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Publications

Meta-Analysis Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Ppublish 6 citations

PubMed: 36332927 DOI: 10.1136/lupus-2022-000752

Mer-tyrosine kinase: a novel susceptibility gene for SLE related end-stage renal disease.

Lupus Sci Med 9(1)

Authors: Sule Yavuz, Pascal Pucholt, Johanna K Sandling, Matteo Bianchi, Dag Leonard, Karin Bolin, Juliana Imgenberg-Kreuz, Maija-Leena Eloranta, Sergey V Kozyrev, Cristina M Lanata, Andreas Jönsen, Anders A Bengtsson, Christopher Sjöwall, Elisabet Svenungsson, Iva Gunnarsson, Solbritt Rantapää-Dahlqvist, Joanne Nititham, Lindsey A Criswell, Kerstin Lindblad-Toh, Lars Rönnblom

Affiliations

  • Department of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Department of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
  • National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Department of Clinical Sciences Lund, Rheumatology, Lund University, Lund, Sweden.
  • Rheumatology, Skåne University Hospital Lund, Lund, Sweden.
  • Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Östergötland, Sweden.
  • Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
  • Department of Rheumatology, Karolinska University Hospital, Stockholm, Sweden.
  • Department of Public health and Clinical Medicine, Umeå Universitet, Umeå, Sweden.
  • Broad Institute, Cambridge, Massachusetts, USA.

Abstract

OBJECTIVE

Lupus nephritis (LN) is a common and severe manifestation of SLE. The genetic risk for nephritis and progression to end-stage renal disease (ESRD) in patients with LN remains unclear. Herein, we aimed to identify novel genetic associations with LN, focusing on subphenotypes and ESRD.

METHODS

We analysed genomic data on 958 patients with SLE (discovery cohort: LN=338) with targeted sequencing data from 1832 immunological pathway genes. We used an independent multiethnic cohort comprising 1226 patients with SLE (LN=603) as a replication dataset. Detailed functional annotation and functional epigenomic enrichment analyses were applied to predict functional effects of the candidate variants.

RESULTS

A genetic variant (rs56097910) within the gene was associated with ESRD in both cohorts, meta-analysis OR=5.4 (2.8 to 10.6); p=1.0×10. We observed decreased methylation levels in peripheral blood cells from SLE patients with ESRD, compared with patients without renal SLE (p=2.7×10), at one CpG site (cg16333401) in close vicinity to the transcription start site of and located in a DNAse hypersensitivity region in T and B cells. Rs56097910 is linked to altered expression in kidney tissue in public eQTL databases. Two loci were replicated for association with proliferative LN: (rs6924535, p=1.6×10, OR=0.58) and () (rs942960, p=1.2×10, OR=2.64).

CONCLUSION

We identified a novel genetic risk locus, , associated with SLE-ESRD using the data from two large SLE cohorts. Through DNA methylation analysis and functional annotation, we showed that the risk could be mediated through regulation of gene expression. Our results suggest that variants in the gene are important for the risk of developing SLE-ESRD and suggest a role for and in proliferative LN.

MeSH

Protein-Tyrosine Kinases, Kidney Failure, Chronic, Lupus Erythematosus, Systemic, Risk, Dna, Cells, Nephritis, Genes, B-Lymphocytes

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