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Aprioritized Panel of Candidate Genes In: Advances in Genetics Research. Volume 9 ISBN: 978-1- 62081-466-6 Editor: Kevin V. Urbano © 2012 Nova Science Publishers, Inc No part of this digital document may be reproduced, stored in a retrieval system or transmitted commercially in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services. Chapter 1 A PRIORITIZED PANEL OF CANDIDATE GENES TO BE EXPLORED FOR ASSOCIATIONS WITH THE BLOOD PRESSURE RESPONSE TO EXERCISE Garrett I. Ash,1,Amanda L. Augeri,2John D. Eicher,3 Michael L. Bruneau, Jr.1 and Linda S. Pescatello1 1University of Connecticut, Storrs, CT, US 2Hartford Hospital, Hartford, CT, US 3Yale University School of Medicine, New Haven, CT, US ABSTRACT Introduction. Identifying genetic variants associated with the blood pressure (BP) response to exercise is hindered by the lack of standard criteria for candidate gene selection, underpowered samples, and a limited number of conclusive whole genome studies. We developed a prioritized panel of candidate genetic variants that may increase the likelihood of finding genotype associations with the BP response to exercise when used alone or in conjunction with high throughput genotyping studies. Methods. We searched for candidate genetic variants meeting preestablished criteria using PubMed and published systematic reviews. These preestablished criteria were genetic variants: 1) in major BP regulatory pathways and associated with BP, the BP response to exercise or antihypertensive medication, or the health-related fitness phenotype response to exercise; 2) from high throughput genotyping studies of BP meeting statistical significance after Bonferroni correction for multiple testing; 3) associated with energy metabolism and/or body composition as obesity is a major risk factor for hypertension; 4) associated with other established and emerging cardiovascular disease (CVD) risk factors that have been implicated in the etiology of hypertension; and 5) from high throughput genotyping studies of BP meeting arbitrary statistical significance thresholds. Corresponding author: Garrett I. Ash, Department of Kinesiology & Human Performance Laboratory, Neag School of Education, University of Connecticut, 2095 Hillside Rd, U-1110, Storrs, CT 06269-1110, USA, Tel +1 860 486 8976; Fax +1 860 486 1123, Email:[email protected]. 2 Garrett I. Ash,Amanda L. Augeri,John D. Eicher et al. Results. Meeting the inclusion criteria were: 1) 162 variants from 60 candidate genes on 19 chromosomes associated with BP, the BP response to exercise or antihypertensive medication, or the health-related fitness phenotype response to exercise categorized within major BP regulatory pathways including: the renal and renin-angiotensin systems (92 variants, 27 genes, 14 chromosomes); sympathetic nervous system (39 variants, 20 genes, 14 chromosomes); nitric oxide synthase pathway (14 variants, 4 genes, 4 chromosomes); and other related BP regulatory pathways (17 variants, 9 genes, 7 chromosomes); 2) 55 variants on 17 chromosomes from high throughput genotyping studies of BP meeting statistical significance after Bonferroni correction for multiple testing; 3) 61 variants from 22 candidate genes on 15 chromosomes associated with energy metabolism and/or body composition; 4) 86 variants from 30 candidate genes on 16 chromosomes associated with other CVD risk factors including lipids and lipoproteins (43 variants, 14 genes, 10 chromosomes) and inflammatory or thrombotic factors (43 variants, 16 genes, 11 chromosomes); and 5) 149 variants on 20 chromosomes from high throughput genotyping studies of BP meeting arbitrary statistical significance thresholds. Conclusion. This prioritized panel of 513 genetic variants provides genomic information that can serve as a reference for future work investigating the genetic basis of the BP response to exercise. INTRODUCTION Hypertension is a major global public health problem. Exercise decreases BP 5-7 mmHg among those with hypertension [1]. BP reductions of this magnitude lower cardiovascular disease (CVD) risk by 20-30%. Thus, the Joint National Committee 7 recommends exercise as initial lifestyle therapy to prevent, treat, and control high blood pressure (BP) [2]. However, the BP response to exercise training is variable[3,4]. Indeed, the standard deviation often exceeds the mean BP response[5], and exercise does not lower BP in 25% of the people with high BP [3,6,7]. Reasons for this variability are unclear but may include factors such as the law of initial values and regression to the mean[7]; differences in subject