Novel Gene Variants Associated with Cardiovascular Disease in Systemic Lupus Erythematosus

Dag Leonard¹, Andrei Alexsson¹, Johanna Dahlqvist², Kimberly Taylor³, Johanna K Sandling⁴, Christine Bengtsson⁵, Elisabet Svenungsson⁶, Christopher Sjöwall⁷, Andreas Jönsen⁸, Iva Gunnarsson⁶, Anders A. Bengtsson⁸, Solbritt Rantapaa-Dahlqvist⁵, Maija-Leena Eloranta¹, Ann-Christine Syvänen⁴, Lindsey A. Criswell⁹ and Lars Rönnblom¹, ¹Uppsala University, Department of Medical Sciences, Rheumatology and Science for Life Laboratory, Uppsala, Sweden, ²Uppsala University, Department of Medical Biochemistry and Microbiology Science for Life Laboratory, Uppsala, Sweden, ³University of California, San Francisco, Rosalind Russell / Ephraim P. Engleman Rheumatology Research Center, San Francisco, CA, ⁴Uppsala University, Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala, Sweden, ⁵Umeå University, Department of Public Health and Clinical Medicine/ Rheumatology, Umeå, Sweden, ⁶Karolinska Institutet, Department of Medicine, Unit of Rheumatology, Stockholm, Sweden, ⁷Linköping University, Department of Clinical and Experimental Medicine Rheumatology/AIR, Linköping, Sweden, ⁸Lund University, Department of Clinical Sciences, Rheumatology, Lund, Sweden, ⁹Medicine, University of California, San Francisco, Rosalind Russell / Ephraim P. Engleman Rheumatology Research Center, San Francisco, CA

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Bioinformatics, cardiovascular disease and genetics, Lupus, SLE

Session Information

Date: Tuesday, November 15, 2016

Session Title: Systemic Lupus Erythematosus – Clinical Aspects and Treatment - Poster III: Biomarkers and Nephritis

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Patients with Systemic Lupus Erythematosus (SLE) have increased risk of cardiovascular disease (CVD). We asked if single nucleotide polymorphisms (SNPs) analyzed by the Immunochip were associated to CVD in SLE, and followed up with bioinformatics and functional analyses.

Methods: SLE patients (Sweden, n=1055) were genotyped using the 200K Immunochip SNP array (Illumina). The allele frequency was compared between patients with and without myocardial infarction (MI)/angina pectoris (AP), ischemic stroke (stroke)/transitory ischemic attack (TIA), pulmonary embolism/deep vein thrombosis and MI/stroke. Data was analyzed using a logistic regression model with sex and disease duration included as covariates. The SNPs showing the strongest association were re-analyzed in a second group of patients of European descent (United States, n=1043). Information regarding TIA and AP was not available for the US patients. Sex, disease duration and two principal components for population stratification were included as covariates. All patients fulfilled the 1982 ACR-criteria for SLE. Bioinformatic analysis was performed using several databases including RegulomeDB, GTEx and UCSC GB.

Results: An association between a locus located on chromosome 14 and stroke/TIA was shown in both the Swedish (OR 1.8, p=0.0002) and the US (OR 1.6, p=0.03) cohort. The SNP is located in an intron and is conserved in animals but not in humans. The gene variant is located in the middle of a Chip-seq peak for STAT1 and a few bases 3´of a USF2-peak. It is a predicted enhancer in B-cells and also an eQTL. By electrophoretic mobility shift assay (EMSA) we have demonstrated that STAT1 is one of the transcription factors binding at the risk loci. In both the Swedish (OR 2.6, p=0.0006) and US (OR 1.9, p=0.04) cohorts an association was demonstrated between a locus located on chromosome 1 and stroke/MI. The locus is a predicted enhancer in B-cells and is located in an intron 3´of a binding site for a cluster of transcription factors and at a Chip-Seq-peak for CTCF. By EMSA, differential protein binding between the alternative and reference allele was demonstrated using nuclear extract from T-cells activated by PMA/ionomycin. When comparing the level of IL10 in SLE patients with and without the risk gene variant the alternative allele was associated with higher serum levels of IL10 (n=255, p=0.001).

Conclusion: The results indicate that multiple genes in different pathways, including B cell function and cytokine signaling, are involved in the development of CVD in SLE. Thus, CVD in SLE is clearly dependent on the autoimmune and inflammatory disease process, which needs to be considered when therapeutic strategies are developed for the premature CVD observed in SLE patients.

Disclosure: D. Leonard, None; A. Alexsson, None; J. Dahlqvist, None; K. Taylor, None; J. K. Sandling, None; C. Bengtsson, None; E. Svenungsson, None; C. Sjöwall, None; A. Jönsen, None; I. Gunnarsson, None; A. A. Bengtsson, None; S. Rantapaa-Dahlqvist, None; M. L. Eloranta, None; A. C. Syvänen, None; L. A. Criswell, None; L. Rönnblom, None.

To cite this abstract in AMA style:

Leonard D, Alexsson A, Dahlqvist J, Taylor K, Sandling JK, Bengtsson C, Svenungsson E, Sjöwall C, Jönsen A, Gunnarsson I, Bengtsson AA, Rantapaa-Dahlqvist S, Eloranta ML, Syvänen AC, Criswell LA, Rönnblom L. Novel Gene Variants Associated with Cardiovascular Disease in Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/novel-gene-variants-associated-with-cardiovascular-disease-in-systemic-lupus-erythematosus/. Accessed January 15, 2021.

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