Keywords: Molecular genetic pathology
Dr. Weck’s recent research efforts are focused on developing pharmacogenetic testing to predict response to drug therapy. Her laboratory is collaborating in several clinical trials at UNC to study the clinical utility of pharmacogenomic guided therapy. One ongoing clinical trial is a prospective randomized study to determine the utility of pharmacogenomic guided dosing of warfarin, incorporating genotyping for variants in the VKORC1 and CYP2C9 genes associated with altered warfarin response. Dr. Weck is a member of the International Warfarin Pharmacogenomics Consortium, whose goals are to study the effect of clinical and genetic factors on warfarin response and to devise a pharmacogenomic dosing algorithm for warfarin. This work has resulted in two recent publications. Plans are underway to further analyze genomic and clinical factors associated with warfarin response in different ethnic populations including African Americans. In addition, Dr. Weck has collaborated with a group in Brazil to identify VKORC1 mutations associated with warfarin resistance. Dr. Weck has is also a co-investigator in a multicenter collaborative clinical trial to study the efficacy of CYP2D6 genotype-guided dosing for tamoxifen in breast cancer that includes UNC and several other sites across North Carolina. The preliminary results of this trial indicated that CYP2D6 genotype-guided dosing of tamoxifen resulted in normalization of plasma concentration of endoxifen, the active metabolite of tamoxifen, in women who are CYP2D6 intermediate metabolizers. The tamoxifen trial has been expanded to include 500 women across North Carolina, with escalated recruitment of African American and Hispanic women. Dr. Weck is also collaborating with investigators in the Departments of Cardiology to conduct a clinical trial on the efficacy of CYP2C19 genotype-guided dosing for clopidogrel.
Another major effort is translation of new knowledge of the genetic causes of disease into diagnostic testing. Dr. Weck’s laboratory has developed mutation testing for genes associated with primary ciliary dyskinesia, X-linked Alport syndrome, and focal segmental glomerulosclerosis (FSGS). The goal is to better characterize the spectrum, incidence and genotype-phenotype correlation of mutations associated with disease and to develop clinical testing in those genes with clinical utility. The UNC molecular genetics laboratory is now one of the only laboratories in the country that offers clinical genetic testing for mutations associated with these diseases. Finally, efforts are underway to incorporate whole exome sequencing technology for clinical diagnosis. Dr. Weck collaborated on a study to evaluate the accuracy of massively parallel sequencing for detection of genetic variants associated with primary ciliary dyskinesia, published recently in the journal Genetics in Medicine. She is co-investigator on two new NIH grant submissions to continue this work.