A functional variant of the dimethylarginine dimethylaminohydrolase-2 gene is associated with myocardial infarction in type 2 diabetic patients

Mannino, Gaia Chiara; Pezzilli, Serena; Averta, Carolina; Fuoco, Anastasia; Spiga, Rosangela; Mancuso, Elettra; Fatta, Concetta Di; Perticone, Francesco; Prudente, Sabrina; Trischitta, Vincenzo; Andreozzi, Francesco; Sesti, Giorgio

doi:10.1186/s12933-019-0906-1

Cited by 8 publications

(9 citation statements)

References 38 publications

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“…Despite large-scale GWASs providing robust evidence for genetic variants influencing metabolic pathways and CVDs, [19][20][21][22][23][24] it is unclear whether genetic variants exist for CVD within the basis of individual chronic metabolic diseases. The aim of our study was to identify genetic variations associated with CVD among individuals with HTN, DM, and DL, respectively; for which we found varied meaningful loci for CVD.…”

Section: Discussionmentioning

confidence: 99%

Identification of susceptibility loci for cardiovascular disease in adults with hypertension, diabetes, and dyslipidemia

et al. 2021

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Background Hypertension (HTN), diabetes mellitus (DM), and dyslipidemia (DL) are well-known risk factors of cardiovascular disease (CVD), but not all patients develop CVDs. Studies have been limited investigating genetic risk of CVDs specific to individuals with metabolic diseases. This study aimed to identify disease-specific and/or common genetic loci associated with CVD susceptibility in chronic metabolic disease patients. Methods We conducted a genome-wide association study (GWAS) of a multiple case–control design with data from the City Cohort within Health EXAminees subcohort of the Korean Genome and Epidemiology Study (KoGES_HEXA). KoGES_HEXA is a population-based prospective cohort of 173,357 urban Korean adults that had health examinations at medical centers. 42,393 participants (16,309 HTN; 5,314 DM; 20,770 DL) were analyzed, and each metabolic disease group was divided into three CVD case-controls: coronary artery disease (CAD), ischemic stroke (IS), and cardio-cerebrovascular disease (CCD). GWASs were conducted for each case–control group with 7,975,321 imputed single nucleotide polymorphisms using the Phase 3 Asian panel from 1000 Genomes Project, by logistic regression and controlled for confounding variables. Genome-wide significant levels were implemented to identify important susceptibility loci. Results Totaling 42,393 individuals, this study included 16,309 HTN (mean age [SD], 57.28 [7.45]; 816 CAD, 398 IS, and 1,185 CCD cases), 5,314 DM (57.79 [7.39]; 361 CAD, 153 IS, and 497 CCD cases), and 20,770 DL patients (55.34 [7.63]; 768 CAD, 295 IS, and 1,039 CCD cases). Six genome-wide significant CVD risk loci were identified, with relatively large effect sizes: 1 locus in HTN (HTN-CAD: 17q25.3/CBX8-CBX4 [OR, 2.607; P = 6.37 × 10−9]), 2 in DM (DM-IS: 4q32.3/MARCH1-LINC01207 [OR, 5.587; P = 1.34 × 10−8], and DM-CCD: 17q25.3/RPTOR [OR, 3.511; P = 1.99 × 10−8]), and 3 in DL (DL-CAD: 9q22.2/UNQ6494-LOC101927847 [OR, 2.282; P = 7.78 × 10−9], DL-IS: 3p22.1/ULK4 [OR, 2.162; P = 2.97 × 10−8], and DL-CCD: 2p22.2/CYP1B1-CYP1B1-AS1 [OR, 2.027; P = 4.24 × 10−8]). Conclusions This study identified 6 susceptibility loci and positional candidate genes for CVDs in HTN, DM, and DL patients using an unprecedented study design. 1 locus (17q25.3) was commonly associated with CAD. These associations warrant validation in additional studies for potential therapeutic applications.

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Section: Discussionmentioning

confidence: 99%

Identification of susceptibility loci for cardiovascular disease in adults with hypertension, diabetes, and dyslipidemia

et al. 2021

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“…Hepatic IR was found to be an independent risk factor for GSD ( Biddinger et al, 2008 ; Chang et al, 2008 ); therefore, we infer that ADMA plays a promoting role in the process of gallstone development. ADMA is an endogenous inhibitor of nitric oxide (NO) synthetase, and endothelial dysfunction due to reduced bioavailability of nitric oxide (NO) is a risk factor for atherogenesis ( Qin et al, 2021 ), myocardial infarction ( Mannino et al, 2019 ), and chronic kidney disease ( Shah et al, 2021 ). At the same time, studies have shown that GB hypomotility plays a key role in gallbladder (GB) normal relaxation ( Chen et al, 1997 ; Swartz-Basile et al, 2000 ), while GB hypomotility is also a required factor for gallstone pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Changes and Correlations of the Intestinal Flora and Liver Metabolite Profiles in Mice With Gallstones

et al. 2021

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There is increasing appreciation for the roles of the gut-liver axis in liver and gall diseases. Specific gut microbes are associated with susceptibility to gallstone diseases, while the relationship between intestinal flora and liver metabolism in the formation of gallstones remains unclear. In this study, an experimental group of model mice was given a lithogenic diet, and a control group was given a normal diet. Both groups were fed for 8 weeks. Integrating 16S rRNA gene sequencing and non-targeted metabolomics to explore the impact of the lithogenic diet on intestinal flora and liver metabolism, Spearman correlation analysis reveals the network of relationships between the intestine and liver. Our findings showed that the gut microbiome and liver metabolome compositions of the test group were significantly changed compared with those of the normal group. Through our research, biomarkers of gallstones were identified at the phylum (5), class (5), order (5), family (7), and genus levels. We predicted the function of the differential flora. We analyzed the liver metabolism of mice with gallstones paired with their flora, and the results showed that there were 138 different metabolites between the two groups. The metabolic pathways enriched by these differential metabolites are highly consistent with the functions of the disordered flora. We focused on an analysis of the relationship between deoxycholic acid, asymmetric dimethylarginine, glucosamine, tauroursodeoxycholic acid, and the disordered flora. This provides a basis for the establishment of the intestine-liver axis in gallstone disease. This research provides a theoretical basis for the research and development of probiotics and prebiotics.

