Biology subjects

Tsao, P. S.

Publications and source records attributed to Tsao, P. S..

9 recordsLinked to original sources

bioRxiv2026

Maternal E-cigarette Exposure Augments Murine Abdominal Aortic Aneurysm

Background: Smoking and family history are major risk factors for abdominal aortic aneurysm (AAA). Smoking and nicotine are modulators of DNA methylation, capable of causing heritable epigenetic alterations. Nicotine infusion and e-cigarette (e-cig) vaping augment murine AAA. We investigated the effects of murine maternal e-cig vaping on offspring experimental AAA, and impacts on transgenerational DNA methylation and accessibility. Methods: We performed perinatal e-cig nicotine vaping in two strains of adult female mice (ApoE-/- and C57BL/6J). Mice were mated to control males, and treated through gestation. A parallel group were instead sacrificed after treatment, for DNA analysis. Offspring were aged to adulthood, and AAAs were then induced by elastase (C57BL/6J) or angiotensin-II infusion (ApoE-/-), and ultrasound-tracked for 4 weeks. In a second cohort, parental and offspring aortic tissue and blood DNA underwent RRBS and ATAC-seq analysis respectively. Offspring abdominal aortic anatomy was examined, and stiffness was assessed with ex vivo arterial myography. Results: Maternal e-cig exposure increased offspring AAA growth in both models and genders. AAA incidence was increased in ApoE-/- males, and observed effects were overall more pronounced in males. Maternal vape exposure altered aortic DNA methylation and blood DNA accessibility in mothers and offspring, with differential sites in numerous genes identified, including AAA-related genes and pathways. Pathways were enriched for transcription factors, inflammation/immune-related genes, and angiogenesis genes, with similar changes identified in exposed mothers. Male offspring displayed more differential genes. Significant changes were located in genes known to harbor AAA risk loci in humans, and overlapped with published epigenetic alterations in human smokers. Differences also occurred in offspring aortic structure and stiffness. Conclusions: Maternal e-cig nicotine exposure augments AAA growth in multiple models across generations. These effects are accompanied by broad epigenetic DNA reprogramming of key AAA modulator genes and pathways.

genomics↗

bioRxiv2024

Mitochondrial Transplantation promotes protective effector and memory CD4+ T cell response during Mycobacterium tuberculosis infection and diminishes exhaustion and senescence in elderly CD4+ T cells

Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (M.tb), remains a significant health concern worldwide, especially in populations with weakened or compromised immune systems, such as the elderly. Proper adaptive immune function, particularly a CD4+ T cell response, is central to host immunity against M.tb. Chronic infections, such as M.tb, as well as aging promote T cell exhaustion and senescence, which can impair immune control and promote progression to TB disease. Mitochondrial dysfunction contributes to T cell dysfunction, both in aging and chronic infections and diseases. Mitochondrial perturbations can disrupt cellular metabolism, enhance oxidative stress, and impair T-cell signaling and effector functions. This study examined the impact of mitochondrial transplantation (mito-transfer) on CD4+ T cell differentiation and function using aged mouse models and human CD4+ T cells from elderly individuals. Our study revealed that mito-transfer in naive CD4+ T cells promoted the generation of protective effector and memory CD4+ T cells during M.tb infection in mice. Further, mito-transfer enhanced the function of elderly human T cells by increasing their mitochondrial mass and modulating cytokine production, which in turn reduced exhaustion and senescence cell markers. Our results suggest that mito-transfer could be a novel strategy to reestablish aged CD4+ T cell function, potentially improving immune responses in the elderly and chronic TB patients, with a broader implication for other diseases where mitochondrial dysfunction is linked to T cell exhaustion and senescence.

