Genetic risk factors for vascular aging: molecular mechanisms, polymorphism of candidate genes and gene networks

(1) Background: There are no successive treatments for heart failure with preserved ejection fraction (HFpEF) because of complex interactions between environmental, histological, and genetic risk factors. The objective of the study is to investigate changes in cardiomyocytes and molecular networks associated with HFpEF. (2) Methods: Dahl salt-sensitive (DSS) rats developed HFpEF when fed with a high-salt (HS) diet for 7 weeks, which was confirmed by in vivo and ex vivo measurements. Shotgun proteomics, microarray, Western blot, and quantitative RT-PCR analyses were further carried out to investigate cellular and molecular mechanisms. (3) Results: Rats with HFpEF showed diastolic dysfunction, impaired systolic function, and prolonged repolarization of myocytes, owing to an increase in cell size and apoptosis of myocytes. Heatmap of multi-omics further showed significant differences between rats with HFpEF and controls. Gene Set Enrichment Analysis (GSEA) of multi-omics revealed genetic risk factors involved in cardiac muscle contraction, proteasome, B cell receptor signaling, and p53 signaling pathway. Gene Ontology (GO) analysis of multi-omics showed the inflammatory response and mitochondrial fission as top biological processes that may deteriorate myocyte stiffening. GO analysis of protein-to-protein network indicated cytoskeleton protein, cell fraction, enzyme binding, and ATP binding as the top enriched molecular functions. Western blot validated upregulated Mff and Itga9 and downregulated Map1lc3a in the HS group, which likely contributed to accumulation of aberrant mitochondria to increase ROS and elevation of myocyte stiffness, and subsequent contractile dysfunction and myocardial apoptosis. (4) Conclusions: Multi-omics analysis revealed multiple pathways associated with HFpEF. This study shows insight into molecular mechanisms for the development of HFpEF and may provide potential targets for the treatment of HFpEF.

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Molecular mechanisms of the genetic risk factors in pathogenesis of Alzheimer disease

Frontiers in Bioscience ◽

10.2741/4480 ◽

2017 ◽

Vol 22 (1) ◽

pp. 180-192 ◽

Cited By ~ 6

Author(s):

Taisuke Tomita

Keyword(s):

Risk Factors ◽

Alzheimer Disease ◽

Genetic Risk ◽

Molecular Mechanisms ◽

Genetic Risk Factors

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Array-based multiplex analysis of candidate genes reveals two independent and additive genetic risk factors for myocardial infarction in the Finnish population

Human Molecular Genetics ◽

10.1093/hmg/7.9.1453 ◽

1998 ◽

Vol 7 (9) ◽

pp. 1453-1462 ◽

Cited By ~ 73

Author(s):

T Pastinen

Keyword(s):

Risk Factors ◽

Myocardial Infarction ◽

Candidate Genes ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Finnish Population ◽

Multiplex Analysis

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A genome-wide association study highlights a regulatory role for IFNG-AS1 contributing to cutaneous leishmaniasis in Brazil

10.1101/2020.01.13.903989 ◽

2020 ◽

Cited By ~ 1

Author(s):

Léa C. Castellucci ◽

Lucas Almeida ◽

Svetlana Cherlin ◽

Michaela Fakiola ◽

Edgar Carvalho ◽

...

Keyword(s):

