@article {Yavuze000752, author = {Sule Yavuz and Pascal Pucholt and Johanna K Sandling and Matteo Bianchi and Dag Leonard and Karin Bolin and Juliana Imgenberg-Kreuz and Maija-Leena Eloranta and Sergey V Kozyrev and Cristina M Lanata and Andreas J{\"o}nsen and Anders A Bengtsson and Christopher Sj{\"o}wall and Elisabet Svenungsson and Iva Gunnarsson and Solbritt Rantap{\"a}{\"a}-Dahlqvist and ImmunoArray Development Consortium and DISSECT Consortium and Joanne Nititham and Lindsey A Criswell and Kerstin Lindblad-Toh and Lars R{\"o}nnblom}, title = {Mer-tyrosine kinase: a novel susceptibility gene for SLE related end-stage renal disease}, volume = {9}, number = {1}, elocation-id = {e000752}, year = {2022}, doi = {10.1136/lupus-2022-000752}, publisher = {Archives of Disease in childhood}, 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{\texttimes}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{\texttimes}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{\texttimes}10-5, OR=0.58) and APOA1BP (NAXE) (rs942960, pmeta=1.2{\texttimes}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.Data are available upon reasonable request. The datasets generated during the current study are not publicly available due to them containing information that could compromise research participant privacy and consent, but are available from the corresponding authors on reasonable request and on a collaborative basis.}, URL = {https://lupus.bmj.com/content/9/1/e000752}, eprint = {https://lupus.bmj.com/content/9/1/e000752.full.pdf}, journal = {Lupus Science \& Medicine} }