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

Bieli, C., Eder, W., Frei, R., Braun-Fahrländer, C., Klimecki, W., Waser, M., Riedler, J., Mutius, E. v., Scheynius, A., Pershagen, G., Doekes, G., Lauener, R., & Martinez, F. D. (2007). A polymorphism in CD14 modifies the effect of farm milk consumption on allergic diseases and CD14 gene expression. Journal of Allergy and Clinical Immunology, 120(6), 1308-1315.

PMID: 17919709;Abstract:

Background: Consumption of farm milk in early life is associated with less asthma and allergies. Objective: We hypothesized that genetic variation in the innate immunity receptor CD14 might modify the association between farm milk consumption and asthma and atopy. Methods: Questionnaire data, serum IgE levels, and genotypes for 4 single nucleotide polymorphisms in CD14 were assessed in farmers' and nonfarmers' children from 2 European populations (Allergy and Endotoxin study, n = 576; Prevention of Allergy Risk factors for Sensitization in children related to Farming and Anthroposophic Lifestyle study, n = 1539). In a subsample (n = 222) CD14 gene expression was measured in peripheral blood leukocytes. The effects of farm milk and CD14 genotypes on asthma, allergies, and CD14 expression and their interactions were investigated. Results: We found a significant interaction between genetic variation in CD14/-1721 and farm milk consumption. Adjusted odds ratios for the association between farm milk and asthma varied between the genotypes: AA, 0.18 (95% CI, 0.07-0.47); AG, 0.47 (95% CI, 0.26-0.86); and GG, 0.98 (95% CI, 0.46-2.08). Similar patterns were observed for symptoms of allergic rhinoconjunctivitis and pollen sensitization. CD14/-1721 also modified the association between farm milk and CD14 gene expression (adjusted geometric means ratios: AA, 1.61 (95% CI, 0.98-2.66); AG, 1.11 (95% CI, 0.71-1.72); and GG, 0.76 (95% CI, 0.39-1.48). Conclusion: The protective effect of farm milk consumption on allergic diseases is stronger in children carrying the A allele in CD14/-1721 than in children homozygous for the G allele. This might be mediated through farm milk-induced upregulated CD14 gene expression. Clinical implications: Our results support the hypothesis that the inverse association between farm milk consumption and allergic diseases is mediated by CD14-activated innate immune mechanisms. © 2007 American Academy of Allergy, Asthma & Immunology.

Oshiro, M. M., Futscher, B. W., Lisberg, A., Wozniak, R. J., Klimecki, W. T., Domann, F. E., & Cress, A. E. (2005). Epigenetic regulation of the cell type-specific gene 14-3-3sigma. Neoplasia (New York, N.Y.), 7(9), 799-808.

Epigenetic control participates in processes crucial in mammalian development, such as X-chromosome inactivation, gene imprinting, and cell type-specific gene expression. We provide evidence that the p53-inducible gene 14-3-3sigma is a new example of a gene important to human cancer, where epigenetic mechanisms participate in the control of normal cell type-specific expression, as well as aberrant gene silencing in cancer cells. Like a previously identified cell type-specific gene maspin, 14-3-3sigma is a p53-inducible gene; however, it participates in G2/M arrest in response to DNA-damaging agents. 14-3-3Sigma expression is restricted to certain epithelial cell types, including breast and prostate, whereas expression is absent in nonepithelial tissues such as fibroblasts and lymphocytes. In this report, we show that in normal cells expressing 14-3-3sigma, the 14-3-3sigma CpG island is unmethylated; associated with acetylated histones, unmethylated histone H3 lysine 9; and an accessible chromatin structure. By contrast, normal cells that do not express 14-3-3sigma have a methylated 14-3-3sigma CpG island with hypoacetylated histones, methylated histone H3 lysine 9, and an inaccessible chromatin structure. These findings extend the spectrum of cell type-specific genes controlled, partly, by normal epigenetic mechanisms, and suggest that this subset of genes may represent important targets of epigenetic dysregulation in human cancer.

Kripke, D. F., Rex, K. M., Ancoli-Israel, S., Nievergelt, C. M., Klimecki, W., & Kelsoe, J. R. (2008). Delayed sleep phase cases and controls. Journal of circadian rhythms, 6, 6.

Delayed sleep phase disorder (DSPD) is a condition in which patients have difficulty falling asleep before the early morning hours and commonly have trouble awakening before late morning or even early afternoon. Several studies have suggested that variations in habitual bedtime are 40-50% heritable.

Tantisira, K., Klimecki, W. T., Lazarus, R., Palmer, L. J., Raby, B. A., Kwiatkowski, D. J., Silverman, E., Vercelli, D., Martinez, F. D., & Weiss, S. T. (2004). Toll-like receptor 6 gene (TLR6): single-nucleotide polymorphism frequencies and preliminary association with the diagnosis of asthma. Genes and immunity, 5(5), 343-6.

Toll-like receptor 6 (TLR6) is one of a series of highly conserved innate immune receptors. We resequenced TLR6 in DNA samples from 24 African Americans, 23 European Americans, and 24 Hispanic Americans, identifying 53 SNPs, 22 with an allele frequency >5%. Significant differences in SNP frequencies among the three populations were noted. In all, 11 SNPs caused amino-acid changes, including one with a frequency >5% in all three populations. Utilizing this SNP (Ser249Pro), we performed exploratory nested case-control disease-association studies, including one involving 56 African Americans with asthma and 93 African American controls. The minor allele of this SNP was associated with decreased risk for asthma (odds ratio 0.38, 95% CI 0.16-0.87, P=0.01), an effect consistent with the known biology of the toll-like receptors. Although replication of this finding in other, larger samples is needed, variation in TLR6 may have relevance to the pathogenesis of immunologically mediated diseases.

LeVan, T. D., Guerra, S., Klimecki, W., Vasquez, M. M., Lohman, I. C., Martinez, F. D., Halonen, M., & Wright, A. L. (2006). The impact of CD14 polymorphisms on the development of soluble CD14 levels during infancy. Genes and Immunity, 7(1), 77-80.

PMID: 16395394;Abstract:

CD14 is a receptor involved in the recognition of lipopolysaccharide and other bacterial wall components that may be involved in the balance between infectious and allergic disease and the early polarization towards TH1. Our group has shown an association between polymorphisms in the 5′ flanking region of the CD14 gene and plasma soluble CD14 (sCD14) levels at 11 years of age. However, whether this association is present at birth and in infancy remains to be determined. In this study, we measured sCD14 levels in plasma from the umbilical cord (n = 387) and at 3 months (n = 357) and 1 year (n=312) of age in non-selected healthy infants to assess their relationship with CD14 genotypes at -4190, -2838, -1720 and -260 (relative to translation start site). There was no relation of CD14 genotypes with sCD14 at birth. However, there was a significant association between CD14 genotypes and sCD14 as early as 3 months. Longitudinal analysis suggests that CD14 polymorphisms modulate sCD14 levels up to 1 year of age. This association early in life may have an impact on TH1 polarization and subsequent protection against allergic disease. © 2006 Nature Publishing Group All rights reserved.