A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus

Abstract

Genome-wide association studies have recently identified at least 15 susceptibility loci for systemic lupus erythematosus (SLE). To confirm additional risk loci, we selected SNPs from 2,466 regions that showed nominal evidence of association to SLE (P < 0.05) in a genome-wide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. This replication effort identified five new SLE susceptibility loci (P < 5 × 10−8): TNIP1 (odds ratio (OR) = 1.27), PRDM1 (OR = 1.20), JAZF1 (OR = 1.20), UHRF1BP1 (OR = 1.17) and IL10 (OR = 1.19). We identified 21 additional candidate loci with P≤ 1 × 10−5. A candidate screen of alleles previously associated with other autoimmune diseases suggested five loci (P < 1 × 10−3) that may contribute to SLE: IFIH1, CFB, CLEC16A, IL12B and SH2B3. These results expand the number of confirmed and candidate SLE susceptibility loci and implicate several key immunologic pathways in SLE pathogenesis.

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Figure 1: Overview of experimental design.
Figure 2: Newly discovered genome-wide significant associations in SLE.
Figure 3

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Acknowledgements

We thank the many affected individuals and physicians who contributed DNA samples and clinical data for this study; M.I. Kamboh and P. Davies for the use of Alzheimer's disease samples as controls in our study; B. Neale for assistance in the percent of genetic variance explained calculation; and S. Sanna and C. Willer for assistance in generating regional association plots. Genotyping of the Swedish samples by the 12K chips was performed using equipment of the SNP technology platform in Uppsala. We thank C. Enström and A.-C. Wiman for assistance with genotyping. Financial support was obtained from the Swedish Research Council for Medicine, the Knut and Alice Wallenberg Foundation the Swedish Rheumatism Association, the King Gustaf V 80th Birthday Foundation, COMBINE, and a Target Identification in Lupus (TIL) grant from the Alliance for Lupus Research, US. This work was supported in part by R01 AR44804, K24 AR02175, the Mary Kirkland Center for Lupus Research, RO1 AR43727 and Institute for Clinical and Translational Research UL1RR025005. These studies were performed in part in the General Clinical Research Center, Moffitt Hospital, University of California, San Francisco, with funds provided by the National Center for Research Resources, 5 M01 RR-00079, US Public Health Service.

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V.G. and J.K.S. performed the primary statistical analyses and contributed to initial manuscript preparation; J.K.S managed DNA samples and performed genotyping. G.H. contributed to the statistical analyses and experimental design. K.E.T. and S.A.C. performed statistical analyses and contributed to manuscript preparation. X.S., W.O. and R.C.F. managed DNA samples and contributed to experimental design. G.N., I.G., E.S., L.P., G.S., A.J., A.A.B., S.R.-D., E.C.B, E.E.B., G.S.A., J.C.E., R.R.-G., G.M. Jr., J.D.R., L.M.V., R.P.K., S.M. and M.A.P. provided samples and phenotype information. A.L. managed samples and oversaw genotyping efforts. P.K.G. provided samples and contributed to the initial manuscript preparation. M.F.S. and R.K. contributed statistical analyses and contributed to the selection of the ancestry-informative markers. L.R., L.A.C. and A.-C.S. contributed samples, input into experimental design, data interpretation and initial manuscript preparation; A.-C.S. oversaw genotyping efforts. R.R.G. and T.W.B. contributed to experimental design and interpretation, statistical analyses and initial manuscript preparation. All authors contributed to the final paper.

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Correspondence to Robert R Graham.

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Competing interests

The authors Robert R Graham, Timothy W Behrens, Geoff Hom, Vesela Gateva, Xin Sun, Ward Ortmann and Ricardo C Ferreira were fulltime employees of Genentech, Inc at the time of the work. Robert R Graham and Timothy W Behrens have applied for a patent based on this work.

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Gateva, V., Sandling, J., Hom, G. et al. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet 41, 1228–1233 (2009). https://doi.org/10.1038/ng.468

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