Who's Who at the Arizona Respiratory Center

Activities

The Analytical Genetics Laboratory (AGL) uses DNA analysis to explore the relationship between the naturally occurring person-to-person variation in the DNA that is passed from parent to child and important health-related characteristics such as susceptibility to disease and response to drugs and toxicants. The identification of a strong association between a particular "version" of the DNA sequence for a gene and an important health-related characteristic accomplishes several things. It adds evidence to support a role for that particular gene in the process being tested. For example, we have recently found that a particular version of a gene called TLR-2 is strongly associated with the protection from asthma that growing up in a microbially rich environment, such as a dairy farm, can provide. Because of this, other researchers now have another piece of evidence supporting a role for TLR-2 in a process that involves the recognition of environmental microbes, and the signaling process that translates that recognition into protection from asthma.

These studies are important not only for adding supportive evidence about genes that are already "placed" within functional processes, but to generate new ideas regarding new genes that may not have been previously considered to be involved in a process. In collaboration with the Children's Asthma Research and Education Network, the AGL is testing large numbers of genes in an effort to identify which genes influence childrens' response to asthma medication. Early results from these studies suggests that new classes of genes that have not typically been associated with response to drugs may be critical to drug response.

In addition to the research project-based efforts of my group, we are actively developing and applying novel genomics techniques to assist our work and that of other researchers. We are bringing a high-throughput DNA methylation analysis process online that is currently being used by two groups on campus. In collaboration with Donata Vercelli's group, we have successfully used a new technique called phylogenetic shadowing to identify and prioritize genomic sites in the currently un-annotated region, 5' to the first exon of interleukin-13, that could participate in the regulation of expression of IL-13. This method, first described in Science by Eddie Rubin's group at Berkeley, involves sequencing the genomic region in a group of evolutionarily diverse primates to identify small regions that have a lower than expected rate of DNA base mutation through evolutionary time, suggesting that these regions may have functional importance that has created a selection bias toward their conservation.

Selected Publications

• Klimecki WT, Tuggle, JT, Gilbreath AE, Gwynne P, Gaskin M, Winick JD, Shmulewitz D, Friedman J, Gallagher S, Xia J, Raich T. A 3-dimensional microarray system for parallel genotyping of single nucleotide polymorphisms. Nature Genetics 23: 55,1999
• Lazarus, R, Klimecki WT, Palmer LJ, Kwiatkowski D, Silverman E, Brown A, Martinez F, Wiess ST. Single nucleotide polymorphisms in the Interleukin 10 gene: Differences in frequencies, linkage disequilibrium patterns and haplotypes in three American subpopulations. Genomics. 80:223-227, 2002
• Raby, B, Klimecki WT, Laprise C, Renaud Y, Faith J, Lemire M, Greenwood C, Weiland KM, Lange C, Palmer LJ, Lazarus R, Vercelli D, Kwiatkowski DJ, Silverman EK, Martinez FD, Hudson TJ, Weiss ST. Common functional polymorphisms in Toll-like Receptor 4 (TLR4) are not associated with asthma or atopy-related phenotypes. Am. J. Respir. Crit. Care Med. 166(11): 1449-1456, 2002
• Lazarus R, Vercelli D, Palmer LJ, Klimecki WT, Silverman EK, Richter B, Riva A, Ramoni M, Martinez FD, Weiss ST, Kwiatkowski DJ. Single nucleotide polymorphisms in innate immunity genes: abundant variation and potential role in complex human disease. Immunol. Rev. 190: 9-25, 2002
• Lazarus R, Klimecki WT, Raby BA, Vercelli D, Palmer LJ, Kwiatkowski DJ, Silverman EK, Martinez F, Weiss ST. Single nucleotide polymorphisms in the Toll-like receptor 9 gene (TLR9): Frequencies, pairwise linkage disequilibrium, and haplotypes in three U.S. ethnic groups and exploratory case-control disease association studies. Genomics 81: 85-91, 2003
• Yu L, Kalla K, Guthrie E, Vidrine A, Klimecki WT. Genetic variation in genes associated with arsenic metabolism: GST-Omega and Purine Nucleoside Phosphorylase polymorphisms in European and Indigenous Americans. Environ. Health Perspectives Toxicogenomics 111: 1421-1428, 2003
• Eder W, Klimecki WT, von Mutius, E, Riedler J, Braun-Fahrlander C, Nowak D, Martinez FD, ALEX-Team. TLR2 as a major gene for asthma in children of European farmers. J. Allergy Clin. Immunol. 113: 482-488, 2004
• Flores-Munguia R, Siegel E, Klimecki WT, Giuliano
• AR. Performance Assessment of Eight High-Throughput Real-Time PCR Assays for the Quantitation of Oncogenic HPV Types. J. Molecular Diagnostics 6: 115-124, 2004
• Tantisira K, Klimecki WT, Lazarus R, Palmer LJ, Raby BA, Kwiatkowski DJ, Silverman E, Vercelli D, Martinez FD, Weiss ST. Toll-like receptor 6 gene (TLR6): Single-nucleotide polymorphism frequencies and preliminary association with the diagnosis of asthma. Genes and Immunity 5: 347-353, 2004
• Lazarus R, Raby BA, Lange C, Silverman EK, Kwiatkowski DJ, Vercelli D, Klimecki WT, Martinez FM, Weiss ST. Toll-like receptor 10 (TLR10) genetic variation is associated with asthma in two independent samples. Am. J. Resp. Crit. Care Medicine 170(6): 594-600, 2004
• Yu L, Martinez FM, Klimecki WT. Automated, high throughput sex typing assay. BioTechniques, 37(4): 662-664, 2004
• Burgess JL, Fierro MA, Lantz C, Hysong TA, Fleming JE, Gerkin R, Hnizdo E, Conley SM, Klimecki WT. Longitudinal decline in lung function: Evaluation of Interleukin-10 genetic polymorphisms in firefighters. J. Occup. Environ. Medicine 46: 1013-1022, 2004
• Yu L, Rodriguez YY, Brink K, Klimecki WT. Quantitative analysis of amplification bias in whole genome amplification. Submitted, Nucleic Acids Research.
• Meza MM, Yu L, Rodriguez YY, Guild M, Thompson D, Gandolfi AJ, Klimecki WT. Developmentally restricted genetic determinants of arsenic metabolism: Association between urinary methylated arsenic and CYT19 polymorphisms in children. Submitted, Environmental Health Perspectives.