Association of STAT4 polymorphism with severe renal insufficiency in lupus nephritis

Karin Bolin; Johanna K Sandling; Agneta Zickert; Andreas Jönsen; Christopher Sjöwall; Elisabet Svenungsson; Anders A Bengtsson; Maija-Leena Eloranta; Lars Rönnblom; Ann-Christine Syvänen; Iva Gunnarsson; Gunnel Nordmark

doi:10.1371/journal.pone.0084450

Association of STAT4 polymorphism with severe renal insufficiency in lupus nephritis

PLoS One. 2013 Dec 27;8(12):e84450. doi: 10.1371/journal.pone.0084450. eCollection 2013.

Affiliations

¹ Section of Rheumatology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
² Molecular Medicine, Department of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
³ Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
⁴ Section of Rheumatology, Department Clinical Sciences, Lund University, Lund, Sweden.
⁵ Rheumatology/AIR, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
⁶ Section of Rheumatology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden ; Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

Abstract

Lupus nephritis is a cause of significant morbidity in systemic lupus erythematosus (SLE) and its genetic background has not been completely clarified. The aim of this investigation was to analyze single nucleotide polymorphisms (SNPs) for association with lupus nephritis, its severe form proliferative nephritis and renal outcome, in two Swedish cohorts. Cohort I (n = 567 SLE cases, n = 512 controls) was previously genotyped for 5676 SNPs and cohort II (n = 145 SLE cases, n = 619 controls) was genotyped for SNPs in STAT4, IRF5, TNIP1 and BLK. Case-control and case-only association analyses for patients with lupus nephritis, proliferative nephritis and severe renal insufficiency were performed. In the case-control analysis of cohort I, four highly linked SNPs in STAT4 were associated with lupus nephritis with genome wide significance with p = 3.7 × 10(-9), OR 2.20 for the best SNP rs11889341. Strong signals of association between IRF5 and an HLA-DR3 SNP marker were also detected in the lupus nephritis case versus healthy control analysis (p <0.0001). An additional six genes showed an association with lupus nephritis with p <0.001 (PMS2, TNIP1, CARD11, ITGAM, BLK and IRAK1). In the case-only meta-analysis of the two cohorts, the STAT4 SNP rs7582694 was associated with severe renal insufficiency with p = 1.6 × 10(-3) and OR 2.22. We conclude that genetic variations in STAT4 predispose to lupus nephritis and a worse outcome with severe renal insufficiency.

Publication types

Clinical Trial
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Case-Control Studies
Female
Genetic Predisposition to Disease*
Genome-Wide Association Study
Humans
Lupus Nephritis / complications
Lupus Nephritis / genetics*
Male
Polymorphism, Single Nucleotide*
Renal Insufficiency, Chronic / etiology
Renal Insufficiency, Chronic / genetics*
STAT4 Transcription Factor / genetics*
Severity of Illness Index

Substances

STAT4 Transcription Factor
STAT4 protein, human

Grants and funding

This study was supported by the Swedish Research Council for Medicine, the Knut and Alice Wallenberg Foundation, the Swedish Rheumatism Foundation, the King Gustav V 80-year Foundation, the Ragnar Söderberg Foundation, Combine, the County Council of Östergötland, Swedish Society for Medical Research, the Ingrid Asp Research Foundation, The Swedish Heart-Lung foundation, Stockholm County Council and Karolinska Institutet (ALF), The Foundation in memory of Clas Groschinsky and the Swedish Society of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.