Dataset Information

FN3K expression in COPD: a potential comorbidity factor for cardiovascular disease.

ABSTRACT:

Introduction

Cigarette smoking and oxidative stress are common risk factors for the multi-morbidities associated with chronic obstructive pulmonary disease (COPD). Elevated levels of advanced glycation endproducts (AGE) increase the risk of cardiovascular disease (CVD) comorbidity and mortality. The enzyme fructosamine-3-kinase (FN3K) reduces this risk by lowering AGE levels.

Methods

The distribution and expression of FN3K protein in lung tissues from stable COPD and control subjects, as well as an animal model of COPD, was assessed by immunohistochemistry. Serum FN3K protein and AGE levels were assessed by ELISA in patients with COPD exacerbations receiving metformin. Genetic variants within the FN3K and FN3K-RP genes were evaluated for associations with cardiorespiratory function in the Subpopulations and Intermediate Outcome Measures in COPD Study cohort.

Results

This pilot study demonstrates that FN3K expression in the blood and human lung epithelium is distributed at either high or low levels irrespective of disease status. The percentage of lung epithelial cells expressing FN3K was higher in control smokers with normal lung function, but this induction was not observed in COPD patients nor in a smoking model of COPD. The top five nominal FN3K polymorphisms with possible association to decreased cardiorespiratory function (p<0.008-0.02), all failed to reach the threshold (p<0.0028) to be considered highly significant following multi-comparison analysis. Metformin enhanced systemic levels of FN3K in COPD subjects independent of their high-expression or low-expression status.

Discussion

The data highlight that low and high FN3K expressors exist within our study cohort and metformin induces FN3K levels, highlighting a potential mechanism to reduce the risk of CVD comorbidity and mortality.

SUBMITTER: Alderawi A

PROVIDER: S-EPMC7677354 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Publications

FN3K expression in COPD: a potential comorbidity factor for cardiovascular disease.

Alderawi Amr A Caramori Gaetano G Baker Emma H EH Hitchings Andrew William AW Rahman Irfan I Rossios Christos C Adcock Ian I Cassolari Paolo P Papi Alberto A Ortega Victor E VE Curtis Jeffrey L JL Dunmore Simon S Kirkham Paul P

BMJ open respiratory research 20201101 1

<h4>Introduction</h4>Cigarette smoking and oxidative stress are common risk factors for the multi-morbidities associated with chronic obstructive pulmonary disease (COPD). Elevated levels of advanced glycation endproducts (AGE) increase the risk of cardiovascular disease (CVD) comorbidity and mortality. The enzyme fructosamine-3-kinase (FN3K) reduces this risk by lowering AGE levels.<h4>Methods</h4>The distribution and expression of FN3K protein in lung tissues from stable COPD and control subje ...[more]

PMID: 33208304

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Project description:Background: Cardiovascular diseases are the leading causes of mortality worldwide. One reason behind this lethality lies in the fact that often cardiovascular illnesses develop into systemic failure due to the multiple connections to organismal metabolism. This in turn is associated with co-morbidities and multimorbidity. The prevalence of coexisting diseases and the relationship between the molecular origins adds to the complexity of the management of cardiovascular diseases and thus requires a profound knowledge of the genetic interaction of diseases. Objective: In order to develop a deeper understanding of this phenomenon, we examined the patterns of comorbidity as well as their genetic interaction of the diseases (or the lack of evidence of it) in a large set of cases diagnosed with cardiovascular conditions at the national reference hospital for cardiovascular diseases in Mexico. Methods: We performed a cross-sectional study of the National Institute of Cardiology. Socioeconomic information, principal diagnosis that led to the hospitalization and other conditions identified by an ICD-10 code were obtained for 34,099 discharged cases. With this information a cardiovascular comorbidity networks were built both for the full database and for ten 10-years age brackets. The associated cardiovascular comorbidities modules were found. Data mining was performed in the comprehensive ClinVar database with the disease names (as extracted from ICD-10 codes) to establish (when possible) connections between the genetic associations of the genetic interaction of diseases. The rationale is that some comorbidities may have a stronger genetic origin, whereas for others, the environment and other factors may be stronger. Results: We found that comorbidity networks are highly centralized in prevalent diseases, such as cardiac arrhythmias, heart failure, chronic kidney disease, hypertension, and ischemic diseases. Said comorbidity networks are actually modular on their connectivity. Modules recapitulate physiopathological commonalities, e.g., ischemic diseases clustering together. This is also the case of chronic systemic diseases, of congenital malformations and others. The genetic and environmental commonalities behind some of the relations in these modules were also found by resorting to clinical genetics databases and functional pathway enrichment studies. Conclusions: This methodology, hence may allow the clinician to look up for non-evident comorbidities whose knowledge will lead to improve therapeutically designs. By continued and consistent analysis of these types of patterns, we envisaged that it may be possible to acquire, strong clinical and basic insights that may further our advance toward a better understanding of cardiovascular diseases as a whole. Hopefully these may in turn lead to further development of better, integrated therapeutic strategies.

