Floyd Chilton
- Professor, Nutritional Sciences
- Professor, BIO5 Institute
- Member of the Graduate Faculty
- Professor, Cancer Biology - GIDP
- Professor, Innovations in Aging - GIDP
- (520) 621-5327
- Bioscience Research Labs, Rm. 370
- Tucson, AZ 85721
- fchilton@arizona.edu
Biography
Dr. Chilton is passionate about providing solutions to overcome physical and emotional suffering so that people can live better, more joyful lives. He is a successful innovator in a wide range of areas including an academic professor (with over 140 scientific publications), an entrepreneur (starting several companies and one non-profit organization), and an inventor (holding over 25 patents). Dr. Chilton is widely recognized in academia and industry for his work on nutrition in the context of variation in the human genome and has been a pioneer in the areas of personalized or precision nutrition and wellness. Dr. Chilton has over 30 years of continuous funding from the National Institutes of Health. Currently he serves as a Professor of Nutritional Sciences, Associate Director of the BIO5 Institute, and Director of the Precision Nutrition and Wellness Initiative at the University of Arizona.
Specifically, Dr. Chilton’s work examines how genetic and epigenetic variations interact with human diets (especially the modern Western diet) to drive inflammation and inflammatory disorders (including cardiovascular disease and cancer), as well as psychiatric/developmental disorders (ADHD, autism spectrum disorder, and depression). These precision-, individualized- and population-based research approaches provide a wide range of opportunities to benefit humans that include: 1) providing a long-sought pathogenetic mechanism that underscores the different biologic behavior of inflammatory diseases in different racial/ethnic populations; 2) discovering new biomarkers of disease aggressiveness for early diagnostic and therapeutic intervention; 3) revealing new therapeutic strategies to affect disease aggressiveness using precision gene-based dietary, wellness and/or pharmacologic interventions; and 4) creating therapeutic foods and supplements that optimize immune system and brain development for different populations around the world. Dr. Chilton has won numerous awards for this work, including the Alumni Achievement Award at Western Carolina University, the Denham Harmon Outstanding Research Achievement Award from the American College for Advancement of Medicine and the 2016 Established Investigator Award at Wake Forest School of Medicine.
Currently, his laboratory focuses on precision health as it relates to genetic variations associated with polyunsaturated fatty acid (PUFA) biosynthesis and metabolism and how gene-diet interactions impact molecular and clinical phenotypes associated with human health. Specifically, his work addresses the role of gene-diet interactions in driving inflammation and inflammatory disorders (including cardiovascular disease and cancer) as well as psychiatric/developmental disorders (ADHD, autism spectrum disorder and depression). His lab also examines how gene-diet interactions caused by the modern Western diet lead to marked changes (excesses and deficiencies) in PUFA levels and signaling in circulation, cells and tissues and how specific human nutrition supplementation strategies can be used to normalize these changes.
In addition to his research, Dr. Chilton has also had the opportunity to touch hundreds of thousands of lives as an author of five lay books focused on nutrition, diet, and physical and mental health. These books include Inflammation Nation (Simon and Schuster), Win the War Within (Rodale), The Gene Smart Diet (Rodale) and Made to Crave Action Plan (Zondervan). His most recent book, The Rewired Brain addresses the issue of the unconscious mind, its capacity to negatively impact our lives, and how thought patterns induce genetic (epigenetic) changes that alter brain circuitry. This gives humans the capacity to rewire and change their minds and thus their lives.
Degrees
- Ph.D. Biochemistry
- Wake Forest University, Winston-Salem, North Carolina, United States
- Thesis Title - Relationships between platelet-activating factor and arachidonate in polymorphonuclear leukocytes
- B.S. Biology / Chemistry
- Western Carolina University, Cullowhee, North Carolina, United States
Work Experience
- Wake Forest School of Medicine (2018 - Ongoing)
- Wake Forest School of Medicine (2016 - 2018)
- Wake Forest School of Medicine (2010 - 2016)
- Wake Forest School of Medicine (2007 - 2010)
- Wake Forest School of Medicine (2006 - 2018)
- Wake Forest and Harvard Center for Botanical Lipids, Wake Forest School of Medicine (2005 - 2010)
- Wake Forest School of Medicine (2004 - 2018)
- Wake Forest School of Medicine (1999 - 2001)
- Center at Wake Forest University School of Medicine (1999 - 2001)
- Wake Forest School of Medicine (1997 - 2002)
- Wake Forest School of Medicine (1996 - 2003)
- Wake Forest School of Medicine (1992 - 2003)
- Wake Forest School of Medicine (1991 - 1996)
- John Hopkins University School of Medicine, Johns Hopkins Asthma and Allergy Center (1986 - 1991)
- Wake Forest School of Medicine (1982 - 1984)
Interests
No activities entered.
