JCI - Kallikrein genes are associated with lupus and glomerular basement membrane–specific antibody

Kallikrein genes are associated with lupus and glomerular basement membrane–specific antibody–induced nephritis in mice and humans

Kui Liu, Quan-Zhen Li, Angelica M. Delgado-Vega, Anna-Karin Abelson, Elena Sánchez, Jennifer A. Kelly, Li Li, Yang Liu, Jinchun Zhou, Mei Yan, Qiu Ye, Shenxi Liu, Chun Xie, Xin J. Zhou, Sharon A. Chung, Bernardo Pons-Estel, Torsten Witte, Enrique de Ramón, Sang-Cheol Bae, Nadia Barizzone, Gian Domenico Sebastiani, Joan T. Merrill, Peter K. Gregersen, Gary G. Gilkeson, Robert P. Kimberly, Timothy J. Vyse, Il Kim, Sandra D’Alfonso, Javier Martin, John B. Harley, Lindsey A. Criswell, The Profile Study Group, The Italian Collaborative Group, The German Collaborative Group, The Spanish Collaborative Group, The Argentinian Collaborative Group, The SLEGEN Consortium, Edward K. Wakeland, Marta E. Alarcón-Riquelme, Chandra Mohan

Published in Volume 119, Issue 4

J Clin Invest. 2009; 119(4):911–923 doi:10.1172/JCI36728

Abstract | Full text | PDF | Supplemental material

I mmune-mediated nephritis contributes to disease in systemic lupus erythematosus, Goodpasture syndrome (caused by antibodies specific for glomerular basement membrane [anti-GBM antibodies]), and spontaneous lupus nephritis. Inbred mouse strains differ in susceptibility to anti-GBM antibody–induced and spontaneous lupus nephritis. This study sought to clarify the genetic and molecular factors that may be responsible for enhanced immune-mediated renal disease in these models. When the kidneys of 3 mouse strains sensitive to anti-GBM antibody–induced nephritis were compared with those of 2 control strains using microarray analysis, one-fifth of the underexpressed genes belonged to the kallikrein gene family, which encodes serine esterases. Mouse strains that upregulated renal and urinary kallikreins exhibited less evidence of disease. Antagonizing the kallikrein pathway augmented disease, while agonists dampened the severity of anti-GBM antibody–induced nephritis. In addition, nephritis-sensitive mouse strains had kallikrein haplotypes that were distinct from those of control strains, including several regulatory polymorphisms, some of which were associated with functional consequences. Indeed, increased susceptibility to anti-GBM antibody–induced nephritis and spontaneous lupus nephritis was achieved by breeding mice with a genetic interval harboring the kallikrein genes onto a disease-resistant background. Finally, both human SLE and spontaneous lupus nephritis were found to be associated with kallikrein genes, particularly KLK1 and the KLK3 promoter, when DNA SNPs from independent cohorts of SLE patients and controls were compared. Collectively, these studies suggest that kallikreins are protective disease-associated genes in anti-GBM antibody–induced nephritis and lupus.

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Figure 6

KLK association in SLE patients — second validation study.

(A) The Haploview plot shows the genotyped markers in the KLK locus, from KLK1 at the centromeric limit until KLK14 at the telomeric end, as well as the linkage disequilibrium between them measured by the D prime coefficient. Blocks were defined by the solid spine method implemented in Haploview version 4.1. Dataset: UCSF (n = 595 SLE patients) plus SLEGEN (n = 689 SLE patients and n = 3,718 controls). (B) In the indicated numbers of SLE patients and healthy controls, 56 KLK SNPs were tested for disease association using logistic regression analysis, with the phenotype “SLE” as the outcome variable (shown in blue). To examine whether the risks conferred by the KLK polymorphisms were influenced by the presence of nephritis, we tested the KLK SNPs for association, considering the phenotype “nephritis” as the outcome variable. Red indicates significant differences compared with controls; green indicates significant differences between cases with nephritis and cases without nephritis calculated by a metaanalysis, in order to control for heterogeneity among the contributing clinical centers. (C) The observed linkage disequilibrium blocks across the KLK locus were tested for haplotype association, using both omnibus and haplotype-specific association statistics (T test) as implemented in PLINK. Shown are significant haplotype associations when SLE patients were compared with controls (blue), when patients with lupus nephritis were compared with controls (red), and the case-only analysis (green). Besides the SNPs indicated in B and the blocks indicated in C, none of the other SNPs/blocks shown in A showed significant disease associations. For a larger version of this figure, see Supplemental Figure 1.