ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 0288

Targeted Sequencing Revealed Novel Candidate Genetic Contributions to Lupus Nephritis in a Cohort of Swedish Patients with Systemic Lupus Erythematosus

Sule Yavuz1, Pascal Pucholt2, Dag Leonard2, Juliana Imgenberg-Kreuz2, Matteo Bianchi2, Johanna Sandling2, Iva Gunnarsson3, Swedish Sle Network2 and Lars Ronnblom2, 1Uppsala University Rheumatology, Doral, FL, 2Uppsala University, Uppsala, Sweden, 3Karolinska Institute, Stockholm, Sweden

Meeting: ACR Convergence 2020

Keywords: ,

Session Information

Date: Friday, November 6, 2020

Session Title: SLE – Etiology & Pathogenesis Poster

Session Type: Poster Session A

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

Background/Purpose: Lupus nephritis (LN) is a common debilitating manifestation of Systemic Lupus Erythematosus (SLE). Despite improved understanding of underlying mechanisms driving to LN and early treatment strategies, yet 10% of LN patients progress to end-stage renal disease (ESRD) in 5 years after the onset of LN[1]

Methods: To explore novel genetic associations, we performed a case-case analysis in a quality-controlled dataset of 958 Swedish patients with SLE (337 with LN) and 1030 healthy individuals. We stratified patients based on their histopathologic phenotype as proliferative, pure membranous LN, and ESDR. Mixed phenotypes were excluded. Targeted capture and enrichment was performed using a NimbleGen array, including 1853 genes selected based on their known involvement in systemic inflammatory autoimmune diseases. Variant and gene-level aggregate association testing were performed separately using Plink and SKAT-O respectively[2].

Results: We identified seven candidate loci (P ≤ 1× 10− 5) associated with proliferative nephritis, five with membranous nephritis, and seven with ESRD. The strongest associations with proliferative nephritis, membranous nephritis, and ESRD corresponded to chr14q23.3 (p=5.58×10-6 ), LTF (p =1.64×10-6 ), and MERTK(p=9.52×10-6), respectively. The gene-based aggregate association, which potentiates the power to detect gene regions with aggregation of functional common and rare variants revealed two additional potentially novel genes, CTF1 (p= 2.97×10-5, FDR=0.03) and FBXL19 (3.14×10-5, FDR=0.03),  that were associated with membranous nephritis.

Conclusion: We revealed novel genetic risk loci in association with ESRD and candidate genes in association with membranous nephritis in Swedish SLE patients.  

1.Davidson A, Aranow C, Mackay M. Lupus nephritis: challenges and progress. Curr Opin Rheumatol. 2019 Aug.

2.Lee S, Emond MJ, Bamshad MJ, Barnes KC, Rieder MJ, Nickerson DA, et al. Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. Am J Hum Genet. 2012 Aug; 91(2):224-237.

Disclosure: S. Yavuz, None; P. Pucholt, None; D. Leonard, None; J. Imgenberg-Kreuz, None; M. Bianchi, None; J. Sandling, None; I. Gunnarsson, None; S. Sle Network, None; L. Ronnblom, None.

To cite this abstract in AMA style:

Yavuz S, Pucholt P, Leonard D, Imgenberg-Kreuz J, Bianchi M, Sandling J, Gunnarsson I, Sle Network S, Ronnblom L. Targeted Sequencing Revealed Novel Candidate Genetic Contributions to Lupus Nephritis in a Cohort of Swedish Patients with Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/targeted-sequencing-revealed-novel-candidate-genetic-contributions-to-lupus-nephritis-in-a-cohort-of-swedish-patients-with-systemic-lupus-erythematosus/. Accessed April 13, 2021.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/targeted-sequencing-revealed-novel-candidate-genetic-contributions-to-lupus-nephritis-in-a-cohort-of-swedish-patients-with-systemic-lupus-erythematosus/