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Kelsey Dawes

Mentor: Robert Philibert, M.D./Ph.D.
Lab Room: 2-115 MEB
Lab Phone: 319-361-2081

Genetic and Gene-Methylation Interaction Effects in cg19693031 Models Predict HbA1c and Type 2 Diabetes Status in African Americans

The development of Type 2 Diabetes Mellitus (T2D) is driven by the interplay of genetic and environmental factors. Whereas the HbA1c is a robust tool for assessing T2D status, its low sensitivity is further limited by genetic variances, erythropathies and pharmacological therapies. Furthermore, the clinical utility of HbA1c is limited by its inability to capture the early stages of the disease and identify patients that are at high risk for diabetic complications. Conceivably, epigenetic approaches, in particular those that incorporate genetic information, could address these limitations.

In prior work, others have shown that the DNA methylation status at cg19693031 in TXNIP is inversely correlated with HbA1c values. However, in these older studies, the association was not strong, did not include those of African ethnicity, used a more limited array and did not consider possible confounding genetics. To test and extend these prior findings, we first conducted epigenome-wide association analyses (EWAS) of HbA1c values followed by genome-wide genetic interaction analyses in an African American cohort. Replicating previous findings, we found that cg19693031 was the top-ranked probe (p-value = 7.43e-12, R² = 0.19). The incorporation of local genetic additive and interactive (GxMeth) effects into a regression model including cg19693031 did not significantly improve the correlation to HbA1c values or prediction of T2D status. However, the addition of trans GxMeth effects significantly improved both the correlation to HbA1c values (p-value < 2.2e-16, R² = .71) and prediction of T2D status between T2D and control subjects (AUC 0.7857, 71% sensitivity, 84% specificity). Additionally, the significant trans-GxMeth loci mapped to biological pathways that have been previously reported to be involved in the development of diabetic complications.

We conclude cg19693031 is strongly associated with HbA1c levels in African Americans and that combining genetic with epigenetic information improves the correlation to HbA1c and prediction of T2D status. Our findings suggest GxMeth analyses may provide novel risk stratification tools for diabetic complications, and incorporation of these analyses into prediction algorithms may provide an additional tool for researchers or clinicians.

Dawes, Kelsey, Willem Philibert, Benjamin Darbro, Ronald L. Simons, and Robert Philibert. 2022. "Additive and Interactive Genetically Contextual Effects of HbA1c on cg19693031 Methylation in Type 2 Diabetes" Genes 13, no. 4: 683. https://doi.org/10.3390/genes13040683 Allan Andersen, Rachel Reimer, Kelsey Dawes, Ashley Becker, Natasha Hutchens, Shelly Miller, Meesha Dogan, Brandon Hundley, James A Mills, Jeffrey D Long & Robert Philibert (2021) DNA Methylation Differentiates Smoking from Vaping and Non-combustible Tobacco Use, Epigenetics, DOI: 10.1080/15592294.2021.1890875

Dawes, Kelsey, Allan Andersen, Kyra Vercande, Emma Papworth, Willem Philibert, Steven RH Beach, Frederick X. Gibbons, Meg Gerrard, and Robert Philibert. "Saliva DNA methylation detects nascent smoking in adolescents." Journal of child and adolescent psychopharmacology 29, no. 7 (2019): 535-544.

Philibert, Robert, Shelly Miller, Amanda Noel, Kelsey Dawes, Emma Papworth, Donald W. Black, Steven RH Beach, Jeffrey D. Long, James A. Mills, and Meeshanthini Dogan. "A Four Marker Digital PCR Toolkit for Detecting Heavy Alcohol Consumption and the Effectiveness of Its Treatment." Journal of Insurance Medicine 48, no. 1 (2019): 90-102.

Robert Philibert , Jeffrey D. Long , James A. Mills , S. R. H. Beach , Frederick X. Gibbons , Meg Gerrard , Ron Simons , Paulo B. Pinho , Douglas Ingle , Dawes, Kelsey , Timur Dogan & Meeshanthini Dogan (2020): A simple, rapid, interpretable, actionable and implementable digital PCR based mortality index, Epigenetics, DOI: 10.1080/15592294.2020.1841874

Dawes, K., Dogan, M., Simons, R., Philibert, R. Addition of Genetic and Gene-Methylation Effects Improves Prediction of cg19693031 Models of HbA1C and Type 2 Diabetes Status in African Americans; (Abstract #2035). Presented at the 70th Annual Conference of American Society of Human Genetics, 2020 Oct 27-31, Virtual Meeting.

