Next Generation Sequencing Assessment of Mitochondrial Oxidative DNA Damage in Cognitive Impairment: Shedding Light on Health Disparities in Mexican Americans

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2022-08
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Abstract

Currently, Alzheimer's Disease (AD) is listed as the 5th and 7th leading cause of death in the US aging (individuals 65+ years of age) and general population, respectively. The US aging population has been expanding over time and is projected to triple over the next two to three decades. As this demographic shift occurs, the impact of age-related diseases, including AD will increase. Due to differences in biology, behavior, socio-economic status and health care access, this impact will not be distributed evenly across racial and ethnic divides in the US population. Unfortunately, most scientific data exists for non-Hispanic Whites (NHWs). Although limited in scope, the observations that we have for admixed populations such as Hispanics clearly show that racial/ethnic disparities and etiologies for AD exist; however, the details of these disparities remain to be elucidated. Collaborative research efforts from the Texas Alzheimer's Research and Care Consortium (TARCC) aim to identify ethnicity-specific factors that influence the development and progression of AD among Mexican Americans (MAs) compared to their NHW counterparts, and to better understand the role these factors play. Common risk factors for developing cognitive impairment (CI) in the MA population are stroke, diabetes, obesity, and depression. Although the reasons for the association between cognitive decline and comorbidities remain unclear, the incidence of these comorbid conditions is known to vary greatly across race and ethnicity. Diabetes for example is three times more prevalent among MAs relative to NHWs. Accumulating evidence indicates a correlation between common pathological changes observed in AD and DNA damage, particularly within the mitochondrial genome (mtDNA), which is positioned to be particularly vulnerable to DNA damage. Age-associated decline in mitochondrial function generates an accumulation of reactive oxygen species that are capable of damaging essential biomolecules including DNA and may help explain some of the racial and ethnic differences in etiology that exist for AD. Many forms of oxidative DNA damage exist, but oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is one of the most prevalent lesions and an indicator of mitochondrial dysfunction. Damaged mtDNA, such as 8oxoG serve as important markers of age-related systemic inflammation and upon release into peripheral circulation may exacerbate the physiology and pathophysiology contributing to AD development and/or progression. Current methods for the detection of oxidized bases are limited, costly, cumbersome, and lack reproducibility. Here we describe the use of Illumina-based next-generation sequencing to quantify variants of oxidatively modified G residues in mtDNA of MA vs NHW TARCC participants. Our first study focused on investigating whether impaired mitochondrial function, represented by levels of oxidative DNA damage indicative of 8oxoG differed between MAs and NHWs. Additionally, we evaluated the effects of sex, CI, and type-2 diabetes (T2D) on risk for AD. We discovered variants representing 8oxoG from buffy coat were significantly higher in MAs compared to NHWs. Interestingly, MA females were especially affected, and years of education was significantly associated with 8oxoG load in MAs. We report suggestive evidence that 8oxoG mutational load is associated with cognitive impairment. Further, we identified individual mtDNA haplotypes that render an increased risk for oxidative DNA damage. Our second study used blood-based measurements of 8oxoG from both buffy coat and plasma to determine associations with population, sex, and T2D, for AD risk. We investigate genomic regions specially burdened by 8oxoG affecting mitochondrial function in relation to population and disease. Lastly, we characterize differences in 8oxoG mutational load between buffy coat and plasma portions of blood on assessing AD risk and endophenotype. Our results show that both buffy coat and plasma were significantly associated with population, sex, years of education, and suggest association with AD.

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