characteristics such as ethnicity [4,8], gender [4], age [4,8], and body mass index [4,8,9]; and differences in the frequency, intensity, time and type or FITT components of the exercise interventions [4,8]. In addition, genetic factors have a significant role that remains to be defined [10]. Exercise genomics is the study of genetic factors contributing to human variation in the response of health-related fitness phenotypes such as the BP response to exercise [11]. A list of terms and definitions related to exercise genomics used and italicized in this chapter are displayed in Table 1. Experts consider genomics and the identification of responders and nonresponders to exercise interventions as key areas of research that will drive advancements in exercise science in the 21st century[12]. Future research in exercise genomics aims to: 1) gain insight in the mechanisms of biological processes related to exercise; and 2) use genetic information to design individualized exercise prescriptions to prevent, treat, and control disease processes and optimize sports performance. However, despite the promise of exercise genomics, our understanding of what specific genetic factors account for the BP response to exercise remains poor. To date genetic variants from 20 different genes have been reported to be associated with the BP response following a single bout of acute exercise (i.e., postexercise hypotension) [10,13-16] or chronic exercise (i.e., an exercise training program) [17-30]. A Prioritized Panel of Candidate Genes to be Explored for Associations ... 3 Table 1. Key Genetic Terms and Definitions Included in this Chapter [11,63,64] 3‟ untranslated region The 3‟ end of a gene is the end of the deoxyribonucleic acid at which the carbon atom attached to the next genetic sequence is the third carbon atom clockwise from the oxygen atom in the last base. The 3‟ untranslated region of a gene is the sequence between the 3‟ end and the protein coding region of the gene. It is transcribed into messenger ribonucleic acid but does not encode any protein sequence. 5‟ untranslated region The 5‟ end of a gene is the end of the deoxyribonucleic acid at which the carbon atom attached to the next genetic sequence is the fifth carbon atom clockwise from the oxygen atom in the last base. The 5‟ untranslated region of a gene is the sequence between the 5‟ end and the protein coding region of the gene. It is transcribed into messenger ribonucleic acid but does not encode any protein sequence. Allele One of the different forms of a gene that can exist at a single genetic location or locus. Allele, major The allele of a given variant occurring with greatest frequency in the population. Allele, minor The allele of a given variant occurring with least frequency in the population. Coding synonymous Located within the coding region of a gene‟s sequence but not causing a change in the amino acid sequence of the final protein. Complex phenotype A phenotype influenced by genetic as well as environmental factors. Copy number variant A variant in which some individuals have more or less than two copies of an entire gene sequence. This variation occurs because some chromosome copies are missing the gene, some have one copy of the gene, and some have multiple copies of the gene. Epigenomics The study of chemical modifications of the genome that do not alter the genetic sequence but can alter the physical and chemical behavior of the genetic material. Epigenetic The study of heritable changes in gene expression and other phenotypes caused by mechanisms other than changes in the underlying deoxyribonucleic acid sequence. Exercise genomics The study of genetic factors contributing to human variation in the response of health-related fitness phenotypes to exercise. High throughput genotyping The use of a collection of microscopic spots of genetic material attached to a solid surface in order to genotype a high number of genetic variants simultaneously. Genetic variant A genetic sequence variation present at a particular position, where different individuals can have any of two or more alleles. Genome wide association study A study testing the association of a phenotype with a large set of common genetic variants across the entire genome. 4 Garrett I. Ash,Amanda L. Augeri,John D. Eicher et al. Table 1. (Continued) Genome wide linkage study A study of genetic variants across the entire genome examining the non-random co-segregation of a trait of interest and genotype. The goal of these studies is to map a trait to a specific chromosomal locus where
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