Walter Klimecki

Walter Klimecki

Associate Professor, Veterinary Medicine
Assistant Professor, Medicine - (Research Scholar Track)
Associate Professor, Pharmacology and Toxicology
Associate Professor, Public Health
Associate Professor, Genetics - GIDP
Adjunct Associate Professor, Nursing
Associate Professor, BIO5 Institute
Contact
(520) 626-7470

Work Summary

Walter Klimecki's research program involves the balance between the particular DNA sequence “versions” of genes that we inherit from our ancestors, and the particular environmental exposures that we experience throughout our lives. The Klimecki lab studies diseases resulting from human exposure to arsenic, contributing to a better understanding of the inherited genetic differences between people that result in altered chemical processing of arsenic after it enters the body.

Research Interest

Walter T. Klimecki, DVM, PhD, is an Associate Professor in the Department of Pharmacology and Toxicology in the College of Pharmacy at the University of Arizona. Dr. Klimecki holds joint appointments in the College of Medicine, the College of Public Health, and the Arizona Respiratory Center. He is a Full Member of the Southwest Environmental Health Sciences Center (SWEHSC) where, together with BIO5 director Martinez and BIO5 Statistics Consulting Service director Billheimer, he leads the Integrative Health Sciences (IHS) Center at SWEHSC. The IHS is a translational research support core at SWEHSC, focused on lowering the “activation energy” for translational research.Dr. Klimecki’s research focuses on the toxicology of metals in the environment, an issue particularly relevant in our mining-intensive state. His research work has encompassed a wide range of experimental approaches, from epidemiological studies of arsenic-exposed human populations, to laboratory models including cell culture and rodents. Using cutting edge genetics tools, Dr. Klimecki’s group recently published the first report of an association between human ancestry and response to environmental toxicants. In this provocative work, his group found that individuals whose genomes were comprised of DNA with its origins in the indigenous American populations processed ingested arsenic in a less harmful manner than did individuals whose genomes had their origins in Europe. Using laboratory models his group made ground-breaking discoveries of the impact of arsenic exposure on a process known as autophagy, in which cells digest parts of their own machinery in a sort of “cash for clunkers” arrangement. The ability of arsenic to perturb this process is only now being appreciated by the toxicology community, thanks to the work of the Klimecki Lab. Dr. Klimecki was recently elected as a Vice President-elect to the Metals Specialty Section of the Society of Toxicology, the preeminent scientific toxicology organization in the world. Dr. Klimecki’s research is highly collaborative: his grants and publications have included many BIO5 members, including BIO5 director Fernando Martinez, and BIO5 members Donata Vercelli, Dean Billheimer, and Marilyn Halonen.

Publications

Lazarus, R., Vercelli, D., Palmer, L. J., Klimecki, W. J., Silverman, E. K., Richter, B., Riva, A., Ramoni, M., Martinez, F. D., Weiss, S. T., & Kwiatkowski, D. J. (2002). Single nucleotide polymorphisms in innate immunity genes: Abundant variation and potential role in complex human disease. Immunological Reviews, 190, 9-25.

PMID: 12493003;Abstract:

Under selective pressure from infectious microorganisms, multicellular organisms have evolved immunological defense mechanisms, broadly categorized as innate or adaptive. Recent insights into the complex mechanisms of human innate immunity suggest that genetic variability in genes encoding its components may play a role in the development of asthma and related diseases. As part of a systematic assessment of genetic variability in innate immunity genes, we have thus far have examined 16 genes by resequencing 93 unrelated subjects from three ethnic samples (European American, African American and Hispanic American) and a sample of European American asthmatics. Approaches to discovering and understanding variation and the subsequent implementation of disease association studies are described and illustrated. Although highly conserved across a wide range of species, the innate immune genes we have sequenced demonstrate substantial interindividual variability predominandy in the form of single nucleotide polymorphisms (SNPs). Genetic variation in these genes may play a role in determining susceptibility to a range of common, chronic human diseases which have an inflammatory component. Differences in population history have produced distinctive patterns of SNP allele frequencies, linkage disequilibrium and haplotypes when ethnic groups are compared. These and other factors must be taken into account in the design and analysis of disease association studies.

Klimecki, W., Gomez-Rubio, P., Meza-Montenegro, M. M., Cantu-Soto, E., & Klimecki, W. -. (2010). Genetic association between intronic variants in AS3MT and arsenic methylation efficiency is focused on a large linkage disequilibrium cluster in chromosome 10. Journal of applied toxicology : JAT, 30(3).