Courses
2024-25 Courses
-
Directed Research
NSC 392 (Fall 2024) -
Directed Research
PSIO 492 (Fall 2024) -
Dissertation
NSC 920 (Fall 2024) -
Honors Independent Study
MCB 399H (Fall 2024) -
Honors Independent Study
NROS 399H (Fall 2024) -
Honors Thesis
NSC 498H (Fall 2024)
2023-24 Courses
-
Directed Research
NSC 392 (Spring 2024) -
Directed Rsrch
MCB 392 (Spring 2024) -
Dissertation
NSC 920 (Spring 2024) -
Nutrigeno Disease Prv+In
NSC 475 (Spring 2024) -
Nutrigeno Disease Prv+In
NSC 575 (Spring 2024) -
Research
NSC 900 (Spring 2024) -
Directed Rsrch
MCB 392 (Fall 2023) -
Dissertation
NSC 920 (Fall 2023)
2022-23 Courses
-
Directed Rsrch
MCB 392 (Spring 2023) -
Dissertation
NSC 920 (Spring 2023) -
Honors Thesis
MCB 498H (Spring 2023) -
Nutrigeno Disease Prv+In
NSC 475 (Spring 2023) -
Nutrigeno Disease Prv+In
NSC 575 (Spring 2023) -
Directed Research
MCB 792 (Fall 2022) -
Directed Research
PHCL 692 (Fall 2022) -
Dissertation
NSC 920 (Fall 2022) -
Honors Thesis
MCB 498H (Fall 2022) -
Independent Study
NSC 399 (Fall 2022)
2021-22 Courses
-
Directed Rsrch
MCB 492 (Summer I 2022) -
Directed Research
NSC 392 (Spring 2022) -
Dissertation
NSC 920 (Spring 2022) -
Honors Independent Study
PSIO 399H (Spring 2022) -
Honors Thesis
PSIO 498H (Spring 2022) -
Independent Study
NSC 399 (Spring 2022) -
Nutrigeno Disease Prv+In
NSC 475 (Spring 2022) -
Nutrigeno Disease Prv+In
NSC 575 (Spring 2022) -
Research
PS 900 (Spring 2022) -
Directed Research
NSC 392 (Fall 2021) -
Dissertation
NSC 920 (Fall 2021) -
Honors Independent Study
PSIO 399H (Fall 2021) -
Honors Thesis
PSIO 498H (Fall 2021) -
Independent Study
ECOL 399 (Fall 2021) -
Research
PS 900 (Fall 2021)
2020-21 Courses
-
Research
PS 900 (Summer I 2021) -
Dissertation
NSC 920 (Spring 2021) -
Nutrigeno Disease Prv+In
NSC 475 (Spring 2021) -
Nutrigeno Disease Prv+In
NSC 575 (Spring 2021) -
Research
PS 900 (Spring 2021) -
Thesis
NSC 910 (Spring 2021) -
Directed Research
NSC 392 (Fall 2020) -
Research
PS 900 (Fall 2020) -
Rsrch Meth Psio Sci
PS 700 (Fall 2020)
2019-20 Courses
-
Directed Research
MCB 792 (Spring 2020) -
Nutrigeno Disease Prv+In
NSC 475 (Spring 2020) -
Nutrigeno Disease Prv+In
NSC 575 (Spring 2020) -
Research
PS 900 (Spring 2020) -
Nutrigeno Disease Prv+In
NSC 475 (Fall 2019) -
Nutrigeno Disease Prv+In
NSC 575 (Fall 2019)
2018-19 Courses
-
Nutrigeno Disease Prv+In
NSC 475 (Spring 2019) -
Nutrigeno Disease Prv+In
NSC 575 (Spring 2019)
Scholarly Contributions
Journals/Publications
- Mullins, V. A., Graham, S., Cummings, D., Wood, A., Ovando, V., Skulas-Ray, A. C., Polian, D., Wang, Y., Hernandez, G. D., Lopez, C. M., Raikes, A. C., Brinton, R. D., & Chilton, F. H. (2022). Effects of Fish Oil on Biomarkers of Axonal Injury and Inflammation in American Football Players: A Placebo-Controlled Randomized Controlled Trial. Nutrients, 14(10).More infoThere are limited studies on neuroprotection from repeated subconcussive head impacts (RSHI) following docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) supplementation in contact sports athletes. We performed a randomized, placebo-controlled, double-blinded, parallel-group design trial to determine the impact of 26 weeks of DHA+EPA supplementation (n = 12) vs. placebo (high-oleic safflower oil) (n = 17) on serum concentrations of neurofilament light (NfL), a biomarker of axonal injury, and inflammatory cytokines (interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a)) in National Collegiate Athletic Association Division I American football athletes. DHA+EPA supplementation increased ( < 0.01) plasma DHA and EPA concentrations throughout the treatment period. NfL concentrations increased from baseline to week 26 in both groups (treatment (
