Genetic Variation In RUNX1 Binding Sites Linked To Psoriasis, Rheumatoid Arthritis

NEW YORK (Reuters Health) - Genetic polymorphisms in transporter proteins that affect runt-related transcription factor (RUNX1) binding are associated with susceptibility to psoriasis and to rheumatoid arthritis, two research teams report in the December issue of Nature Genetics, published online November 9.

RUNX1 is involved in hematopoietic and endothelial cell development and CD4 silencing, explain Dr. Anne M. Bowcock, of Washington University School of Medicine in St. Louis, and her colleagues. Previous research has linked an altered RUNX1 binding site to systemic lupus erythematosus.

Dr. Bowcock's team analyzed DNA from 242 nuclear families affected by psoriasis and observed variability in a locus containing two genes: encoding solute carrier family 9, isoform 3 regulatory factor 1 (SLC9A3R1) and an N-acetyl-transferase NAT9.

They found that five different single nucleotide polymorphisms abnormally transmitted in psoriasis families were frequently present in noncoding DNA in or downstream from SLC9A3R1 or NAT9. One of the psoriasis-associated alleles lacked the normal RUNX1 binding site.

"SLC9A3R1 is expressed in T cells and in epithelial cells," Dr. Bowcock told Reuters Health. "Reduction or loss of SLC9A3R1 in psoriatic skin may perturb T-cell development or activation," she suggested.

Moreover, "we believe RUNX1 binding is required to turn on the SLC9A3R1 gene at an appropriate level," Dr. Bowcock added. "But the question remains, is RUNX1 a gene activator or a gene suppressor?"

In future studies, she and her associates "would like to know exactly what effect RUNX1 has," and will explore the possibility that the transcription factor "is involved in thymic selection."

Meanwhile, a Japanese team led by Dr. Ryo Yamada, at the Institute of Physical and Chemical Research in Kanagawa, report in the same issue of Nature Genetics that the gene encoding solute carrier family 22, member 4 (SLC22A4) is a susceptibility gene for another autoimmune disease, rheumatoid arthritis.

These investigators observed that SLC22A4 is expressed in the synovial tissues of patients with rheumatoid arthritis and in the joints of mice with collagen-induced arthritis. Stimulation of synoviocytes with tumor-necrosis factor alpha doubled the levels of SLLC22A4 mRNA.

Just as the American team found that SLC9A3R1 single nucleotide polymorphisms affected RUNX1 binding, Dr. Yamada's team observed that a single nucleotide polymorphism in SLC9A3R1 altered this protein's affinity to RUNX1.

Nat Genet: November 9, 2003 online edition.

MeSH Headings: Transcription Factors : Polymorphism, Single Nucleotide