs) associated with SLE as instrumental variables (IVs) from three independent genome-wide association studies (GWAS), the three largest to date for SLE of European ancestry. Then we conducted two-sample Mendelian randomization (2SMR) analyses to estimate the effects of IVs on the odds of CHD and traditional coronary risk factors (including high LDL cholesterol levels, low HDL cholesterol levels, Apolipoprotein A-I, Apolipoprotein B, diabetes mellitus, and hypertension). Additionally, we searched for common risk loci between SLE and premature coronary atherosclerosis. Furthermore, we retrospectively reviewed the lipid profile of treatment-naïve SLE patients and age-matched healthy controls. Results Genetically predicted SLE did not increase the odds of CHD. Nevertheless, we found mild causal relationships between SLE and decreased HDL cholesterol levels, and between SLE and decreased apolipoprotein A-I. There was one common risk locus (rs597808) between SLE and premature coronary atherosclerosis at a genome-wide significance level (P<5 ×10−8). Retrospective analysis showed decreased HDL-cholesterol (0.98±0.516mmol/L vs. 1.46±0.307mmol/L in female, 0.76±0.199mmol/L vs. 1.19±0.257mmol/L in male; both P<0.001) and apolipoprotein A-I (1.06±0.314g/L vs. 1.37±0.205g/L in female, 0.87±0.174g/L vs. 1.24±0.200g/L in male; both P<0.001) in naïve SLE patients. Conclusion SLE may accelerate coronary atherosclerosis in young patients by reducing HDL cholesterol and apolipoprotein A-I intrinsically, but it seems not to play a predominant role in CHD development in old patients.

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Association between systemic lupus erythematosus and cancer: findings from cohort studies and Mendelian randomization analysis

10.21203/rs.3.rs-841744/v1 ◽

2021 ◽

Author(s):

Dongqing Gu ◽

Mingshuang Tang ◽

Huijie Cui ◽

Min Zhang ◽

Yutong Wang ◽

...

Keyword(s):

Cohort Studies ◽

Lupus Erythematosus ◽

Odds Ratio ◽

Observational Studies ◽

Mendelian Randomization ◽

Meta Analysis ◽

European Ancestry ◽

Mendelian Randomization Analysis ◽

Increased Risk ◽

Randomization Analysis

Abstract Background Observational studies suggested that systemic lupus erythematosus (SLE) was associated with an increased risk of cancer, however, the causal effect remains unclear. We aim to determine the causality between SLE and cancer using a meta-analysis and Mendelian randomization (MR) approach. Methods A systematic search was conducted using PubMed to identify cohort studies published before January 21, 2021. Meta-analysis was performed to calculate relative risk (RR) and corresponding 95% confidence intervals (CI), and the potentially causal relationships identified by observational studies were further validated using two-sample Mendelian randomization. Results Through meta-analysis of 43 cohort studies involving 231,499 patients, we observed an increased overall cancer risk among SLE patients (RR = 1.62, 95% CI, 1.47–1.79). Site-specific analysis suggested that SLE patients were associated with an increased risk of 17 cancers. Mendelian randomization analysis indicated that genetically predisposed SLE was causally associated with an increased risk of lymphoma (odds ratio = 1.0004, 95% CI, 1.0001–1.0007, P = 0.0035), whereas a decreased risk of bladder cancer (odds ratio = 0.9996, 95% CI, 0.9994–0.9998, P = 0.00004) in European ancestry. However, no relationship was observed between genetically predisposed SLE and risk of colon, pancreatic, lung, cervical and Non-melanoma skin cancer in European ancestry, liver cancer and lung cancer in Asian ancestry. Conclusions Findings from meta-analysis and Mendelian randomization analysis suggested that SLE might be causally associated with an increased risk of lymphoma. However, inconsistent results were observed between SLE and risk of bladder cancer.

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Alcohol intake and risk of systemic lupus erythematosus: a Mendelian randomization study

Lupus ◽

10.1177/0961203318817832 ◽

2018 ◽

Vol 28 (2) ◽

pp. 174-180 ◽

Cited By ~ 3

Author(s):

S C Bae ◽

Y H Lee

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Alcohol Intake ◽

Mendelian Randomization ◽

Inverse Association ◽

Causal Association ◽

Systemic Lupus ◽

Regression Methods ◽

Genome Wide ◽

Weighted Median

Objectives This study aimed to examine whether alcohol intake is causally associated with systemic lupus erythematosus (SLE). Methods We performed a two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW), weighted median, and MR-Egger regression methods. We used the publicly available summary statistics of alcohol intake frequency from the UK Biobank genome-wide association studies (GWASs; n = 336,965) as the exposure and an SLE GWAS consisting of 1311 SLE and 1783 control subjects of European descent as the outcome. Results We selected 20 single nucleotide polymorphisms (SNPs) associated with alcohol intake frequency at genome-wide significance as instrumental variables to improve inference. The IVW method found no evidence to support a causal association between alcohol intake and SLE (beta = –0.413, SE = 0.513, p = 0.421). The MR-Egger regression revealed that directional pleiotropy was unlikely to bias the result (intercept = 0.031, p = 0.582). The MR-Egger analysis found no causal association between alcohol intake and SLE (beta = –1.494, SE = 1.996, p = 0.464). Likewise, the weighted median approach also did not provide evidence of a causal association between alcohol intake and SLE (beta = –0.538, SE = 0.574, p = 0.349). The MR estimates determined using the IVW, weighted median, and MR-Egger regression methods were consistent and results from a “leave-one-out” analysis demonstrated that no single SNP was driving the IVW point estimate. Conclusions The results of MR analysis do not support a causal inverse association between alcohol intake and SLE occurrence.

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