Interplay between Mitochondrial DNA Haplogroups, Mitochondrial Function, Oxidative Stress, and Hypertension

National Institute On Aging

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Abstract

Thus far, there are few studies that examine the contribution of mtDNA haplogroup to differences in risk factors for age-related health disparities such as in hypertension. The Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study examines the interaction of race and socioeconomic status on the development of age-associated health disparities among middle-aged AAs and whites residing in Baltimore City. It is possible that population differences in haplogroups could contribute to disparities in mitochondrial function and oxidative stress, and thus contribute to hypertension health disparities. Therefore, we hypothesize that mtDNA haplogroups will influence the presence of age-associated health disparities in hypertension among AAs and whites in the HANDLS cohort and will correlate with mitochondrial health and function. We also predict that mitochondrial health and function will be further influenced by poverty status and other social determinates of health. Establishing whether mtDNA haplogroups influence mitochondrial function and hypertension will contribute to the understanding of population disparities in age-related diseases, and thus this proposal is highly aligned with the NIA mission. Preliminary Results: Previously, we reported racial differences in the transcriptome of HANDLS participants with or without hypertension. Interestingly, in these hypertensive and normotensive women there were significant differential expression in hypertension and inflammation-related mRNAs. In a follow up study of this cohort of women, we found that there were higher levels of the DNA damage sensor protein poly-(ADP-ribose) polymerase 1 (PARP1) in AA women with hypertension compared to normotensive AA women. PARP1 levels were also higher in AA women with hypertension compared to white hypertensive women. Since PARP1 is involved in oxidative stress, these data suggest that differential PARP1 expression might play a role in hypertension-related health disparities. These data indicate that there is differential gene expression by hypertension and race in HANDLS participants, which may influence oxidative stress levels. Importantly, recent research suggests that mtDNA haplogroup can affect both mitochondrial function, transcription of mitochondrial genes, and also nuclear gene expression. However, most studies are performed in immortalized cell lines, especially artificially created cybrid lines. Few studies investigate the changes in mitochondrial function or damage in cells from community-dwelling individuals. In addition, few studies have examined whether hypertension is correlated with a specific mtDNA haplogroup in a racially diverse cohort. Examining the relationship between mtDNA haplogroups, hypertension, and differences in mitochondrial function and oxidative damage will lead to a greater understanding of mitochondrial connection in aging and age-related health disparities. Our specific aims for this project will include: Aim 1: SNP haplotyping of HANDLS cohort of hypertensive participants, Aim 2: Examine the impact of haplogroup on mitochondrial function and oxidative damage in a hypertension subset within the context of race and selected social determinants of health and Aim 3: Examine the impact of haplogroup on oxidative damage to nuclear DNA in a hypertension subset within the context of race and selected social determinants of health.