Dawes, K., Papworth, E., Becker, A., Philibert, W., Hundley, B., Hutchens, N., Gibbons, F., Gerrard, M., Philibert, R. Dose and Time Dependency of the AHRR cg05575921 Demethylation Response in Nascent Smoking. Presented at the 71st Annual Meeting of The American Society of Human Genetics, October, 2019 in Houston, Texas.

Dawes, Kelsey, Allan Andersen, Emma Papworth, Brandon Hundley, Natasha Hutchens, Heba El Manawy, Ashley Becker, Luke Sampson, Willem Philibert, Frederick Gibbons, Meg Gerrard, and Robert Philibert. “Refinement of cg05575921 demethylation response in nascent smoking.” Clinical Epigenetics 12, 92 (2020). Https://doi.org/10.1186/s13148-020-00882-w

Philibert, R.; Mills, J.A.; Long, J.D.; Salisbury, S.E.; Comellas, A.; Gerk, A; Dawes, K.; Vander Weg, M.; Hoffman, E.A. The Reversion of cg05575921 Methylation in Smoking Cessation: A Potential Tool for Incentivizing Healthy Aging. Genes 2020, 11, 1415. https://doi.org/10.3390/genes11121415

Dawes, K., Miller, S., Gerrard, M. and Philibert, R., 2021, June. An epigentics, longitudinal assessment of the co-morbidity of alcohol consumption and substance use in adolecents. Alcoholism-Clinical and Experimental Research (Vol. 45, pp. 98A-98A).

Philibert, R., S. Miller, K. Dawes , J. Mills, and J. Long. The saliva DNA form of the alchohol signature DNA methylation test outperforms carbohydrate deficient transferrin assessments for predicting heavy alchohol consumption. Alcoholism-Clinical and Experimental Research vol. 45, pp. 164A-164A.

Philibert, R. A., K. Dawes, M. Dogan, W. Philibert, B. Hundley, J. Mills, J. Long et al. The Reversion Curve of cg05575921 Methylation in Response to Smoking Cessation: A New Dynamic Epigenetic Tool for Monitoring and Incentivizing Smoking Cessation. European Journal of Human Genetics, vol. 28, no. SUPPL 1, pp. 742-743.

Philibert, Robert, Willem Philibert, Allan Andersen, Kelsey Dawes, Eric Hoffman, and Meesha Dogan. Reversion of DNA methylation at cardiac risk predictor LOCI demenstrates the potential of epigenetics to guide CHD prevention therapy using DNA from blood or saliva. Journal of the American College of Cardiology 77, no. 18_Supplement_1 (2021): 1577-1577.

Dawes, K., Dogan, M., Simons, R. and Philibert, R., 2021. Ingtegrated genetic-epigenetic framework predicts Type 2 Diabetes and provides novel insight into diabetic complications. Journal of the American College of Cardiology, 77(18_Supplement_1), pp.1609-1609.

Dawes, K.; Sampson, L.; Reimer, R.; Miller, S.; Philibert, R.; Andersen, A. Epigenetic Analyses of Alcohol Consumption in Combustible and Non-Combustible Nicotine Product User”. Epigenomes 2021, 5(3), 18. https://doi.org/10.3390/epigenomes5030018

Dawes, K., Andersen, A., Reimer, R. et al. The relationship of smoking to cg05575921 methylation in blood and saliva DNA samples from several studies. Sci Rep 11, 21627 (2021). Https://doi.org/10.1038/s41598-021-01088-7

Philibert, Robert, Kelsey Dawes, Willem Philibert, Allan M. Andersen, and Eric A. Hoffman. 2022. Alcohol Use Intensity Decreases in Response to Successful Smoking Cessation Therapy Genes 13, no. 1: 2. https://doi.org/10.3390/genes13010002

Honors and Awards

  • Carver College of Medicine’s Scholar Travel Award - 2019
  • Carver College of Medicine's Scholar Travel Award - September 2020
  • John Pappajohn Entrepreneurial Center, Ideastorm Competition, 2nd place - Health Initiatives (Diabetes Screening Test)
  • John Pappajohn Entrepreneurial Center, Iowa Innovation Challenge – Elevator Pitch Competition (Finalist, November 2020)
  • AAAS Science Program for Excellence in Science
  • Bertelsmann Udacity Tech Scholarship
  • UI Innovators, NSF iCorp grant
  • UI Dare to Discover (2021 Campaign)
  • UI Graduate & Professional Student Government, Research Grant