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“…Despite large-scale GWASs providing robust evidence for genetic variants in uencing metabolic pathways and CVDs, [18][19][20][21][22][23] it is unclear whether genetic variants exist for CVD within the basis of individual chronic metabolic diseases. The aim of our study was to identify genetic variations associated with CVD among individuals with HTN, DM, and DL, respectively; for which we found varied meaningful loci for CVD.…”

Section: Discussionmentioning

confidence: 99%

Identification of Susceptibility Loci for Cardiovascular Disease in Adults With Hypertension, Diabetes and Dyslipidemia 

Song

Choi

Kwon

et al. 2020

Preprint

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Background: Hypertension (HTN), diabetes mellitus (DM), and dyslipidemia (DL) are well-known risk factors of cardiovascular disease (CVD), but not all patients develop CVDs. Studies have been limited investigating genetic risk of CVDs specific to individuals with metabolic diseases. This study aimed to identify disease-specific and/or common genetic loci associated with CVD susceptibility in chronic metabolic disease patients.Methods: We conducted a genome-wide association study (GWAS) of a multiple case-control design with data from the City Cohort within Health EXAminees subcohort of the Korean Genome and Epidemiology Study (KoGES_HEXA). KoGES_HEXA is a population-based prospective cohort of 173,357 urban Korean adults that had health examinations at medical centers. 42,393 participants (16,309 HTN; 5,314 DM; 20,770 DL) were analyzed, and each metabolic disease group was divided into three CVD case-controls: coronary artery disease (CAD), ischemic stroke (IS), and cardio-cerebrovascular disease (CCD). GWASs were conducted for each case-control group with 7,975,321 imputed single nucleotide polymorphisms using Phase 1/2 Asian panels from 1000 Genomes Project, by logistic regression and controlled for confounding variables. Genome-wide significant levels were implemented to identify important susceptibility loci.Results: Totaling 42,393 individuals, this study included 16,309 HTN (mean age [SD], 57.28 [7.45]; 816 CAD, 398 IS, and 1,185 CCD cases), 5,314 DM (57.79 [7.39]; 361 CAD, 153 IS, and 497 CCD cases), and 20,770 DL patients (55.34 [7.63]; 768 CAD, 295 IS, and 1,039 CCD cases). Six genome-wide significant CVD risk loci were identified, with relatively large effect sizes: 1 locus in HTN (HTN-CAD: 17q25.3/CBX8-CBX4 [OR, 2.607; P = 6.37 × 10−9]), 2 in DM (DM-IS: 4q32.3/MARCH1-LINC01207 [OR, 5.587; P = 1.34 × 10−8], and DM-CCD: 17q25.3/RPTOR [OR, 3.511; P = 1.99 × 10−8]), and 3 in DL (DL-CAD: 9q22.2/UNQ6494-LOC101927847 [OR, 2.282; P = 7.78 × 10−9], DL-IS: 3p22.1/ULK4 [OR, 2.162; P = 2.97 × 10−8], and DL-CCD: 2p22.2/CYP1B1-CYP1B1-AS1 [OR, 2.027; P = 4.24 × 10−8]).Conclusions: This study identified 6 susceptibility loci and positional candidate genes for CVDs in HTN, DM, and DL patients using an unprecedented study design. 1 locus (17q25.3) was commonly associated with CAD. These associations warrant validation in additional studies for potential therapeutic applications.

show abstract

A functional variant of the dimethylarginine dimethylaminohydrolase-2 gene is associated with myocardial infarction in type 2 diabetic patients

Cited by 8 publications

References 38 publications

Identification of susceptibility loci for cardiovascular disease in adults with hypertension, diabetes, and dyslipidemia

Identification of susceptibility loci for cardiovascular disease in adults with hypertension, diabetes, and dyslipidemia

Changes and Correlations of the Intestinal Flora and Liver Metabolite Profiles in Mice With Gallstones

Identification of Susceptibility Loci for Cardiovascular Disease in Adults With Hypertension, Diabetes and Dyslipidemia

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A functional variant of the dimethylarginine dimethylaminohydrolase-2 gene is associated with myocardial infarction in type 2 diabetic patients

Cited by 8 publications

References 38 publications

Identification of susceptibility loci for cardiovascular disease in adults with hypertension, diabetes, and dyslipidemia

Identification of susceptibility loci for cardiovascular disease in adults with hypertension, diabetes, and dyslipidemia

Changes and Correlations of the Intestinal Flora and Liver Metabolite Profiles in Mice With Gallstones

Identification of Susceptibility Loci for Cardiovascular Disease in Adults With Hypertension, Diabetes and Dyslipidemia&nbsp;

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Identification of Susceptibility Loci for Cardiovascular Disease in Adults With Hypertension, Diabetes and Dyslipidemia