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Meta-Analysis
. 2022 Nov;9(1):e000752.
doi: 10.1136/lupus-2022-000752.

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

Sule Yavuz  1 , Pascal Pucholt  2 , Johanna K Sandling  2 , Matteo Bianchi  3 , Dag Leonard  2 , Karin Bolin  2 , Juliana Imgenberg-Kreuz  2 , Maija-Leena Eloranta  2 , Sergey V Kozyrev  3 , Cristina M Lanata  4 , Andreas Jönsen  5   6 , Anders A Bengtsson  5   6 , Christopher Sjöwall  7 , Elisabet Svenungsson  8   9 , Iva Gunnarsson  8   9 , Solbritt Rantapää-Dahlqvist  10 ; ImmunoArray Development Consortium; DISSECT Consortium; Joanne Nititham  4 , Lindsey A Criswell  4 , Kerstin Lindblad-Toh  3   11 , Lars Rönnblom  1
Affiliations
Meta-Analysis

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

Sule Yavuz et al. Lupus Sci Med. 2022 Nov.

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 MERTK gene was associated with ESRD in both cohorts, meta-analysis OR=5.4 (2.8 to 10.6); p=1.0×10-6. We observed decreased methylation levels in peripheral blood cells from SLE patients with ESRD, compared with patients without renal SLE (p=2.7×10-4), at one CpG site (cg16333401) in close vicinity to the transcription start site of MERTK and located in a DNAse hypersensitivity region in T and B cells. Rs56097910 is linked to altered MERTK expression in kidney tissue in public eQTL databases. Two loci were replicated for association with proliferative LN: PRDM1 (rs6924535, pmeta=1.6×10-5, OR=0.58) and APOA1BP (NAXE) (rs942960, pmeta=1.2×10-5, OR=2.64).

Conclusion: We identified a novel genetic risk locus, MERTK, 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 MERTK gene are important for the risk of developing SLE-ESRD and suggest a role for PRDM1 and APOA1BP in proliferative LN.

Keywords: Autoimmune Diseases; Lupus Erythematosus, Systemic; Polymorphism, Genetic.

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Conflict of interest statement

Competing interests: PP is now an employee of Olink Proteomics.

Figures

Figure 1
Figure 1
Regional association plots of the MERTK region. The regional association plots display results of the analysis of SLE-ESRD (n=35;73) versus SLE without nephritis (n=620;623) in (A) discovery and (B) replication datasets, respectively. Imputed SNVs are indicated by plus signs. (C) Meta-analysis of discovery and replication SLE-ESRD association analyses. All overlapping SNVs analysed in the discovery and replication cohorts are included. For the meta-analysis candidate, SNVs from the discovery cohort analysis are indicated in black. (D) Epigenetic analysis in SLE-ESRD (n=20) versus non-renal SLE (n=302) revealed a CpG site with decreased methylation in ESRD. (E) Genes and their chromosomal position in the region. ESRD, end-stage renal disease; SNV, single nucleotide variant
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