Research Abstract:
Our major interest is the genetic basis of human complex disease. One ongoing project is the investigation of the genetic basis of autoimmune diseases with a major emphasis on the inflammatory disease of skin and joints, psoriasis and psoriatic arthritis. Other diseases currently under investigation in my laboratory include the epilepsies, melanoma, asthma and obesity.
We recently identified two regions on human chromosome 17q25 associated with psoriasis. The first region harbors two genes, NAT9 and SLC9A3R1. The gene in the second region is RAPTOR (regulatory protein of mTOR). This is involved in regulation of cell growth in response to a variety of signals including nutrient deprivation and immune stimulation. The predisposing variants all lie within non-coding DNA and one variant within the first region abolishes a binding site for the transcription factor RUNX1/AML1. Alterations of RUNX1 binding have also been described in genes associated with lupus erythematosus and with rheumatoid arthritis. Hence, RUNX1 is likely to play an important role in tolerance. We are using genomic approaches to investigate the role of RUNX in normal and diseased states.
Additional susceptibility loci are being identified with state-of-the art approaches to complex genetic disease including family collection, high throughput genotyping and statistical analyses. Once genetic variants are identified we use functional genomic approaches to determine the consequences of predisposing genetic alterations. These include inactivation of these genes in animal models such as the mouse.
Selected Publications:
Bashiardes S, Veile R, Helms C, et al. Direct genomic selection: Overcoming a technical hurdle in identifying variation and mutations in large genomic regions. Nat Methods 2005 2:63-69.
Bowcock AM, Cookson WO. The genetics of psoriasis, psoriatic arthritis and atopic dermatits. Hum Mol Genet 2004 13:R43-R55.
Gordon D, Hayes C, Jahnndis C, Bowcock AM, Ott J. A transmission disequilibrium test for general pedigrees that is robust to the presence of random genotyping errors and any number of untyped parents. Eur J Hum Genet 2004 12:752-761.
Helms C, Cao L, Krueger JG, et al. A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with psoriasis susceptibility. Nat Genet 2003 35:349-356.
Zhou X, Krueger JG, Kao MC, et al. Novel mechanisms of T-cell and dendritic cell activation revealed by profiling of psoriasis on the 63,100-element oligonucleotide array. Physiol Genomics 2003 13:69-78.
Last Updated: 06/26/2007 |