The <i>ENPP1</i> Q121 Variant Predicts Major Cardiovascular Events in High-Risk Individuals

Bacci, Simonetta; Rizza, Stefano; Prudente, Sabrina; Spoto, Belinda; Powers, Christine; Facciorusso, Antonio; Pacilli, Antonio; Lauro, Davide; Testa, Alessandra; Zhang, Xu Dong; Stolfo, Giuseppe Di; Mallamaci, Francesca; Tripepi, Giovanni; Xu, Rui; Mangiacotti, Davide; Aucella, Filippo; Lauro, Renato; Gervino, Ernest V.; Hauser, Thomas H.; Copetti, Massimiliano; Cosmo, Salvatore De; Pellegrini, Fabio; Zoccali, Carmine; Federici, Massimo; Doria, Alessandro; Trischitta, Vincenzo

doi:10.2337/db10-1300

Cited by 37 publications

(29 citation statements)

References 53 publications

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“…In obesity with diabetes, ENPP1 K121Q polymorphism is associated with elevated cardiovascular events (29), coronary artery calcification, and higher aortic stiffness in dialysis (30), though these findings have not been broadly replicated. We linked ENPP1 K121Q to modestly decreased ENPP1 enzymatic activity (6), but ENPP1 K121Q also can increase insulin resistance (31).…”

Section: Discussionmentioning

confidence: 99%

Mono-allelic and bi-allelic ENPP1 deficiency promote post-injury neointimal hyperplasia associated with increased C/EBP homologous protein expression

Serrano¹,

Yu²,

Terkeltaub³

2014

Atherosclerosis

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Objective Bi-allelic function-inactivating ENPP1 mutations cause artery media calcification (AMC) with associated severe myointimal hyperplasia in generalized arterial calcification of infancy (GACI), whereas mono-allelic ENPP1 deficiency is phenotypically normal. Here, we tested if ENPP1 deficiency promotes abnormal vascular smooth muscle cell (VSMC)-driven responses to injury, with or without calcification. The ER stress mediator C/EBP homologous protein (CHOP) affects neointimal hyperplasia and atherosclerosis, and has paradoxical effects on bone formation. Hence, we assessed relationships between ENPP1 and CHOP in VSMCs. Methods We studied ENPP1-deficient mice and control littermates subjected to left carotid artery ligation, and isolated and studied VSMCs from these and Chop−/− mice, or with CHOP siRNA treatment. Results Normal Enpp1−/+ mice, in addition to Enpp1−/− mice prior to AMC development, had accelerated neointimal hyperplasia in response to carotid artery ligation at 7-8 weeks age. Neointimal hyperplasia was Iinked with robust artery media CHOP expression in situ, but with marked AMC only in injured Enpp1−/− arteries. Cultured, ENPP1-deficient and CHOP-deficient VSMCs had increased migration and proliferation to PDGF. Cultured Chop−/− VSMCs demonstrated increased Pi donor-induced calcification. CHOP was significantly increased in Pi donor treated Enpp1−/− and Enpp1−/+ cultured VSMCs. CHOP siRNA treatment of Enpp1−/− VSMCs increased calcification, associated with elevated expression of tissue nonspecific alkaline phosphatase and the master osteoblastic transcription factor RUNX2. Conclusions Both mono-allelic and bi-allelic ENPP1 deficiency promote dysregulated VSMC function, with robust lesion CHOP expression and enhanced neointimal hyperplasia after injury in vivo, but marked post-injury calcification limited to Enpp1−/−mice. Intimal hyperplasia in GACI appears regulated by biologic effects of ENPP1 deficiency other than calcification, including ER stress. VSMC CHOP excess in ENPP1 deficiency may primarily function to limit VSMC calcification.

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Section: Discussionmentioning

confidence: 99%

Mono-allelic and bi-allelic ENPP1 deficiency promote post-injury neointimal hyperplasia associated with increased C/EBP homologous protein expression

Serrano¹,

Yu²,

Terkeltaub³

2014

Atherosclerosis

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“…Insulin resistance and cardiovascular pathology may share a common genetic background (Bacci et al, 2011). It is highly significant to view the trophic attributes of injury to the endothelium as source of the evolutionary traits of emerging atherosclerotic plaques; indeed, Insulin-like growth factor-1 stabilizes the atherosclerotic plaque by altering smooth muscle phenotype (von der Thusen et al, 2011).…”

Section: The Individual Smooth Muscle Cell/macrophagementioning

confidence: 99%

Parametric Determination of Hypoxic Ischemia in Evolution of Atherogenesis

Agius¹

2012

Atherogenesis

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“…It remains unclear whether the same genetic variants influence CVD burden in individuals with T2D. All CVD-associated SNPs in general populations do not associate with risk in individuals with T2D [8-11], and variants have been described that impact CVD risk only in the presence of diabetes [12,9] or whose effects are modified by factors such as glycemic control [13] and obesity [14] in diabetes patients. In an effort to gain further insight into the performance of GRS in patients with T2D, we tested a composite GRS of SNPs associated with CVD events and CVD risk factors.…”

mentioning

confidence: 99%

Analysis of a cardiovascular disease genetic risk score in the Diabetes Heart Study

et al. 2015

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Aims It remains unclear whether the high cardiovascular disease (CVD) burden in people with type 2 diabetes (T2D) is associated with genetic variants that contribute to CVD in general populations. Recent studies have examined genetic risk scores of single nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) for their cumulative contribution to CVD-related traits. Most analyses combined SNPs associated with a single phenotypic class, e.g. lipids. In the present analysis, we examined a more comprehensive risk score comprised of SNPs associated with a broad range of CVD risk phenotypes. Methods The composite risk score was analyzed for potential associations with subclinical CVD, self-reported CVD events, and mortality in 983 T2D-affected individuals of European descent from 466 Diabetes Heart Study (DHS) families. Genetic association was examined using marginal models with generalized estimating equations for subclinical CVD and prior CVD events and Cox proportional hazards models with sandwich-based variance estimation for mortality; analyses were adjusted for age and sex. Results An increase in genetic risk score was significantly associated with higher levels of coronary artery calcified plaque (p=1.23 × 10−4); however, no significant associations with self-reported myocardial infarction and CVD events and all-cause and CVD mortality were observed. Conclusions These results suggest that a genetic risk score of SNPs associated with CVD events and risk factors does not significantly account for CVD risk in the DHS, highlighting the limitations of applying current genetic markers for CVD in individuals with diabetes.

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The ENPP1 Q121 Variant Predicts Major Cardiovascular Events in High-Risk Individuals

Cited by 37 publications

References 53 publications

Mono-allelic and bi-allelic ENPP1 deficiency promote post-injury neointimal hyperplasia associated with increased C/EBP homologous protein expression

Mono-allelic and bi-allelic ENPP1 deficiency promote post-injury neointimal hyperplasia associated with increased C/EBP homologous protein expression

Parametric Determination of Hypoxic Ischemia in Evolution of Atherogenesis

Analysis of a cardiovascular disease genetic risk score in the Diabetes Heart Study

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