- Fernandez, M. L., Blomquist, S. A., Hallmark, B., & Chilton, F. H. (2021). Omega-3 Supplementation and Heart Disease: A Population-Based Diet by Gene Analysis of Clinical Trial Outcomes. Nutrients, 13(7).More infoOmega-3 (-3) polyunsaturated fatty acids (PUFA) and their metabolites have long been recognized to protect against inflammation-related diseases including heart disease. Recent reports present conflicting evidence on the effects of -3 PUFAs on major cardiovascular events including death. While some studies document that -3 PUFA supplementation reduces the risk for heart disease, others report no beneficial effects on heart disease composite primary outcomes. Much of this heterogeneity may be related to the genetic variation in different individuals/populations that alters their capacity to synthesize biologically active -3 and omega 6 (-6) PUFAs and metabolites from their 18 carbon dietary precursors, linoleic acid (LA, 18:2 -6) and alpha-linolenic (ALA, 18:3, -3). Here, we discuss the role of a gene-by-dietary PUFA interaction model that takes into consideration dietary exposure, including the intake of LA and ALA, -3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in determining the efficacy of -3 PUFA supplementation. We also review recent clinical trials with -3 PUFA supplementation and coronary heart disease in the context of what is known about fatty acid desaturase ( gene-by-dietary PUFA interactions. Given the dramatic differences in the frequencies of variants that impact the efficiency of -3 and -6 PUFA biosynthesis, and their downstream signaling products among global and admixture populations, we conclude that large clinical trials utilizing "one size fits all" -3 PUFA supplementation approaches are unlikely to show effectiveness. However, evidence discussed in this review suggests that -3 PUFA supplementation may represent an important opportunity where precision interventions can be focused on those populations that will benefit the most from -3 PUFA supplementation.
- Snider, J. M., You, J. K., Wang, X., Snider, A. J., Hallmark, B., Zec, M. M., Seeds, M. C., Sergeant, S., Johnstone, L., Wang, Q., Sprissler, R., Carr, T. F., Lutrick, K., Parthasarathy, S., Bime, C., Zhang, H. H., Luberto, C., Kew, R. R., Hannun, Y. A., , Guerra, S., et al. (2021). Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality. The Journal of clinical investigation, 131(19).More infoThere is an urgent need to identify the cellular and molecular mechanisms responsible for severe COVID-19 that results in death. We initially performed both untargeted and targeted lipidomics as well as focused biochemical analyses of 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in patients with severe COVID-19. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 group IIA (sPLA2-IIA), with a median value that was 9.6-fold higher than that for patients with mild disease and 5.0-fold higher than the median value for survivors of severe COVID-19. Elevated sPLA2-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA2-IIA levels as a central node in the stratification of patients who died from COVID-19. Random forest analysis and least absolute shrinkage and selection operator-based (LASSO-based) regression analysis additionally identified sPLA2-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than did either one alone. An independent cohort (n = 154) confirmed higher plasma sPLA2-IIA levels in deceased patients compared with levels in plasma from patients with severe or mild COVID-19, with the PLA-BUN index-based decision tree satisfactorily stratifying patients with mild, severe, or fatal COVID-19. With clinically tested inhibitors available, this study identifies sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality.