Project description:Comorbidity or a combination of several diseases in the same individual is a common and widely investigated phenomenon. However, the genetic background for non-random disease combinations is not fully understood. Modern technologies and approaches to genomic data analysis enable the investigation of the genetic profile of patients burdened with several diseases (polypathia, disease conglomerates) and its comparison with the profiles of patients with single diseases. An association study featuring three groups of patients with various combinations of cardiovascular disorders and a control group of relatively healthy individuals was conducted. Patients were selected as follows: presence of only one disease, ischemic heart disease (IHD); a combination of two diseases, IHD and arterial hypertension (AH); and a combination of several diseases, including IHD, AH, type 2 diabetes mellitus (T2DM), and hypercholesterolemia (HC). Genotyping was performed using the "My Gene" genomic service (www.i-gene.ru). An analysis of 1,400 polymorphic genetic variants and their associations with the studied phenotypes are presented. A total of 14 polymorphic variants were associated with the phenotype "IHD only," including those in the APOB, CD226, NKX2-5, TLR2, DPP6, KLRB1, VDR, SCARB1, NEDD4L, and SREBF2 genes, and intragenic variants rs12487066, rs7807268, rs10896449, and rs944289. A total of 13 genetic markers were associated with the "IHD and AH" phenotype, including variants in the BTNL2, EGFR, CNTNAP2, SCARB1, and HNF1A genes, and intragenic polymorphisms rs801114, rs10499194, rs13207033, rs2398162, rs6501455, and rs1160312. A total of 14 genetic variants were associated with a combination of several diseases of cardiovascular continuum (CVC), including those in the TAS2R38, SEZ6L, APOA2, KLF7, CETP, ITGA4, RAD54B, LDLR, and MTAP genes, along with intragenic variants rs1333048, rs1333049, and rs6501455. One common genetic marker was identified for the "IHD only" and "IHD and AH" phenotypes: rs4765623 in the SCARB1 gene; two common genetic markers, rs663048 in SEZ6L and intragenic rs6501455, were identified for the "IHD and AH" phenotype and a combination of several diseases (syntropy); there were no common genetic markers for the "syntropy" and "IHD only" phenotypes. Classificatory analysis of the relationships between the associated genes and metabolic pathways revealed that lipid-metabolizing genes are involved in the development of all three CVC variants, whereas immunity-response genes are specific to the "IHD only" phenotype. The study demonstrated that comorbidity presents additional challenges in association studies of disease predisposition, since the genetic profile of combined forms of pathology can be markedly different from those for isolated "single" forms of a disease.

Dataset Information

FN3K expression in COPD: a potential comorbidity factor for cardiovascular disease.

Introduction

Methods

Results

Discussion

Publications

FN3K expression in COPD: a potential comorbidity factor for cardiovascular disease.

Similar Datasets

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