Levels of Angiotensin-Converting Enzyme and Apolipoproteins Are Associated with Alzheimer’s Disease and Cardiovascular Diseases

Chun, Xu; García, D. Muñoz; Lu, Yongke; Ozuna, Kaysie; Adjeroh, Donald A.; Wang, Kesheng; Neuroimaging, on behalf of The Alzheimer’s Disease

doi:10.3390/cells11010029

Cited by 13 publications

(7 citation statements)

References 59 publications

(74 reference statements)

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“…We found rs7412-T is significantly associated with lower Apolipoprotein B (apoB), Lipoprotein A, LDL, total cholesterol, and lower risk of lipoprotein metabolism disorder (ICD10: E78) across ancestries with concordant effects. This is consistent with published evidence of rs7412-T association with lipid biomarkers in Europeans, Africans, Asians, and Hispanics 28–36 ; lower apoB has been linked to reduced AD risk, with causality to be confirmed 32,37–43 . As expected, rs429358-C, is associated with higher risk of dementia and cognitive disorders (F01-F09), intracranial hemorrhage and cerebrovascular disease (ICD10: I60-I69).…”

Section: Resultssupporting

confidence: 91%

Whole-genome sequencing of half-a-million UK Biobank participants

Li,

Carss,

Halldorsson

et al. 2023

Preprint

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Summary ParagraphWhole-genome sequencing (WGS) provides a comprehensive view of the genome, enabling detection of coding and non-coding genetic variation, and surveying complex regions which are difficult to genotype. Here, we report on whole-genome sequencing of 490,640 UK Biobank participants, building on previous genotyping1and whole-exome sequencing (WES) efforts2,3. This advance deepens our understanding of how genetics influences disease biology and further enhances the value of this open resource for the study of human biology and health. Coupling this dataset with rich phenotypic data, we surveyed within- and cross-ancestry genomic associations with health-related phenotypes and identified novel genetic and clinical insights. While most genome-wide significant associations with disease traits were primarily observed in Europeans, we also identified strong or novel signals in individuals of African and Asian ancestries. Deeper capture of exonic variation in both coding and UTR sequences, strengthened and surfaced novel insights relative to WES analyses. This landmark dataset, representing the largest collection of WGS and available to the UK Biobank research community, will enable advances into our understanding of the human genome, and facilitate the discovery of new diagnostics, therapeutics with higher efficacy and improved safety profile, and enable precision medicine strategies with the potential to improve global health.Abstract FigureGraphic summary.Framework of the WGS UKB study. This figure captures the flow of this manuscript. We start with the collection of patient samples by UK Biobank and followed by the strategy taken to perform WGS. We continue with quality control performed on GraphTyper and DRAGEN datasets, followed by variant calling of SNPs, in/dels, and structural variants (SV). Thereafter we defined the phenotypes (binary and quantitative) associated with SV, SNPs and at the gene level (rare variant analysis) and conclude with the definition of five ancestry groups and collective association effect as a cross-ancestry meta-analysis.

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Section: Resultssupporting

confidence: 91%

Whole-genome sequencing of half-a-million UK Biobank participants

Li,

Carss,

Halldorsson

et al. 2023

Preprint

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“…It is strongly recommended to promote future research to address these existing disparities and to gain a clearer understanding of the specific function of ACE in clearing amyloid-β. Such insights could potentially prove valuable in preventing the buildup of amyloid-β in the brain, which is a characteristic feature of conditions like AD [ 82 ] and CAA [ 83 ].…”

Section: Amyloid-β Clearance In the Brainmentioning

confidence: 99%

Advances in Amyloid-β Clearance in the Brain and Periphery: Implications for Neurodegenerative Diseases

Ullah,

Lee

2023

Exp Neurobiol

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This review examines the role of impaired amyloid-β clearance in the accumulation of amyloid-β in the brain and the periphery, which is closely associated with Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). The molecular mechanism underlying amyloid-β accumulation is largely unknown, but recent evidence suggests that impaired amyloid-β clearance plays a critical role in its accumulation. The review provides an overview of recent research and proposes strategies for efficient amyloid-β clearance in both the brain and periphery. The clearance of amyloid-β can occur through enzymatic or non-enzymatic pathways in the brain, including neuronal and glial cells, blood-brain barrier, interstitial fluid bulk flow, perivascular drainage, and cerebrospinal fluid absorption-mediated pathways. In the periphery, various mechanisms, including peripheral organs, immunomodulation/immune cells, enzymes, amyloid-β-binding proteins, and amyloid-β-binding cells, are involved in amyloid-β clearance. Although recent findings have shed light on amyloid-β clearance in both regions, opportunities remain in areas where limited data is available. Therefore, future strategies that enhance amyloid-β clearance in the brain and/or periphery, either through central or peripheral clearance approaches or in combination, are highly encouraged. These strategies will provide new insight into the disease pathogenesis at the molecular level and explore new targets for inhibiting amyloid-β deposition, which is central to the pathogenesis of sporadic AD (amyloid-β in parenchyma) and CAA (amyloid-β in blood vessels).

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“…A recent study reported reduced levels of apoA-II proteins (but not apoA-I) in patients with Alzheimer’s disease or mild cognitive impairment, as compared to normal cognitive individuals [ 136 ]. In addition, increased apoA-II was found in patients with endocrine-metabolic diseases, as compared to non-endocrine-metabolic diseases individuals, while no difference was found in apoA-II when patients with cardiovascular disease were compared with non-cardiovascular disease individuals [ 136 ].…”

Section: Role Of Apoa-ii In Various Pathologiesmentioning

confidence: 99%

Apolipoprotein A-II, a Player in Multiple Processes and Diseases

et al. 2022

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Apolipoprotein A-II (apoA-II) is the second most abundant apolipoprotein in high-density lipoprotein (HDL) particles, playing an important role in lipid metabolism. Human and murine apoA-II proteins have dissimilar properties, partially because human apoA-II is dimeric whereas the murine homolog is a monomer, suggesting that the role of apoA-II may be quite different in humans and mice. As a component of HDL, apoA-II influences lipid metabolism, being directly or indirectly involved in vascular diseases. Clinical and epidemiological studies resulted in conflicting findings regarding the proatherogenic or atheroprotective role of apoA-II. Human apoA-II deficiency has little influence on lipoprotein levels with no obvious clinical consequences, while murine apoA-II deficiency causes HDL deficit in mice. In humans, an increased plasma apoA-II concentration causes hypertriglyceridemia and lowers HDL levels. This dyslipidemia leads to glucose intolerance, and the ensuing high blood glucose enhances apoA-II transcription, generating a vicious circle that may cause type 2 diabetes (T2D). ApoA-II is also used as a biomarker in various diseases, such as pancreatic cancer. Herein, we provide a review of the most recent findings regarding the roles of apoA-II and its functions in various physiological processes and disease states, such as cardiovascular disease, cancer, amyloidosis, hepatitis, insulin resistance, obesity, and T2D.

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Levels of Angiotensin-Converting Enzyme and Apolipoproteins Are Associated with Alzheimer’s Disease and Cardiovascular Diseases

Cited by 13 publications

References 59 publications

Whole-genome sequencing of half-a-million UK Biobank participants

Whole-genome sequencing of half-a-million UK Biobank participants

Advances in Amyloid-β Clearance in the Brain and Periphery: Implications for Neurodegenerative Diseases

Apolipoprotein A-II, a Player in Multiple Processes and Diseases

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