- Yang, C., Hallmark, B., Chai, J. C., O'Connor, T. D., Reynolds, L. M., Wood, A. C., Seeds, M., Chen, Y. I., Steffen, L. M., Tsai, M. Y., Kaplan, R. C., Daviglus, M. L., Mandarino, L. J., Fretts, A. M., Lemaitre, R. N., Coletta, D. K., Blomquist, S. A., Johnstone, L. M., Tontsch, C., , Qi, Q., et al. (2021). Impact of Amerind ancestry and FADS genetic variation on omega-3 deficiency and cardiometabolic traits in Hispanic populations. Communications biology, 4(1), 918.More infoLong chain polyunsaturated fatty acids (LC-PUFAs) have critical signaling roles that regulate dyslipidemia and inflammation. Genetic variation in the FADS gene cluster accounts for a large portion of interindividual differences in circulating and tissue levels of LC-PUFAs, with the genotypes most strongly predictive of low LC-PUFA levels at strikingly higher frequencies in Amerind ancestry populations. In this study, we examined relationships between genetic ancestry and FADS variation in 1102 Hispanic American participants from the Multi-Ethnic Study of Atherosclerosis. We demonstrate strong negative associations between Amerind genetic ancestry and LC-PUFA levels. The FADS rs174537 single nucleotide polymorphism (SNP) accounted for much of the AI ancestry effect on LC-PUFAs, especially for low levels of n-3 LC-PUFAs. Rs174537 was also strongly associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides (TGs) and E-selectin in MESA Hispanics. Our study demonstrates that Amerind ancestry provides a useful and readily available tool to identify individuals most likely to have FADS-related n-3 LC-PUFA deficiencies and associated cardiovascular risk.
- Cai, Z., Li, C. F., Han, F., Liu, C., Zhang, A., Hsu, C. C., Peng, D., Zhang, X., Jin, G., Rezaeian, A. H., Wang, G., Zhang, W., Pan, B. S., Wang, C. Y., Wang, Y. H., Wu, S. Y., Yang, S. C., Hsu, F. C., D'Agostino, R. B., , Furdui, C. M., et al. (2020). Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis. Molecular cell, 80(2), 263-278.e7.More infoCancer metastasis accounts for the major cause of cancer-related deaths. How disseminated cancer cells cope with hostile microenvironments in secondary site for full-blown metastasis is largely unknown. Here, we show that AMPK (AMP-activated protein kinase), activated in mouse metastasis models, drives pyruvate dehydrogenase complex (PDHc) activation to maintain TCA cycle (tricarboxylic acid cycle) and promotes cancer metastasis by adapting cancer cells to metabolic and oxidative stresses. This AMPK-PDHc axis is activated in advanced breast cancer and predicts poor metastasis-free survival. Mechanistically, AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively. Importantly, these phosphorylation events mediate PDHc function in cancer metastasis. Our study reveals that AMPK-mediated PDHA phosphorylation drives PDHc activation and TCA cycle to empower cancer cells adaptation to metastatic microenvironments for metastasis.
- Dosso, B., Waits, C. M., Simms, K. N., Sergeant, S., Files, D. C., Howard, T. D., Langefeld, C. D., Chilton, F. H., & Rahbar, E. (2020). Impact of rs174537 on Critically Ill Patients with Acute Lung Injury: A Secondary Analysis of the OMEGA Randomized Clinical Trial. Current developments in nutrition, 4(10), nzaa147.More infoNutrition in the intensive care unit is vital for patient care; however, immunomodulatory diets rich in PUFAs like γ-linolenic acid (GLA), EPA, and DHA remain controversial for patients with acute respiratory distress syndrome. We postulate that genetic variants impacting PUFA metabolism contribute to mixed responses to PUFA-rich diets.
