Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Association of STAT4, IRF5 and BLK Polymorphisms with Severity and Outcome in Lupus Nephritis.
Eriksson1, Karin G., Zickert2, Agneta, Sandling3, Johanna K., Jonsen4, Andreas, Svenungsson2, Elisabet, Ronnblom1, Lars, Behrens5, Timothy W.
Section of Rheumatology, Uppsala University, Uppsala, Sweden
Rheumatology Unit, Karolinska Institutet, Stockholm, Sweden
Molecular Medicine, Uppsala University, Uppsala, Sweden
Section of Rheumatology, Lund University, Lund, Sweden
Genentech Inc, South San Francisco, CA
Department of Medical Sciences, Section of Rheumatology, Uppsala University, Uppsala, Sweden
Background/Purpose:
Lupus nephritis (LN) is a cause of significant morbidity and mortality and occurs in 15–50 % of patients with SLE. Proliferative nephritis is considered the most severe form. Approximately 10 % of LN patients develop end stage renal disease (ESRD). Several susceptibility genes for SLE have been identified where an association with LN has been shown for single nucleotide polymorphisms (SNPs) in STAT4 and ITGAM (1–3). In a previous study, Swedish patients with SLE and controls were genotyped on a custom 12K SNP chip (Illumina Infinium II) (4). The aim of this investigation was to analyze the genetic data from our previous study (4) for association with LN, in particular proliferative nephritis and renal outcome.
Methods:
A total of 567 Swedish Caucasian patients with SLE and 512 matched controls were included. All patients fulfilled the ACR criteria for SLE and 195 (34.4 %) had a history of LN. Renal biopsies were available from 153 patients where 92 (60.1 %) had a proliferative nephritis, WHO class III or IV. During follow-up (median 14 years, range 0–46), 11.1 % reached ESRD. Case-control analyses were performed for patients with LN, proliferative nephritis and ESRD, respectively. The allele frequencies in cases and controls were compared with Fisher's exact test and the results compared with analysis of all SLE patients versus controls.
Results:
We detected strong signals of association between SNPs rs11889341 in STAT4 (OR 2.2, 95% CI 1.7–2.8), rs2070197 in IRF5 (OR 2.0, 95% CI 1.5–2.7) and rs3135394 as a marker for HLA-DR3 (OR 1.95, 95% CI 1.4–2.6), in the analysis of LN patients versus controls (all p < 0.0001). In addition, six genes showed an association with LN with OR 1.5–2.2, p < 0.001 (PMS2, TNIP1, CARD11, ITGAM, BLK and IRAK1). When analyzing only the patients with proliferative nephritis versus controls the OR for association increased for STAT4, IRF5 and BLK to 2.4, 2.2 and 1.7 respectively (all p < 0.01). For patients in ESRD the OR for STAT4, IRF5 and BLK increased further to 2.9, 3.1 and 2.1 whereas the OR for association with the HLA-DR3 marker was decreased to 1.7. The association between the risk alleles in IRF5, STAT4 and BLK and LN phenotypes was stronger than the association to SLE per se.
Conclusion:
Risk alleles in STAT4, IRF5 and BLK are associated with an increased risk for LN. The association with the severe form, proliferative nephritis, was particularly strong and the risk of developing ESRD was even more striking. On the contrary, the HLA-DR3 marker did not display a strong association with LN. We conclude that variations in genes in immunological pathways predispose to LN severity and renal outcome.
References
1Kim-Howard, X, et al. Ann Rheum Dis 2010; 69(7): 1329–1332.
2Sigurdsson, S, et al. Hum Mol Genet 2008; 17(18): 2868–2876.
3Taylor, KE, et al. PLoS Genet 2008; 4(5): e1000084.
4Gateva, V, et al. Nat Genet 2009; 41(11): 1228–1233.
To cite this abstract, please use the following information:
Eriksson, Karin G., Zickert, Agneta, Sandling, Johanna K., Jonsen, Andreas, Svenungsson, Elisabet, Ronnblom, Lars, et al; Association of STAT4, IRF5 and BLK Polymorphisms with Severity and Outcome in Lupus Nephritis. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2480
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