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Novel gene variants associated with cardiovascular disease in systemic lupus erythematosus and rheumatoid arthritis
Dag Leonard1, Elisabet Svenungsson2, Johanna Dahlqvist3
1Department of Medical Sciences, Science for Life Laboratory, Rheumatology, Uppsala University, Uppsala, Sweden.
Insights
Genetic variants in IL19 and SRP54-AS1 loci are associated with cardiovascular disease (CVD) risk in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients. These findings suggest shared immune pathways contribute to CVD in these inflammatory rheumatic diseases.
Area of Science:
- Genetics and Immunology
- Cardiovascular Disease Research
- Rheumatology
Background:
- Patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) face elevated risks of cardiovascular disease (CVD).
- The genetic underpinnings of CVD in these autoimmune conditions are not fully understood.
- Investigating autoimmunity risk loci may reveal novel associations with CVD.
Purpose of the Study:
- To determine if single nucleotide polymorphisms (SNPs) at known autoimmunity risk loci are associated with CVD in patients with SLE and RA.
- To identify specific genetic variants that contribute to CVD risk in these patient populations.
- To explore potential shared immune pathways in the pathogenesis of CVD in inflammatory rheumatic diseases.
Main Methods:
- Genotyping of 1045 SLE patients using the 200K Immunochip SNP array.
- Comparison of allele frequencies between patients with and without CVD manifestations, with replication in a second SLE cohort (n=1043) and an RA cohort (n=824).
- Analysis of publicly available population genetic data, electrophoretic mobility shift assays, cytokine level measurements, and antiphospholipid antibody (aPL) assessments.
Main Results:
- Two novel risk loci associated with increased CVD risk in SLE were identified: an IL19 risk allele (rs17581834(T)) linked to stroke/myocardial infarction (MI) in both SLE and RA, and an SRP54-AS1 risk allele (rs799454(G)) associated with stroke/transient ischemic attack in SLE.
- The IL19 risk allele was not associated with CVD in general population controls, suggesting disease-specific mechanisms.
- SLE patients with the IL19 risk allele exhibited higher plasma IL-10 levels and aPL occurrence, and the allele affected protein binding.
Conclusions:
- The IL19 risk allele's association with stroke/MI in SLE and RA, but not in the general population, points to shared immune pathways in CVD pathogenesis.
- These findings highlight specific genetic risk factors for CVD in inflammatory rheumatic diseases.
- Further research into immune pathways could lead to targeted CVD prevention strategies for SLE and RA patients.
Objectives:
Patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have increased risk of cardiovascular disease (CVD). We investigated whether single nucleotide polymorphisms (SNPs) at autoimmunity risk loci were associated with CVD in SLE and RA.
Methods:
Patients with SLE (n=1045) were genotyped using the 200K Immunochip SNP array (Illumina). The allele frequency was compared between patients with and without different manifestations of CVD. Results were replicated in a second SLE cohort (n=1043) and in an RA cohort (n=824). We analysed publicly available genetic data from general population, performed electrophoretic mobility shift assays and measured cytokine levels and occurrence of antiphospholipid antibodies (aPLs).
Results:
We identified two new putative risk loci associated with increased risk for CVD in two SLE populations, which remained after adjustment for traditional CVD risk factors. An IL19 risk allele, rs17581834(T) was associated with stroke/myocardial infarction (MI) in SLE (OR 2.3 (1.5 to 3.4), P=8.5×10-5) and RA (OR 2.8 (1.4 to 5.6), P=3.8×10-3), meta-analysis (OR 2.5 (2.0 to 2.9), P=3.5×10-7), but not in population controls. The IL19 risk allele affected protein binding, and SLE patients with the risk allele had increased levels of plasma-IL10 (P=0.004) and aPL (P=0.01). An SRP54-AS1 risk allele, rs799454(G) was associated with stroke/transient ischaemic attack in SLE (OR 1.7 (1.3 to 2.2), P=2.5×10-5) but not in RA. The SRP54-AS1 risk allele is an expression quantitative trait locus for four genes.
Conclusions:
The IL19 risk allele was associated with stroke/MI in SLE and RA, but not in the general population, indicating that shared immune pathways may be involved in the CVD pathogenesis in inflammatory rheumatic diseases.
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