- Mullins, V. A., Bresette, W., Johnstone, L., Hallmark, B., & Chilton, F. H. (2020). Genomics in Personalized Nutrition: Can You "Eat for Your Genes"?. Nutrients, 12(10).More infoGenome-wide single nucleotide polymorphism (SNP) data are now quickly and inexpensively acquired, raising the prospect of creating personalized dietary recommendations based on an individual's genetic variability at multiple SNPs. However, relatively little is known about most specific gene-diet interactions, and many molecular and clinical phenotypes of interest (e.g., body mass index [BMI]) involve multiple genes. In this review, we discuss direct to consumer genetic testing (DTC-GT) and the current potential for precision nutrition based on an individual's genetic data. We review important issues such as dietary exposure and genetic architecture addressing the concepts of penetrance, pleiotropy, epistasis, polygenicity, and epigenetics. More specifically, we discuss how they complicate using genotypic data to predict phenotypes as well as response to dietary interventions. Then, several examples (including caffeine sensitivity, alcohol dependence, non-alcoholic fatty liver disease, obesity/appetite, cardiovascular, Alzheimer's disease, folate metabolism, long-chain fatty acid biosynthesis, and vitamin D metabolism) are provided illustrating how genotypic information could be used to inform nutritional recommendations. We conclude by examining ethical considerations and practical applications for using genetic information to inform dietary choices and the future role genetics may play in adopting changes beyond population-wide healthy eating guidelines.
- Poole, L. B., Parsonage, D., Sergeant, S., Miller, L. R., Lee, J., Furdui, C. M., & Chilton, F. H. (2020). Acyl-lipid desaturases and Vipp1 cooperate in cyanobacteria to produce novel omega-3 PUFA-containing glycolipids. Biotechnology for biofuels, 13, 83.More infoDietary omega-3 (n-3), long chain (LC-, ≥ 20 carbons), polyunsaturated fatty acids (PUFAs) derived largely from marine animal sources protect against inflammatory processes and enhance brain development and function. With the depletion of natural stocks of marine animal sources and an increasing demand for n-3 LC-PUFAs, alternative, sustainable supplies are urgently needed. As a result, n-3 18-carbon and LC-PUFAs are being generated from plant or algal sources, either by engineering new biosynthetic pathways or by augmenting existing systems.
- Reynolds, L. M., Dutta, R., Seeds, M. C., Lake, K. N., Hallmark, B., Mathias, R. A., Howard, T. D., & Chilton, F. H. (2020). FADS genetic and metabolomic analyses identify the ∆5 desaturase (FADS1) step as a critical control point in the formation of biologically important lipids. Scientific reports, 10(1), 15873.More infoHumans have undergone intense evolutionary selection to optimize their capacity to generate necessary quantities of long chain (LC-) polyunsaturated fatty acid (PUFA)-containing lipids. To better understand the impact of genetic variation within a locus of three FADS genes (FADS1, FADS2, and FADS3) on a diverse family of lipids, we examined the associations of 247 lipid metabolites (including four major classes of LC-PUFA-containing molecules and signaling molecules) with common and low-frequency genetic variants located within the FADS locus. Genetic variation in the FADS locus was strongly associated (p
- Sergeant, S., Hallmark, B., Mathias, R. A., Mustin, T. L., Ivester, P., Bohannon, M. L., Ruczinski, I., Johnstone, L., Seeds, M. C., & Chilton, F. H. (2020). Prospective clinical trial examining the impact of genetic variation in FADS1 on the metabolism of linoleic acid- and ɣ-linolenic acid-containing botanical oils. The American journal of clinical nutrition, 111(5), 1068-1078.More infoUnexplained heterogeneity in clinical trials has resulted in questions regarding the effectiveness of ɣ-linolenic acid (GLA)-containing botanical oil supplements. This heterogeneity may be explained by genetic variation within the fatty acid desaturase (FADS) gene cluster that is associated with circulating and tissue concentrations of arachidonic acid (ARA) and dihomo-ɣ-linolenic acid (DGLA), both of which may be synthesized from GLA and result in proinflammatory and anti-inflammatory metabolites, respectively.
