Association between Systemic Lupus Erythematosus and Coronary Heart Disease: a retrospective case-control analysis and Mendelian Randomization Study

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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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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Genome-Wide Association Study in African-Americans with Systemic Lupus Erythematosus

10.21236/ada592038 ◽

2013 ◽

Author(s):

John Harley

Keyword(s):

Systemic Lupus Erythematosus ◽

African Americans ◽

Association Study ◽

Lupus Erythematosus ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Systemic Lupus ◽

Genome Wide

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Risk Factors for Clinical Coronary Heart Disease in Systemic Lupus Erythematosus: The Lupus and Atherosclerosis Evaluation of Risk (LASER) Study

The Journal of Rheumatology ◽

10.3899/jrheum.090306 ◽

2009 ◽

Vol 37 (2) ◽

pp. 322-329 ◽

Cited By ~ 58

Author(s):

SAHENA HAQUE ◽

CAROLINE GORDON ◽

DAVID ISENBERG ◽

ANISUR RAHMAN ◽

PETER LANYON ◽

...

Keyword(s):

Risk Factors ◽

Systemic Lupus Erythematosus ◽

Coronary Heart Disease ◽

Heart Disease ◽

Lupus Erythematosus ◽

Clinical Setting ◽

Organ Involvement ◽

Systemic Lupus ◽

Chd Risk ◽

Control Disease

Objective. Accelerated atherosclerosis and premature coronary heart disease (CHD) are recognized complications of systemic lupus erythematosus (SLE), but the exact etiology remains unclear and is likely to be multifactorial. We hypothesized that SLE patients with CHD have increased exposure to traditional risk factors as well as differing disease phenotype and therapy-related factors compared to SLE patients free of CHD. Our aim was to examine risk factors for development of clinical CHD in SLE in the clinical setting.Methods. In a UK-wide multicenter retrospective case-control study we recruited 53 SLE patients with verified clinical CHD (myocardial infarction or angina pectoris) and 96 SLE patients without clinical CHD. Controls were recruited from the same center as the case and matched by disease duration. Charts were reviewed up to time of event for cases, or the same “dummy-date” in controls.Results. SLE patients with clinical CHD were older at the time of event [mean (SD) 53 (10) vs 42 (10) yrs; p < 0.001], more likely to be male [11 (20%) vs 3 (7%); p < 0.001], and had more exposure to all classic CHD risk factors compared to SLE patients without clinical CHD. They were also more likely to have been treated with corticosteroids (OR 2.46; 95% CI 1.03, 5.88) and azathioprine (OR 2.33; 95% CI 1.16, 4.67) and to have evidence of damage on the pre-event SLICC damage index (SDI) (OR 2.20; 95% CI 1.09, 4.44). There was no difference between groups with regard to clinical organ involvement or autoantibody profile.Conclusion. Our study highlights the need for clinical vigilance to identify modifiable risk factors in the clinical setting and in particular with male patients. The pattern of organ involvement did not differ in SLE patients with CHD events. However, the higher pre-event SDI, azathioprine exposure, and pattern of damage items (disease-related rather than therapy-related) in cases suggests that a persistent active lupus phenotype contributes to CHD risk. In this regard, corticosteroids and azathioprine may not control disease well enough to prevent CHD. Clinical trials are needed to determine whether classic risk factor modification will have a role in primary prevention of CHD in SLE patients and whether new therapies that control disease activity can better reduce CHD risk.

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Genetic Profiles for Systemic Lupus Erythematosus in Han Chinese Population: From Genome-Wide Association Study to Exome-Wide Association Study

Journal of Investigative Dermatology Symposium Proceedings ◽

10.1016/j.jisp.2018.10.003 ◽

2018 ◽

Vol 19 (2) ◽

pp. S95-S97 ◽

Cited By ~ 1

Author(s):

Leilei Wen ◽

Lu Liu ◽

Ke Xue ◽

Yong Cui

Keyword(s):

Systemic Lupus Erythematosus ◽

Association Study ◽

Lupus Erythematosus ◽

Chinese Population ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Systemic Lupus ◽

Han Chinese Population ◽

Genome Wide ◽

Genetic Profiles

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Genome-wide search followed by replication reveals genetic interaction ofCD80andALOX5APassociated with systemic lupus erythematosus in Asian populations

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2014-206367 ◽

2015 ◽

Vol 75 (5) ◽

pp. 891-898 ◽

Cited By ~ 12

Author(s):

Yan Zhang ◽

Jing Yang ◽

Jing Zhang ◽

Liangdan Sun ◽

Nattiya Hirankarn ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Genetic Interaction ◽

Systemic Lupus ◽

Asian Populations ◽

Genome Wide ◽

Genome Wide Search

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Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-219209 ◽

2020 ◽

pp. annrheumdis-2020-219209

Author(s):

Xianyong Yin ◽

Kwangwoo Kim ◽

Hiroyuki Suetsugu ◽

So-Young Bang ◽

Leilei Wen ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Large Scale ◽

Meta Analysis ◽

Genetic Correlations ◽

Susceptibility Loci ◽

Systemic Lupus ◽

East Asians ◽

Genome Wide ◽

Causal Variants

ObjectiveSystemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations.MethodsWe newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations.ResultsWe identified 113 genetic regions including 46 novel loci at genome-wide significance (p<5×10−8). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (rg=−0.242) and non-albumin protein (rg=0.238).ConclusionThis study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.

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Identification of ST3AGL4, MFHAS1, CSNK2A2 and CD226 as loci associated with systemic lupus erythematosus (SLE) and evaluation of SLE genetics in drug repositioning

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2018-213093 ◽

2018 ◽

Vol 77 (7) ◽

pp. 1078-1084 ◽

Cited By ~ 10

Author(s):

Yong-Fei Wang ◽

Yan Zhang ◽

Zhengwei Zhu ◽

Ting-You Wang ◽

David L Morris ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Fine Mapping ◽

Lupus Erythematosus ◽

Drug Repositioning ◽

Association Studies ◽

Genome Wide Association Studies ◽

Systemic Lupus ◽

Genome Wide ◽

Causal Variants

ObjectivesSystemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic component in its pathogenesis. Through genome-wide association studies (GWAS), we recently identified 10 novel loci associated with SLE and uncovered a number of suggestive loci requiring further validation. This study aimed to validate those loci in independent cohorts and evaluate the role of SLE genetics in drug repositioning.MethodsWe conducted GWAS and replication studies involving 12 280 SLE cases and 18 828 controls, and performed fine-mapping analyses to identify likely causal variants within the newly identified loci. We further scanned drug target databases to evaluate the role of SLE genetics in drug repositioning.ResultsWe identified three novel loci that surpassed genome-wide significance, including ST3AGL4 (rs13238909, pmeta=4.40E-08), MFHAS1 (rs2428, pmeta=1.17E-08) and CSNK2A2 (rs2731783, pmeta=1.08E-09). We also confirmed the association of CD226 locus with SLE (rs763361, pmeta=2.45E-08). Fine-mapping and functional analyses indicated that the putative causal variants in CSNK2A2 locus reside in an enhancer and are associated with expression of CSNK2A2 in B-lymphocytes, suggesting a potential mechanism of association. In addition, we demonstrated that SLE risk genes were more likely to be interacting proteins with targets of approved SLE drugs (OR=2.41, p=1.50E-03) which supports the role of genetic studies to repurpose drugs approved for other diseases for the treatment of SLE.ConclusionThis study identified three novel loci associated with SLE and demonstrated the role of SLE GWAS findings in drug repositioning.

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