immunology↗

bioRxiv2022

Platelets modulate inflammation and matrix remodeling in abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a highly lethal disease with progressive dilatation of the abdominal aorta accompanied by degradation and remodelling of the vessel wall due to chronic inflammation. Platelets play an important role in cardiovascular diseases but their role in AAA is poorly understood. The present study revealed that platelets play a crucial role in promoting AAA through modulation of inflammation and degradation of the ECM. They are responsible for the up-regulation of SPP1 (osteopontin, OPN) gene expression in macrophages and aortic tissue, which triggers inflammation and remodeling but also platelet adhesion and migration into the abdominal aortic wall and the intraluminal thrombus (ILT). Further, enhanced platelet activation and pro-coagulant activity results in elevated gene expression of various cytokines, Mmp9 and Col1a1 in macrophages and Il-6 and Mmp9 in fibroblasts. Enhanced platelet activation and pro-coagulant activity was also detected in AAA patients. Further, we detected platelets and OPN in the vessel wall and in the ILT of patients who underwent open repair of AAA. Platelet depletion in experimental murine AAA reduced inflammation and ECM remodeling, with reduced elastin fragmentation and aortic diameter expansion. Of note, OPN co-localized with platelets, suggesting a potential role of OPN for the recruitment of platelets into the ILT and the aortic wall. In conclusion, our data strongly supports the potential relevance of anti-platelet therapy to reduce AAA progression and rupture in AAA patients. Translational perspectiveAbdominal aortic aneurysm (AAA) is a severe cardiovascular disease (CVD) with high mortality. Since the role of platelets is unclear, we explored platelet-mediated processes in the pathogenesis of AAA. Results from platelet depleted mice and patients with AAA revealed that platelets modulate inflammatory and stiffness-related gene expression of macrophages and fibroblasts. Further, platelets induce the release of osteopontin important for the recruitment of platelets to the aortic wall and to the intraluminal thrombus (ILT). Consequently, platelet depletion significantly reduced aneurysm growth. Thus, therapeutic targeting of platelet activation might be crucial for the treatment of patients to reduce AAA formation and progression.

molecular biology↗

bioRxiv2021

Effect sizes of causal variants for gene expression and complex traits differ between populations

Despite the growing number of genome-wide association studies (GWAS), it remains unclear to what extent gene-by-gene and gene-by-environment interactions influence complex traits in humans. The magnitude of genetic interactions in complex traits has been difficult to quantify because GWAS are generally underpowered to detect individual interactions of small effect. Here, we develop a method to test for genetic interactions that aggregates information across all trait-associated loci. Specifically, we test whether SNPs in regions of European ancestry shared between European American and admixed African American individuals have the same causal effect sizes. We hypothesize that in African Americans, the presence of genetic interactions will drive the causal effect sizes of SNPs in regions of European ancestry to be more similar to those of SNPs in regions of African ancestry. We apply our method to two traits: gene expression in 296 African Americans and 482 European Americans in the Multi-Ethnic Study of Atherosclerosis (MESA) and low-density lipoprotein cholesterol (LDL-C) in 74K African Americans and 296K European Americans in the Million Veteran Program (MVP). We find significant evidence for genetic interactions in our analysis of gene expression; for LDL-C, we observe a similar point estimate although this is not significant, likely due to lower statistical power. These results suggest that gene-by-gene or gene-by-environment interactions modify the effect sizes of causal variants in human complex traits.

genetics↗

bioRxiv2020

Measuring genetic variation in the multi-ethnic Million Veteran Program (MVP)

The Million Veteran Program (MVP), initiated by the Department of Veterans Affairs (VA), aims to collect consented biosamples from at least one million Veterans. Presently, blood samples have been collected from over 800,000 enrolled participants. The size and diversity of the MVP cohort, as well as the availability of extensive VA electronic health records make it a promising resource for precision medicine. MVP is conducting array-based genotyping to provide genome-wide scan of the entire cohort, in parallel with whole genome sequencing, methylation, and other omics assays. Here, we present the design and performance of MVP 1.0 custom Axiom(R) array, which was designed and developed as a single assay to be used across the multi-ethnic MVP cohort. A unified genetic quality control analysis was developed and conducted on an initial tranche of 485,856 individuals leading to a high-quality dataset of 459,777 unique individuals. 668,418 genetic markers passed quality control and showed high quality genotypes not only on common variants but also on rare variants. We confirmed the substantial ancestral diversity of MVP with nearly 30% non-European individuals, surpassing other large biobanks. We also demonstrated the quality of the MVP dataset by replicating established genetic associations with height in European Americans and African Americans ancestries. This current data set has been made available to approved MVP researchers for genome-wide association studies and other downstream analyses. Further data releases will be available for analysis as recruitment at the VA continues and the cohort expands both in size and diversity.

genetics↗

bioRxiv2019

Assessing a causal relationship between circulating lipids and breast cancer risk via Mendelian randomization