- Snider, A. J., Seeds, M. C., Johnstone, L., Snider, J. M., Hallmark, B., Dutta, R., Moraga Franco, C., Parks, J. S., Bensen, J. T., Broeckling, C. D., Mohler, J. L., Smith, G. J., Fontham, E. T., Lin, H. K., Bresette, W., Sergeant, S., & Chilton, F. H. (2020). Identification of Plasma Glycosphingolipids as Potential Biomarkers for Prostate Cancer (PCa) Status. Biomolecules, 10(10).More infoProstate cancer (PCa) is the most common male cancer and the second leading cause of cancer death in United States men. Controversy continues over the effectiveness of prostate-specific antigen (PSA) for distinguishing aggressive from indolent PCa. There is a critical need for more specific and sensitive biomarkers to detect and distinguish low- versus high-risk PCa cases. Discovery metabolomics were performed utilizing ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) on plasma samples from 159 men with treatment naïve prostate cancer participating in the North Carolina-Louisiana PCa Project to determine if there were metabolites associated with aggressive PCa. Thirty-five identifiable plasma small molecules were associated with PCa aggressiveness, 15 of which were sphingolipids; nine common molecules were present in both African-American and European-American men. The molecules most associated with PCa aggressiveness were glycosphingolipids; levels of trihexosylceramide and tetrahexosylceramide were most closely associated with high-aggressive PCa. The Cancer Genome Atlas was queried to determine gene alterations within glycosphingolipid metabolism that are associated with PCa and other cancers. Genes that encode enzymes associated with the metabolism of glycosphingolipids were altered in 12% of PCa and >30% of lung, uterine, and ovarian cancers. These data suggest that the identified plasma (glyco)sphingolipids should be further validated for their association with aggressive PCa, suggesting that specific sphingolipids may be included in a diagnostic signature for PCa.
- Sorkin, B. C., Kuszak, A. J., Bloss, G., Fukagawa, N. K., Hoffman, F. A., Jafari, M., Barrett, B., Brown, P. N., Bushman, F. D., Casper, S. J., Chilton, F. H., Coffey, C. S., Ferruzzi, M. G., Hopp, D. C., Kiely, M., Lakens, D., MacMillan, J. B., Meltzer, D. O., Pahor, M., , Paul, J., et al. (2020). Improving natural product research translation: From source to clinical trial. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 34(1), 41-65.More infoWhile great interest in health effects of natural product (NP) including dietary supplements and foods persists, promising preclinical NP research is not consistently translating into actionable clinical trial (CT) outcomes. Generally considered the gold standard for assessing safety and efficacy, CTs, especially phase III CTs, are costly and require rigorous planning to optimize the value of the information obtained. More effective bridging from NP research to CT was the goal of a September, 2018 transdisciplinary workshop. Participants emphasized that replicability and likelihood of successful translation depend on rigor in experimental design, interpretation, and reporting across the continuum of NP research. Discussions spanned good practices for NP characterization and quality control; use and interpretation of models (computational through in vivo) with strong clinical predictive validity; controls for experimental artefacts, especially for in vitro interrogation of bioactivity and mechanisms of action; rigorous assessment and interpretation of prior research; transparency in all reporting; and prioritization of research questions. Natural product clinical trials prioritized based on rigorous, convergent supporting data and current public health needs are most likely to be informative and ultimately affect public health. Thoughtful, coordinated implementation of these practices should enhance the knowledge gained from future NP research.
