BOWCOCK LAB AND PROJECTS

Autoimmune/inflammatory diseases:

Psoriasis
Psoriasis is a chronic inflammatory skin disease affecting ~2% of the Northern European population. Approximately 30% of cases also develop psoriatic arthritis. The disease is complex and is due to the presence of specific genetic variants and triggers such as infection with group A beta-hemolytic streptococci and HIV. Genome-wide linkage scans have identified over 20 potential psoriasis loci. Most are likely to harbor variants conferring low risk, but some harbor Mendelian traits such as a locus on chromosome 17q25 mapped by us in 1994 and known as PSORS2 (Tomfohrde et al. 1994).

One major determinant for psoriasis lies within the MHC (multiple histocompatibility locus antigen cluster) on chromosome 6p21 (PSORS1) We recently described refinement of this locus, termed PSORS1, to a haplotype block harboring HLA-C (abstract, supplementary data). We have also identified two regions of susceptibility on chromosome 17q25 (PSORS2) (abstract) harboring common variants predisposing to disease. One of these alters a binding site for RUNX, a transcription factor implicated in a number of other autoimmune or inflammatory diseases and cancer (see Bowcock and Krueger review in Nature Immunology and Helms et al., 2003). Mice where RUNX3 is inactivated develop a variety of inflammatory diseases including asthma and inflammatory bowel disease. Hence, RUNX target genes may also confer risk of a variety of diseases. We are currently also using chromatin immunoprecipitation (CHIP) approaches in combination with 454 DNA resequencing to identify RUNX targets that may be involved in inflammatory diseases and tumorigenesis.

We are also identifying additional PSORS loci with association mapping. This includes PSORS4, mapping to the epidermal differentiation complex (EDC) on chromosome 1q21 (see Sun et al, 2006). Genome-wide association scans with large cohorts of cases and controls and high density SNP arrays are also being pursued via in-house efforts and in collaboration with other groups as part of GAIN (Genetic Association Information Network).

Genetic, Biologic, & Immunologic Determinants of Asthma
Our role in this study is to determine how specific genetic characteristics interact with environmental effects to predispose individuals to develop asthma. We examine a carefully selected cohort of 206 infants with respiratory syncytial virus (RSV) bronchiolitis (the RBEL (RSV Bronchiolitis in Early Life) cohort), ascertained by Dr. Mario Castro (P.I., http://pulmonary.wustl.edu/faculty/castro.html). These children are at substantial risk of developing asthma and are followed for several years. We are evaluating the association between genotypes associated with atopy in genetic markers (primarily SNPs) in previously reported asthma genes and the development of an asthmatic phenotype in the RBEL cohort. The results of this study should lead to an asthma predictive index for children with serious RSV infection and identify those at highest risk for the development of asthma who may benefit from an early intervention or treatment.

Asthma and Nocturnal Hypoxemia in Sickle Cell Anemia
Sickle cell Anemia (SCA), hemoglobin SS, is a single gene disorder, yet few co-morbid conditions and/or genes have been identified that account for its highly variable clinical course. As part of a multicenter study (Michael DeBaun, PI, http://peds.wustl.edu/faculty/DeBaun_Michael_R/) we are attempting to elucidate the genetic, and molecular aspects of how two common co-morbid conditions, asthma and nocturnal oxygen desaturation, increase the incidence rate of pain in SCA. 1800 children with SCA are being examined for susceptibility genes for both of these conditions with state of the art SNP genotyping technologies and global gene expression studies.

Melanoma:
Malignant melanoma, the most serious form of skin cancer, is the most common malignancy in individuals under the age of 30, and its incidence in is rising. Both genetic factors and environment such as UV exposure increase the risk of this cancer. 8-12% of melanoma is inherited in an autosomal dominant fashion with variable penetrance. A chromosome 9p21 locus has been linked to this disease in 50-80% of affected families and one causative gene from this region (CDKN2A or p16) has been identified. Although germline CDKN2A coding mutations co-segregate with melanoma in 25-60% of families predisposed to the disease, approximately 50% of mutation-negative families are linked to 9p21. Hence, a second nearby region may be responsible for melanoma risk. We are examining a cohort patients with malignant melanoma in collaboration with Dr. Lynn Cornelius for coding mutations in CDKN2A, and other potential melanoma candidates. We are also identifying families with multiple affected members with melanoma. These will be used to identify other genes predisposing to melanoma. These studies are important for identifying individuals at risk of developing of melanoma, obtaining additional insights into the cellular mechanisms leading to melanoma, and should ultimately lead to the development of more targeted therapies for this cancer.

Postdoctoral fellowship working on the genetics of melanoma available from June 2007. Please send CV and three letters of recommendation to:

      Dr. Anne Bowcock
      Department of Genetics
      Washington University School of Medicine
      4566 Scott Avenue, St. Louis, MO 63110 

    or email to "bowcock@genetics.wustl.edu"

Other projects in the lab:
Genetic analyses of the epilepsies, Tourette's syndrome and limb abnormalities including club foot.

Teaching:
Co-director (with Dr. D.C. Rao) of the Quantitative Human and Statistical Genetics graduate program. This program was developed to integrate both human and statistical genetics teaching and to provide important expertise for human genetics researchers in the future.
Co-Coursemaster (with Dr. Michael Lovett) "Fundamentals of Mammalian Genetics". This is a 3 credit unit core course that is essential for anyone wishing to master human genetics. It deals with the basics of human genetics, as well as recent and novel developments in the field.
Lecturer in "Medical Genetics" for first year medical students and "Advanced Genetics", a graduate course that illustrates the power of genetics as an experimental tool.

Complete list of publications from 2000 - present

Contact Information: Email: bowcock@genetics.wustl.edu Office Phone: 314-747-3261 Lab Phone: 314-747-1057 FAX: 314-747-2489 Mailing Address:       Department of Genetics       Box 8232       4566 Scott Ave.       St. Louis, MO 63110 Building Address (Biotechnology Building):       4559 Scott Ave, Room 331