Risk Factors ◽

Wound Healing ◽

Cutaneous Leishmaniasis ◽

Candidate Genes ◽

Genetic Risk ◽

Phase 1 ◽

Genetic Risk Factors ◽

Interferon Γ ◽

Phase 2 ◽

Genome Wide

AbstractBackgroundCutaneous leishmaniasis (CL) caused by Leishmania braziliensis remains an important public health problem in Brazil. The goal of this study was to identify genetic risk factors for CL.MethodsGenome-wide analysis was undertaken using DNAs from 956 CL cases and 868 controls (phase 1) and 1110 CL cases and 1178 controls (phase 2) genotyped using Illumina HumanCoreExome BeadChips. Imputation against 1000G data provided 4,498,586 quality-controlled single nucleotide variants (SNVs) common across phase 1 and phase 2 samples. Linear mixed models in FastLMM were used to take account of genetic diversity/ethnicity/admixture. Cellular cytokines were measured using flow cytometry.ResultsCombined analysis across cohorts found no associations that achieved genome-wide significance, commonly accepted as P<5×10-8. Support for variants at wound-healing genes previously studied as candidate genes for CL included SMAD2 (rs115582038/rs75753347; Pimputed_1000G=1.47×10-4). Top novel GWAS hits at P<5×10-5 in plausible candidate genes for CL included SERPINB10 (rs62097497;Pimputed_1000G=2.67×10-6), CRLF3 (rs75270613; Pimputed_1000G=5.12×10-6), STX7 (rs144488134;Pimputed_1000G=6.06×10-6), KRT80 (rs10783496 Pimputed_1000G=6.58×10-6), LAMP3 (rs74285558;Pimputed_1000G=6.54×10-6) and IFNG-AS1 (rs4913269;Pimputed_1000G=1.32×10-5). Of these, LAMP3 (Padjusted=9.25×10-12; +6-fold), STX7 (Padjusted=7.62×10-3; +1.3-fold) and CRLF3 (Padjusted=9.19×10-9; +1.97-fold) were all expressed more highly in CL biopsies compared to normal skin, whereas expression of KRT80 (Padjusted=3.07×10-8; −3-fold) was lower. Notably, the percent peripheral blood CD3+ T cells making interferon-γ in response to Leishmania antigen differed significantly by IFNG-AS1 genotype.ConclusionsIn addition to supporting variants in wound-healing genes as genetic risk factors for CL, our GWAS results provide important novel leads to understanding pathogenesis of CL including through the regulation of interferon-γ responses.

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Polymorphisms in candidate genes in patients with congestive heart failure (CHF) after childhood cancer: A Report from the Childhood Cancer Survivor Study (CCSS)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.9004 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 9004-9004 ◽

Cited By ~ 6

Author(s):

R. Aplenc ◽

J. Blanco ◽

W. Leisenring ◽

S. Davies ◽

M. Relling ◽

...

Keyword(s):

Oxidative Stress ◽

Risk Factors ◽

Cancer Survivors ◽

Childhood Cancer ◽

Candidate Genes ◽

Genetic Polymorphisms ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Smoking History

9004 Background: In cancer survivors, CHF associated with the use of anthracyclines is an important clinical complication. Risk factors for anthracycline associated cardiac toxicity, including cumulative dose, gender, and age, have been described. However, these risk factors do not fully explain the observed clinical variability. Notably, the potential role of genetic risk factors has not been studied. A recent “unifying hypothesis” postulates that the early cardiac damage is mediated mostly by oxidative stress while the more chronic type of toxicity is induced by anthracycline alcohol metabolites synthesized by carbonyl reductases (CBRs). Therefore we hypothesized that genetic polymorphisms in genes encoding for enzymes involved in oxidative stress pathways, and the metabolism of anthracyclines may impact on the risk of anthracycline-related cardiotoxicity. Methods: We conducted a nested case-control study within a cohort of 5,739 patients enrolled in the CCSS. Forty-seven cases with CHF and 195 matched controls (matched for demographics, follow-up and treatment) were genotyped for 10 genetic polymorphisms in 7 genes: catalase (CAT), GSTP, GSTT, GSTM, superoxide dismutase (SOD 1), NQO1, and CBR3. Results: In the subjects who received anthracyclines, multivariable analyses of CHF risk, adjusted for gender, smoking history, recurrence, and family history of heart disease, showed the GSTP +313A>G polymorphism was a significant risk factor, HR = 5.0, p = 0.01 for the A/G genotype vs. A/A; HR = 3.3, p = 0.19 for the G/G genotype vs. A/A. In addition, a suggested association between CBR3 V244M polymorphism and the risk of CHF after treatment with anthracyclines, HR=10.2, p=0.06 for G/G vs. A/A; HR = 4.0, p=0.18 for G/A vs. A/A was seen in an identical multivariable analysis. Conclusions: These data suggest that specific polymorphic genetic variants on a panel of candidate genes relevant to the anthracycline pharmacodynamics may modify the risk of CHF in childhood cancer survivors. Future studies to further refine the role of these novel genetic risk factors affecting a large population are warranted. No significant financial relationships to disclose.

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