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Genetic polymorphisms of dsRNA ligating pattern recognition receptors TLR3, MDA5, and RIG-I. Association with systemic lupus erythematosus and clinical phenotypes

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Abstract

This study aimed to demonstrate possible associations between genetic polymorphisms in Toll-like receptor 3, interferon induced with helicase C domain 1 (IFIH1) and DEAD (Asp-Glu-Ala-Asp) box polypeptide 58 and systemic lupus erythematosus (SLE), including the phenotypes lupus nephritis and malar rash, as well as the presence of autoantibodies against nucleic acid-containing complexes. Genotyping was carried out in two Danish cohorts [Copenhagen (CPH) and Odense (ODE)] totaling 344 patients and was compared with 641 previously genotyped healthy controls. In the ODE cohort, the patients were only genotyped for the rs1990760 polymorphism of IFIH1. Single nucleotide polymorphisms (SNPs) were determined by a multiplex bead-based assay (CPH cohort) or real-time PCR (ODE cohort). Associations were investigated using the Cochran–Armitage trend test. The odds ratio (OR) for minor allele homozygotes versus major allele homozygotes suggested a protective effect of the IFIH1 rs1990760 SNP for SLE in the ODE cohort [OR 0.52, 95 % confidence intervals (95 % CI) 0.31–0.88, Pcorr. = 0.05] but not in the CPH cohort, although the OR suggested a trend in the same direction, and when combining the two patient cohorts, ORs were 0.57, 95 % CI 0.37–0.88. None of the other investigated polymorphisms showed any association with SLE. Regarding phenotypes, we found a statistically significant association between rs1990760 and malar rash in the CPH cohort, with ORs suggesting a protective effect (OR 0.28, 95 % CI 0.13–0.62 for heterozygotes and OR 0.11, 95 % CI 0.03–0.41 for homozygotes, Pcorr. = 0.0001). There were no significant associations between rs1990760 and presence of anti-dsDNA, anti-U1RNP, or anti-Smith antibodies. Our study supports previous findings of an association between the rs1990760 polymorphism of IFIH1 and SLE and indicates that this SNP may also be associated with malar rash in SLE patients although this finding needs confirmation.

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Acknowledgments

The authors thank Pia Grothe Meinke for technical assistance. The authors also thank all patients and healthy control subjects for their participation. The Danish Biotechnology Program, The Novo Nordisk Foundation, The Danish Rheumatism Association, and The Lundbeck Foundation are thanked for financial support.

Conflict of interest

None of the authors has any conflicts of interest.

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Authors and Affiliations

  1. Department of Infectious Diseases and Rheumatology, Institute for Inflammation Research, Rigshospitalet, Copenhagen, Denmark

    C. Enevold, L. Kjær, C. H. Nielsen, R. S. Jacobsen, M. L. F. Hermansen, K. Bendtzen & S. Jacobsen

  2. Department of Neurology, Danish Multiple Sclerosis Center, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

    A. B. Oturai & P. E. Jensen

  3. Department of Rheumatology, Odense University Hospital, Odense, Denmark

    A. Voss

  4. Department of Clinical Immunology, Odense University Hospital, Odense, Denmark

    L. Redder

  5. Section 4242, Department of Infectious Diseases and Rheumatology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark

    S. Jacobsen

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  1. C. Enevold
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  2. L. Kjær
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  3. C. H. Nielsen
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  4. A. Voss
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  5. R. S. Jacobsen
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  6. M. L. F. Hermansen
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  11. S. Jacobsen
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Correspondence to C. Enevold.

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Enevold, C., Kjær, L., Nielsen, C.H. et al. Genetic polymorphisms of dsRNA ligating pattern recognition receptors TLR3, MDA5, and RIG-I. Association with systemic lupus erythematosus and clinical phenotypes. Rheumatol Int 34, 1401–1408 (2014). https://doi.org/10.1007/s00296-014-3012-4

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