DOI

10.17077/etd.dzp4-dg3x

Document Type

Dissertation

Date of Degree

Fall 2015

Degree Name

PhD (Doctor of Philosophy)

Degree In

Epidemiology

First Advisor

Lynch, Charles F

First Committee Member

Burns, Trudy L

Second Committee Member

Wallace, Robert

Third Committee Member

Smith, Brian J

Fourth Committee Member

Domann, Frederick E

Abstract

Reactive oxygen species are formed internally through cellular metabolism and through external sources including radiation and pollutants. They play an important role in physiologic functions; however, when reactive oxygen species exceed our body’s antioxidant defense system, oxidative stress can occur. Oxidative stress has been implicated in aging and aging-related diseases including cancer and cardiovascular disease. Numerous oxidative stress genes produce antioxidative enzymes to mitigate the effects of reactive oxygen species. Single nucleotide polymorphisms within these genes may impact the functionality of antioxidant enzymes produced leaving the body more susceptible to damage from oxidative stress.

The Iowa 65+ Rural Health Study was one of the four study populations in the Established Population for Epidemiologic Studies of the Elderly (EPESE) project initiated by the intramural Epidemiology, Demography and Biometry Program of the National Institute on Aging in 1980. The Iowa cohort was comprised of Iowa county and Washington county residents aged 65 and older at the time of the baseline interview in 1982. Participants completed three in-person interviews and five telephone interviews over eight years which collected data on habits, lifestyle and disease. During the

in-person Year 06 interview participants were asked to donate a blood sample. The DNA extracted from the samples was used in each of the three aims of this project.

The first aim evaluated single nucleotide polymorphisms in selected oxidative stress genes and their association with lifespan while controlling for aging-associated risk factors such as body mass index, comorbidity, alcohol consumption, smoking, and physical activity. Multivariable linear regression models were fit in the framework of the co-dominant genetic model. The oxidative stress genes selected for this project included the sirtuin family of genes (SIRT1-7), two of the forkhead box genes (FOXO1 and FOXO3), superoxide dismutase 2 and 3 (SOD2 and SOD3), glutathione peroxidase (GPX1), AKT, TP53, and CAMK4. A model was fitted with the risk factors before assessing the impact of each single nucleotide polymorphism. The q-value was used to control for the multiple hypothesis tests. Significant associations were detected between human lifespan and SNPs in genes SIRT3, SIRT5, SIRT6, FOXO3, and SOD3; gender modified the effect of SNPs in SIRT3, SIRT5, and AKT1.

The second aim of this project evaluated single nucleotide polymorphisms in selected oxidative stress genes and their association with blood pressure measures while controlling for known risk factors including body mass index, alcohol consumption, smoking, and physical activity. Blood pressure was measured at the baseline and Year 06 interviews. Systolic pressure and diastolic pressure were used to calculate mean arterial pressure and pulse pressure at baseline and Year 06. Multivariable linear regression was used within the co-dominant genetic framework to determine if single nucleotide polymorphisms in SIRT1-7, FOXO1, FOXO3, SOD2-3, GPX1, AKT, TP53, and CAMK4 were associated with systolic, diastolic, mean arterial, or pulse pressure at baseline or Year 06. To examine longitudinal effects, the difference between each measure (i.e., Year 06 systolic – baseline systolic) was calculated for each individual and used to evaluate if any of the single polymorphisms was associated with change in blood pressure measures over time. Significant associations were detected between SIRT1 and SIRT3 and for males in SIRT1 and various blood pressure measures for females. Gender modified the effect of SIRT1, SIRT3, SIRT6, and FOXO1 variants.

The third aim of this project evaluated if these genetic variants were associated with incident stroke while controlling for known risk factors including blood pressure, diabetes, body mass index, alcohol consumption, smoking, and physical activity. Multivariable logistic regression within the framework of the co-dominant genetic model was used. Individuals with the GPX1 genotype TT had 2.76 times the risk of an incident stroke compared to the CC genotype.

This project identified several associations between single nucleotide polymorphisms within oxidative stress genes and lifespan, blood pressure measures, and incident stroke. Gender modified the association of several single nucleotide polymorphisms and lifespan as well as blood pressure measures. These results suggest genetic variation within oxidative stress genes may play a role in aging, blood pressure and incident stroke.

Keywords

Oxidative stress, Reactive oxygen species, Single nucleotide polymorphisms, Sirtuin family of genes

Pages

xii, 196 pages

Bibliography

Includes bibliographical references (pages 114-130).

Copyright

Copyright © 2015 Mindi Joy TenNapel

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