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A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis

Nature Genetics volume 35, pages 349–356 (2003)Cite this article

Abstract

Psoriasis (OMIM 177900) is a chronic inflammatory skin disorder of unknown pathogenesis affecting ∼2% of the Western population1. It occurs more frequently in individuals with human immunodeficiency virus2, and 20–30% of individuals with psoriasis have psoriatic arthritis3. Psoriasis is associated with HLA class I alleles4,5,6, and previous linkage analysis by our group identified a second psoriasis locus at 17q24–q25 (PSORS2; ref. 7). Linkage to this locus was confirmed with independent family sets8,9. Additional loci have also been proposed to be associated with psoriasis10. Here we describe two peaks of strong association with psoriasis on chromosome 17q25 separated by 6 Mb. Associated single-nucleotide polymorphisms (SNPs) in the proximal peak lie in or near SLC9A3R1 (also called EBP50 and NHERF1) and NAT9, a new member of the N-acetyltransferase family. SLC9A3R1 is a PDZ domain–containing phosphoprotein that associates with members of the ezrin-radixin-moesin family and is implicated in diverse aspects of epithelial membrane biology and immune synapse formation in T cells11,12. The distal peak of association is in RAPTOR (p150 target of rapamycin (TOR)-scaffold protein containing WD-repeats)13,14. Expression of SLC9A3R1 is highest in the uppermost stratum Malpighi of psoriatic and normal skin and in inactive versus active T cells. A disease-associated SNP lying between SLC9A3R1 and NAT9 leads to loss of RUNX1 binding. This is the second example of loss of a RUNX1 binding site associated with susceptibility to an autoimmune disease15. It also suggests defective regulation of SLC9A3R1 or NAT9 by RUNX1 as a susceptibility factor for psoriasis.

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Figure 1: Association mapping of PSORS2 identified two regions associated with psoriasis separated by ∼6 Mb.
Figure 2: Identification of a putative RUNX1 site in SNP9 and investigation with in vitro and in vivo assays.
Figure 3: SLC9A3R1 is expressed in the skin and T cells of affected individuals and controls and is downregulated on T-cell activation.

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Acknowledgements

We thank the affected individuals, their families and collaborating clinicians for their participation; M. Allen, D. Keppler, S. Duan, D. L. Lind, E. G. Lovins, S. Marsh, S. Miller, P. Taillon-Miller and R. Rahluwal for technical help; J. P. Kane and C. R. Pullinger for additional samples; T. Chatila for some of the T-cell samples; C. Cather for collection of material from additional affected individuals; H. McLeod and A. Goate for help with pyrosequencing; N. Saccone for discussions; and M. Lovett for encouragement and insightful comments. This study was supported in part by grants from the US National Institutes of Health (to A.M.B., J.G.K., F.C., P.Y.K., D.G. and J.O.) and the National Psoriasis Foundation.

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Authors and Affiliations

  1. Department of Genetics, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Cynthia Helms, Li Cao, Jil A Wright Daw, Jason Robarge & Anne M Bowcock

  2. Laboratory for Investigative Dermatology, The Rockefeller University, New York, 10021, New York, USA

    James G Krueger & Francesca Chamian

  3. Division of Medical Genetics and Department of Biostatistics, University of Washington, Seattle, 98195, Washington, USA

    Ellen M Wijsman

  4. Lab of Statistical Genetics, The Rockefeller University, New York, 10021, New York, USA

    Derek Gordon & Jurg Ott

  5. Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Michael Heffernan & Anne M Bowcock

  6. University of California, San Francisco, 505 Parnassus Ave, Long 1332A, Box 0130, San Francisco, 94143-0130, California, USA

    Pui-Yan Kwok

  7. Department of Internal Medicine, Division of Dermatology, Baylor University Medical Center, Dallas, 75246, Texas, USA

    Alan Menter

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Correspondence to Anne M Bowcock.

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Helms, C., Cao, L., Krueger, J. et al. A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis. Nat Genet 35, 349–356 (2003). https://doi.org/10.1038/ng1268

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