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 approximately 2% of the Western population. It occurs more frequently in individuals with human immunodeficiency virus, and 20-30% of individuals with psoriasis have psoriatic arthritis. Psoriasis is associated with HLA class I alleles, 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 sets. Additional loci have also been proposed to be associated with psoriasis. 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 cells. The distal peak of association is in RAPTOR (p150 target of rapamycin (TOR)-scaffold protein containing WD-repeats). 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 disease. It also suggests defective regulation of SLC9A3R1 or NAT9 by RUNX1 as a susceptibility factor for psoriasis.

Investigation of the SLC22A4 gene (associated with rheumatoid arthritis in a Japanese population) in a United Kingdom population of rheumatoid arthritis patients

“…The slc2f2 (rs3792876) SNP was selected as the most likely functional mutation because polymorphism was predicted to affect binding of a transcription factor, RUNX-1. Several recent reports have suggested that RUNX-1 binding-site polymorphisms may be associated with a number of autoimmune diseases (3,4). There is no doubt that the functional data provide support that the putative RUNX-1 binding site does indeed affect RUNX-1 binding.…”

“…Studies of an intron 1 SNP in linkage disequilibrium (LD) with it showed that the polymorphism affected binding of a transcription regulator, RUNX-1. This was, therefore, thought to be the disease-causing variant, particularly in light of several other recent publications showing that polymorphisms affecting RUNX-1 binding sites may be associated with a variety of autoimmune diseases (3,4).…”

Heritability estimates of innate immunity: an extended twin study

“…13 This suggests that regulation of cytokine production might be influenced by other genes, for example, a regulatory single-nucleotide polymorphism (rSNP). 14,15 The unknown regulatory genes may be localized with linkage analysis, but, to our knowledge, linkage studies of cytokine production capacity have not been reported. Even the heritability of variation in cytokine production is largely unknown.…”

Psoriasis — A possible candidate for vaccination

“…Although sequencing of Cw6 has shown an association between alanine at position 73 and psoriasis in Japanese patients, this was not been confirmed in patients of European extraction. Recently, gene mutations have been reported in regions containing SLC9ARI on the 17q25 locus (Helms et al 2003) and SLC12A8 on the 3q locus (Hewett et al 2002). SLC9ARI is concerned with transport of ions across cell membranes and immune synapse formation in T cells and is adjacent to a putative binding site for the transcription factor RUNXI.…”