- Waits, C. M., Bower, A., Simms, K. N., Feldman, B. C., Kim, N., Sergeant, S., Chilton, F. H., VandeVord, P. J., Langefeld, C. D., & Rahbar, E. (2020). A Pilot Study Assessing the Impact of rs174537 on Circulating Polyunsaturated Fatty Acids and the Inflammatory Response in Patients with Traumatic Brain Injury. Journal of neurotrauma.More infoTraumatic brain injury (TBI) is a leading cause of death and disability in persons under age 45. The hallmark secondary injury profile after TBI involves dynamic interactions between inflammatory and metabolic pathways including fatty acids. Omega-3 polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA) have been shown to provide neuroprotective benefits by minimizing neuroinflammation in rodents. These effects have been less conclusive in humans, however. We postulate genetic variants influencing PUFA metabolism in humans could contribute to these disparate findings. Therefore, we sought to (1) characterize the circulating PUFA response and (2) evaluate the impact of rs174537 on inflammation after TBI. A prospective, single-center, observational pilot study was conducted to collect blood samples from Level-1 trauma patients (N = 130) on admission and 24 h post-admission. Plasma was used to quantify PUFA levels and inflammatory cytokines. Deoxyribonucleic acid was extracted and genotyped at rs174537. Associations between PUFAs and inflammatory cytokines were analyzed for all trauma cases and stratified by race (Caucasians only), TBI (TBI: N = 47; non-TBI = 83) and rs174537 genotype (GG: N = 33, GT/TT: N = 44). Patients with TBI had higher plasma DHA levels compared with non-TBI at 24 h post-injury ( = 0.013). The SNP rs174537 was associated with both PUFA levels and inflammatory cytokines (
- Harris, D. N., Ruczinski, I., Yanek, L. R., Becker, L. C., Becker, D. M., Guio, H., Cui, T., Chilton, F. H., Mathias, R. A., & O'Connor, T. D. (2019). Evolution of Hominin Polyunsaturated Fatty Acid Metabolism: From Africa to the New World. Genome Biol. Evol., 11(5), 1417-1430.More infoThe metabolic conversion of dietary omega-3 and omega-6 18 carbon (18C) to long chain (>20 carbon) polyunsaturated fatty acids (LC-PUFAs) is vital for human life. The rate-limiting steps of this process are catalyzed by fatty acid desaturase (FADS) 1 and 2. Therefore, understanding the evolutionary history of the FADS genes is essential to our understanding of hominin evolution. The FADS genes have two haplogroups, ancestral and derived, with the derived haplogroup being associated with more efficient LC-PUFA biosynthesis than the ancestral haplogroup. In addition, there is a complex global distribution of these haplogroups that is suggestive of Neanderthal introgression. We confirm that Native American ancestry is nearly fixed for the ancestral haplogroup, and replicate a positive selection signal in Native Americans. This positive selection potentially continued after the founding of the Americas, although simulations suggest that the timing is dependent on the allele frequency of the ancestral Beringian population. We also find that the Neanderthal FADS haplotype is more closely related to the derived haplogroup and the Denisovan clusters closer to the ancestral haplogroup. Furthermore, the derived haplogroup has a time to the most recent common ancestor of 688,474 years before present. These results support an ancient polymorphism, as opposed to Neanderthal introgression, forming in the FADS region during the Pleistocene with possibly differential selection pressures on both haplogroups. The near fixation of the ancestral haplogroup in Native American ancestry calls for future studies to explore the potential health risk of associated low LC-PUFA levels in these populations.
- Rahbar, E., Waits, C. M., Kirby, E. H., Miller, L. R., Ainsworth, H. C., Cui, T., Sergeant, S., Howard, T. D., Langefeld, C. D., & Chilton, F. H. (2018). Allele-specific methylation in the genomic region in DNA from human saliva, CD4+ cells, and total leukocytes. Clin. epigenetics, 10, 46.More infoGenetic variants within the fatty acid desaturase () gene cluster (human Chr11) are important regulators of long-chain (LC) polyunsaturated fatty acid (PUFA) biosynthesis in the liver and consequently have been associated with circulating LC-PUFA levels. More recently, epigenetic modifications such as DNA methylation, particularly within the cluster, have been shown to affect LC-PUFA levels. Our lab previously demonstrated strong associations of allele-specific methylation (ASM) between a single nucleotide polymorphism (SNP) rs174537 and CpG sites across the region in human liver tissues. Given that epigenetic signatures are tissue-specific, we aimed to evaluate the methylation status and ASM associations between rs174537 and DNA methylation obtained from human saliva, CD4+ cells and total leukocytes derived from whole blood. The goals were to (1) determine if DNA methylation from these peripheral samples would display similar ASM trends as previously observed in human liver tissues and (2) evaluate the associations between DNA methylation and circulating LC-PUFAs.