ObjectiveTo assess a potential causal relationship between genetic variants associated with plasma lipid traits (high-density lipoprotein cholesterol, HDL; low-density lipoprotein cholesterol, LDL; triglycerides, TG) with risk for breast cancer.\n\nDesignMendelian randomization (MR) study.\n\nSetting and ParticipantsData from genome-wide association studies in up to 215,551 subjects from the Million Veterans Project were used to construct genetic instruments for plasma lipid traits. The effect of these instruments on breast cancer risk was evaluated using genetic data from the BCAC consortium based on 122,977 breast cancer cases and 105,974 controls.\n\nExposuresGenetically modified plasma levels of LDL, HDL, or TG.\n\nMain Outcomes and MeasuresOdds ratio (OR) for breast cancer risk per standard-deviation increase in HDL, LDL, or TG.\n\nResultsWe observed that a 1-SD genetically determined increase in HDL levels is associated with an increased risk for all breast cancers (HDL: OR=1.08, 95% CI=1.04-1.13, P=7.4x10-5).\n\nMultivariable MR analysis, which adjusted for the effects of LDL, TG, body mass index, and age at menarche, corroborated this observation for HDL (OR=1.06, 95% CI=1.03-1.10, P=4.9x10-4) and also a relationship between LDL and breast cancer risk (OR=1.03, 95% CI=1.01-1.07, P=0.02). We did not observe a difference in these relationships when stratified by breast tumor estrogen receptor status. We repeated this analysis using genetic variants independent of the leading association at core HDL pathway genes and found that these variants were also associated with risk for breast cancers (OR=1.11, 95% CI=1.06-1.16, P=1.5x10-6), including gene-specific associations at ABCA1, APOE-APOC1-APOC4-APOC2 and CETP. In addition, we find evidence that genetic variation at the ABO locus affects both lipid levels and breast cancer.\n\nConclusionsGenetically elevated plasma HDL levels appear to increase breast cancer risk. Future studies are required to understand the mechanism underlying this putative causal relationship, with the goal to develop potential therapeutic strategies aimed at altering the HDL-mediated effect on breast cancer risk.

genomics↗

bioRxiv2019

Genome-wide Association Study of Alcohol Consumption and Use Disorder in Multiple Populations (N = 274,424)

Although alcohol consumption level and alcohol use disorder (AUD) diagnosis are both moderately heritable, their genetic risks and overlap are not well understood. We conducted genome-wide association studies of these traits using longitudinal Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) scores (reflecting alcohol consumption) and AUD diagnoses from electronic health records (EHRs) in a single, large multi-ancestry Million Veteran Program sample. Meta-analysis across population groups (N = 274,424) identified 18 genome-wide significant loci, 5 of which were associated with both traits and 13 with either AUDIT-C (N = 8) or AUD (N = 5). A significant genetic correlation between the traits reflects this overlap. However, downstream analyses revealed biologically meaningful points of divergence. Cell-type group partitioning heritability enrichment analyses indicated that central nervous system was the most significant cell type for AUDIT-C and the only significant cell type for AUD. Polygenic risk scores (PRS) for both traits were associated with alcohol-related disorders in two independent samples. Genetic correlations for 188 non-alcohol-related traits were significantly different for the two traits, as were the phenotypes associated with the traits polygenic risk scores. We conclude that EHR-derived, longitudinal, repeated measures of alcohol consumption level and AUD diagnosis can facilitate genetic discovery and help to elucidate the relationship between drinking level and AUD risk. Finally, although heavy drinking is a key risk factor for AUD, it is not a sufficient cause of the disorder.

genetics↗

bioRxiv2017

Genetic analysis of over one million people identifies 535 novel loci for blood pressure.

High blood pressure is the foremost heritable global risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits to date (systolic, diastolic, pulse pressure) in over one million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also reveal shared loci influencing lifestyle exposures. Our findings offer the potential for a precision medicine strategy for future cardiovascular disease prevention.

genetics↗

bioRxiv2017

GWAS of epigenetic ageing rates in blood reveals a critical role for TERT

DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9,907 individuals, we found gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in 3 loci associated extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggested causal influences of menarche and menopause on IEAA and lipid levels on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) locus at 5p15.33 confer higher IEAA (P<2.7x10-11). Causal modelling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the DNA methylation clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.

genetics↗