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

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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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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