- Reynolds, L. M., Howard, T. D., Ruczinski, I., Kanchan, K., Seeds, M. C., Mathias, R. A., & Chilton, F. H. (2018). Tissue-specific impact of FADS cluster variants on FADS1 and FADS2 gene expression. PloS one, 13(3), e0194610.More infoOmega-6 (n-6) and omega-3 (n-3) long (≥ 20 carbon) chain polyunsaturated fatty acids (LC-PUFAs) play a critical role in human health and disease. Biosynthesis of LC-PUFAs from dietary 18 carbon PUFAs in tissues such as the liver is highly associated with genetic variation within the fatty acid desaturase (FADS) gene cluster, containing FADS1 and FADS2 that encode the rate-limiting desaturation enzymes in the LC-PUFA biosynthesis pathway. However, the molecular mechanisms by which FADS genetic variants affect LC-PUFA biosynthesis, and in which tissues, are unclear. The current study examined associations between common single nucleotide polymorphisms (SNPs) within the FADS gene cluster and FADS1 and FADS2 gene expression in 44 different human tissues (sample sizes ranging 70-361) from the Genotype-Tissue Expression (GTEx) Project. FADS1 and FADS2 expression were detected in all 44 tissues. Significant cis-eQTLs (within 1 megabase of each gene, False Discovery Rate, FDR
- Wang, M., Chen, H., Ailati, A., Chen, W., Chilton, F. H., Todd Lowther, W., & Chen, Y. Q. (2018). Substrate specificity and membrane topologies of the iron-containing ω3 and ω6 desaturases from Mortierella alpina. Appl. Microbiol. Biotechnol., 102(1), 211-223.More infoPolyunsaturated fatty acids (PUFAs) are essential lipids for cell function, normal growth, and development, serving as key structural components of biological membranes and modulating critical signal transduction events. Omega-3 (n-3) long chain PUFAs (LC-PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to protect against inflammatory diseases and enhance brain development and function. This had led to a marked increase in demand for fish and fish oils in human diets, supplements, and aquaculture and created a need for new, sustainable n-3 LC-PUFA sources. We have studied for the first time homogenous preparations of the membrane-type ω6 and ω3 fatty acid desaturases from the fungus Mortierella alpina, as a model system to produce PUFAs. These desaturases possess a di-iron metal center and are selective for 18:1 n-9 and 18:2 n-6 acyl-CoA substrates, respectively. Sequence alignments and membrane topology predictions support that these enzymes have unique cap regions that may include the rearrangement and repositioning of the active site, especially when compared to the mammalian stearoyl-coenzyme A desaturase-1 (SCD1) and the related sphingolipid α-hydroxylase (Scs7p) that act upon different substrates.
Presentations
- Chilton, F. (2021). Molecular Networks and Enzymes that Play a Central Role in COVID-19 Mortality. Department Lecture SeriesUniversity of Connecticut, Departments of Nutrition and Pharmacology.
- Chilton, F. (2021). Molecular Networks and Enzymes that Play a Central Role in COVID-19 Mortality. UA, Department LectureUA, Depts Molecular & Cellular Biology, Chemistry & Biochemistry, Cellular & Molecular Medicine, Plant Sciences.
- Chilton, F. (2021). “Molecular Networks and Enzymes that Play a Central Role in COVID-19 Mortality”. Understanding COVID's Long GameThe Scientist Webinars.
- Bresette, W., Skulas-Ray, A. C., Tontsch, C., Tomich, T., Hudson, O., Richter, C. K., Kris-Etherton, P. M., Jensen, G. L., & Chilton, F. (2020, April). In vivo metabolomic and lipidomic response of healthy humans to intravenous lipopolysaccharide challenge. Experimental Biology 2020. San Diego, Ca: Experimental Biology.
- Sarah, B., Coletta, D., Mandarino, L. J., Hallmark, B., Yang, C., Rich, S., Mathias, R., Manichaikul, A. A., & Chilton, F. (2020, April). Fatty Acid Desaturase Gene-Induced Omega-3 Deficiency in Amerindian-Ancestry Hispanic Populations. Experimental Biology 2020. San Diego, CA: Experimental Biolgoy.
Poster Presentations
- Blomquist, S., Coletta, D., Mandarino, L. J., Hallmark, B., Yang, C., Rich, S., Manichaikul, A. W., & Chilton, F. (2020, March). Fatty Acid Desaturase Gene-Induced Omega-3 Deficiency in Amerindian-Ancestry Hispanic Populations. EPI / Lifestyle 2020 Scientific Sessions. Phoenix, AZ: American Heart Association.