Differences in arsenic metabolism are known to play a role in individual variability in arsenic-induced disease susceptibility. Genetic variants in genes relevant to arsenic metabolism are considered to be partially responsible for the variation in arsenic metabolism. Specifically, variants in arsenic (3+ oxidation state) methyltransferase (AS3MT), the key gene in the metabolism of arsenic, have been associated with increased arsenic methylation efficiency. Of particular interest is the fact that different studies have reported that several of the AS3MT single nucleotide polymorphisms (SNPs) are in strong linkage-disequilibrium (LD), which also extends to a nearby gene, CYP17A1. In an effort to characterize the extent of the region in LD, we genotyped 46 SNPs in a 347,000 base region of chromosome 10 that included AS3MT in arsenic-exposed subjects from Mexico. Pairwise LD analysis showed strong LD for these polymorphisms, represented by a mean r(2) of 0.82, spanning a region that includes five genes. Genetic association analysis with arsenic metabolism confirmed the previously observed association between AS3MT variants, including this large cluster of linked polymorphisms, and arsenic methylation efficiency. The existence of a large genomic region sharing strong LD with polymorphisms associated with arsenic metabolism presents a predicament because the observed phenotype cannot be unequivocally assigned to a single SNP or even a single gene. The results reported here should be carefully considered for future genomic association studies involving AS3MT and arsenic metabolism.

Beamer, P. -., Sugeng, A. J., Kelly, M. D., Lothrop, N., Klimecki, W. -., Wilkinson, S. T., & Loh, M. M. (2014). Use of dust fall filters as passive samplers for metal concentrations in air for communities near contaminated mine taillings.. Environmental Science:Processes and Impacts.
Bolt, A. M., Douglas, R. M., & Klimecki, W. T. (2010). Arsenite exposure in human lymphoblastoid cell lines induces autophagy and coordinated induction of lysosomal genes. Toxicology Letters, 199(2), 153-159.

PMID: 20816728;PMCID: PMC2956852;Abstract:

Chronic exposure to inorganic arsenic is associated with diverse, complex diseases, making the identification of the mechanism underlying arsenic-induced toxicity a challenge. An increasing body of literature from epidemiological and in vitro studies has demonstrated that arsenic is an immunotoxicant, but the mechanism driving arsenic-induced immunotoxicity is not well established. We have previously demonstrated that in human lymphoblastoid cell lines (LCLs), arsenic-induced cell death is strongly associated with the induction of autophagy. In this study we utilized genome-wide gene expression analysis and functional assays to characterize arsenic-induced effects in seven LCLs that were exposed to an environmentally relevant, minimally cytotoxic, concentration of arsenite (0.75 μM) over an eight-day time course. Arsenic exposure resulted in inhibition of cellular growth and induction of autophagy (measured by expansion of acidic vesicles) over the eight-day exposure duration. Gene expression analysis revealed that arsenic exposure increased global lysosomal gene expression, which was associated with increased functional activity of the lysosome protease, cathepsin D. The arsenic-induced expansion of the lysosomal compartment in LCL represents a novel target that may offer insight into the immunotoxic effects of arsenic. © 2010 Elsevier Ireland Ltd.

Palmer, S. M., Klimecki, W., Yu, L., Reinsmoen, N. L., Snyder, L. D., Ganous, T. M., Burch, L., & Schwartz, D. A. (2007). Genetic regulation of rejection and survival following human lung transplantation by the innate immune receptor CD14. American Journal of Transplantation, 7(3), 693-699.

PMID: 17217435;Abstract:

We have developed the hypothesis that genetic polymorphisms which alter the expression or function of innate immune receptors contribute to the marked interindividual differences in the onset and severity of lung transplant rejection. In this analysis, we considered the effects of a common promotor polymorphism of the lipopolysaccharide receptor CD14 associated with increased transcriptional activity upon the development of posttransplant rejection and graft survival. Genotyping was performed in 226 lung transplant recipients well characterized with regards to clinical outcomes. An earlier onset of acute rejection, bronchiolitis obliterans syndrome (BOS) and worse posttransplant graft survival due to greater BOS related deaths was evident in patients with the CD14 -159 TT genotype (TT). The adverse effect upon graft survival of the TT genotype remained significant in a multivariate Cox model (Hazard Ratio 1.65, 95% CI, 1.03-2.64, p-value = 0.04) after adjusting for other important covariates. Furthermore, TT patients have significantly greater sCD14, TNF-α and IFN-γ in the peripheral blood implying a heightened state of innate immune activation drives the development of increased post-transplant rejection. Inhibition of innate immune activation through CD14 represents a novel and potentially important therapeutic target to prevent post-transplant rejection and improve outcomes after human lung transplantation. © 2007 The Authors.