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Genotyping for Response to Physical Training GENOTYPING FOR RESPONSE TO PHYSICAL TRAINING A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science By STACY SIMMONS B.S., Wright State University, 2014 _________________________________________________________ 2019 Wright State University WRIGHT STATE UNIVERSITY GRADUATE SCHOOL July 29, 2019 I HEREBY RECOMMEND THAT THE THESIS PREPARED UNDER MY SUPERVISION BY Stacy Simmons ENTITLED Genotyping for Response to Physical Training BE ACCEPTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Master of Science. ___________________________________ Michael Markey, Ph.D. Thesis Director ____________________________________ Madhavi P. Kadakia, Ph.D. Committee on Chair, Department of Biochemistry Final Examination and Molecular Biology _____________________________ Michael Markey, Ph.D. _____________________________ Richard Chapleau, Ph.D. _____________________________ Madhavi Kadakia, Ph.D. _____________________________ Barry Milligan, Ph.D. Interim Dean of the Graduate School ABSTRACT Simmons, Stacy. M.S. Department of Biochemistry and Molecular Biology, Wright State University 2019. Genotyping for Response to Physical Training Understanding the inter-individual variability in physical fitness performance has been the focus of scientific research for decades especially in the United States military. Injury and physical inadequacy cost the U.S military millions of dollars every year. The project PHITE (Precision High Intensity Training through Epigenetics) was funded to investigate this personal complex trait by combing the genetic and epigenetic (non-shared environmental factors) contributions into a single model for physical training response. This project is set up as having 150 male and female recruits between the ages of 18-27 years old. Each participant is randomly put blind into either a high intensity or moderate intensity (group A or group B) 12-week training program. The training response was measured by various means including % change in chest press, lat pull, VO2max, among others and muscle biopsies and blood samples were collected regularly. The genetic contribution was examined by using Taqman qPCR genotyping for common single nucleotide polymorphisms (SNP) found in the literature to contribute to physical performance. By combining the genotyping data with the training response data, it was hypothesized that the training response would be different depending on the training group assigned and that genotype can be used to develop a predictor for training response. There were two main aims that were investigated for this hypothesis: the performance difference between the high and moderate intensity; and whether genotype could be used as a predictor of this training response. Individual training responses and overall performance in each training group was investigated using ANOVA analysis. It was determined that there wasn’t a significant difference iii | P a g e in individual training responses for each group, but overall performance in group B was significantly higher than group A (p=0.0059). Five different analyses were used to investigate whether genotype could be used as a predictor for training response: ANOVA of beneficial allele score, ANOVA of performance score, Fisher’s exact test, ANOVA of individual performance results, and GWAS analysis. 16 SNPs were found to be associated with either individual training responses or overall performance response. These results support the importance of considering genotype in any model of physical training response. iv | P a g e Table of Contents I. INTRODUCTION ..................................................................................................................................... 1 A. Physical Fitness in the Military .......................................................................................................... 1 B. Genotyping Using Single Nucleotide Polymorphisms ....................................................................... 2 1. Aerobic Capacity/Endurance/VO2max .......................................................................................... 3 2. Physical Strength/Response to Training/Muscle Volume ............................................................. 4 3. Blood Pressure/Cardiovascular/Heart Rate .................................................................................. 4 4. Increased BMI/Obesity/Diabetes .................................................................................................. 5 5. Endurance/Strength ...................................................................................................................... 5 6. Other (Bone Density/Height/Metabolism) ................................................................................... 6 7. Epigenetic Modifiers ..................................................................................................................... 6 II. MATERIALS AND METHODS .................................................................................................................. 7 A. Subjects and Training Protocol ......................................................................................................... 7 B. DNA Isolation and Genotyping Analysis ............................................................................................ 9 C. Beneficial Allele Score ..................................................................................................................... 10 D. Statistical Analysis ........................................................................................................................... 11 1. Chi Squared Analysis ................................................................................................................... 11 2. K-Means Clustering and Performance Score .............................................................................. 13 3. Fisher’s Exact Test ....................................................................................................................... 13 4. Analysis of Variance (ANOVA) ..................................................................................................... 14 5. Bonferroni Correction ................................................................................................................. 14 6. Genome Wide Association Study (GWAS) .................................................................................. 14 III. RESULTS........................................................................................................................................... 15 A. AIM I. Training Group A Versus B Physical Performance Parameters ............................................ 15 1. Group A Versus B: Individual Performance Parameters ............................................................. 15 1. Group A Versus B: Performance Score ....................................................................................... 15 B. AIM II. Investigate if genotype can be used to predict phenotype in individual training responses and in overall training response ............................................................................................................. 19 1. Beneficial Allele Score ................................................................................................................. 20 2. Performance Score ...................................................................................................................... 22 3. Fisher’s Exact Test ....................................................................................................................... 34 v | P a g e 4. ANOVA Analysis .......................................................................................................................... 38 5. GWAS Analysis ............................................................................................................................ 44 IV. DISCUSSION ..................................................................................................................................... 46 V. FUTURE DIRECTIONS ........................................................................................................................... 55 VI. SUPPLEMENTARY DATA .................................................................................................................. 56 VII. BIBLIOGRAPHY ................................................................................................................................ 83 vi | P a g e LIST OF TABLES Table 1: Summary of SNPs Chosen for PHITE ............................................................................................... 3 Table 2: Physical Performance Parameters (% Change 0-12 Weeks) ........................................................... 9 Table 3: Chi Squared Analysis of all 42 Completers .................................................................................... 19 Table 4: SNPs Shown to be Associated with Performance Score ............................................................... 22 Table 5: Bonferroni Corrected Fisher’s Exact Test SNP Results .................................................................. 34 Table 6: SNPs Shown to Predict Specific Training Responses by ANOVA ................................................... 38 Table 7: SNPs Shown to Predict Specific Training Responses by GWAS ..................................................... 44 Table 8: SNPs Beneficial Alleles Associated with Overall Performance
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