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Digenic mutations on SCAP and AGXT2 predispose to premature myocardial infarction.

ABSTRACT: Genetic factors play a vital role in the pathogenesis of premature myocardial infarction (PMI). However, current studies explained only small amounts of genetic risk in MI. In this study, we started from a PMI pedigree with three MI patients occurred at the age of 43, 45 and 53 respectively. Sanger sequencing revealed 6 LDLR mutation carriers in the family, but only one was diagnosed with PMI, indicating that the LDLR mutation may not be the reason for PMI. Upon exome-sequencing and bioinformatics analysis, two variants in SCAP and AGXT2 were identified as potential causative mutation for PMI. Further observation revealed that only patients that meet the diagnosis of PMI harbored two variants meantime, while other MI patients or members with no MI carried no more than one of the variants. Screening of the two genes in an independent PMI population identified another variant on SCAP (c.1403 T>C, p.Val468Ala), which was absent in 28, 000 east-Asian population. Further, the two variants on SCAP and AGXT2 were introduced into H293T and EA. hy926 cell lines respectively utilizing CRISPR-Cas9. Functional study revealed that the SCAP mutation impaired SCAP-SREBP feedback mechanism which may lead to a "constitutive activation" effect of cholesterol synthesis related genes, while the AGXT2 mutation reduced its aminotransferase activity leading to a down-regulation of NO production by ADMA accumulation. This study indicates that SCAP and AGXT2 are potential causative genes for PMI. Digenic mutation carriers may manifest a more severe phenotype, namely premature MI.

SUBMITTER: Gao Y

PROVIDER: S-EPMC5725008 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Digenic mutations on <i>SCAP</i> and <i>AGXT2</i> predispose to premature myocardial infarction.

Gao Yuanfeng Y Lee Chongyou C Song Junxian J Li Sufang S Cui Yuxia Y Liu Yongzhen Y Wang Jie J Lu Fengmin F Chen Hong H

Oncotarget 20171024 59

Genetic factors play a vital role in the pathogenesis of premature myocardial infarction (PMI). However, current studies explained only small amounts of genetic risk in MI. In this study, we started from a PMI pedigree with three MI patients occurred at the age of 43, 45 and 53 respectively. Sanger sequencing revealed 6 LDLR mutation carriers in the family, but only one was diagnosed with PMI, indicating that the LDLR mutation may not be the reason for PMI. Upon exome-sequencing and bioinformati ...[more]

PMID: 29245966

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Project description:IntroductionPremature myocardial infarction (MI) generally refers to MI in men ≤55 years or women ≤65 years. Premature MI is a major contributor to cardiovascular disease (CVD), which claimed 17.6 million lives globally in 2016. Reducing premature MI and CVD is a key priority for all nations; however, there is sparse synthesis of information on risk factors associated with premature MI. To address this knowledge gap, we are conducting a systematic review to describe the association between risk factors (demographics, lifestyle factors and biomarkers) and premature MI.Methods and analysisThe following databases were searched from inception to June 2018: CENTRAL, CINAHL, Clinical Trials, EMBASE and MEDLINE. We will include original research articles (case-control, cohort and cross-sectional studies) that report a quantitative relationship between at least one risk factor and premature MI. Two investigators will use predetermined selection criteria and independently screen articles based on title and abstract (primary screening). Articles that meet selection criteria will undergo full-text screening based on criteria used for primary screening (secondary screening). Data will be extracted using predetermined data extraction forms. The Newcastle-Ottawa Scale for case-control and cohort studies will be used to evaluate the risk of bias and will be adapted for cross-sectional studies. Whenever feasible, data will be summarised into a random-effects meta-analysis.Ethics and disseminationTo our knowledge, this will be the first study to synthesise results on the relationship between risk factors and premature MI. These findings will inform healthcare providers on factors associated with risk of premature MI and potentially improve primary prevention efforts by guiding development of interventions. These findings will be summarised and presented at conferences and through publication in a peer-reviewed journal.Prospero registration numberCRD42018076862.

Project description:BACKGROUND:ENAM mutations cause autosomal dominant or recessive amelogenesis imperfecta (AI) and show a dose effect: enamel malformations are more severe or only penetrant when both ENAM alleles are defective. METHODS:Whole exome sequences of recruited AI probands were initially screened for mutations in known AI candidate genes. Sanger sequencing was used to confirm sequence variations and their segregation with the disease phenotype. The co-occurrence of ENAM and LAMA3 mutations in one family raised the possibility of digenic inheritance. Enamel formed in Enam+/+ Ambn+/+ , Enam+/- , Ambn+/- , and Enam+/- Ambn+/- mice was characterized by dissection and backscattered scanning electron microscopy (bSEM). RESULTS:ENAM mutations segregating with AI in five families were identified. Two novel ENAM frameshift mutations were identified. A single-nucleotide duplication (c.395dupA/p.Pro133Alafs*13) replaced amino acids 133-1142 with a 12 amino acid (ATTKAAFEAAIT*) sequence, and a single-nucleotide deletion (c.2763delT/p.Asp921Glufs*32) replaced amino acids 921-1142 with 31 amino acids (ESSPQQASYQAKETAQRRGKAKTLLEMMCPR*). Three families were heterozygous for a previously reported single-nucleotide ENAM deletion (c.588+1delG/p.Asn197Ilefs*81). One of these families also harbored a heterozygous LAMA3 mutation (c.1559G>A/p.Cys520Tyr) that cosegregated with both the AI phenotype and the ENAM mutation. In mice, Ambn+/- maxillary incisors were normal. Ambn+/- molars were also normal, except for minor surface roughness. Ambn+/- mandibular incisors were sometimes chalky and showed minor chipping. Enam+/- incisor enamel was thinner than normal with ectopic mineral deposited laterally. Enam+/- molars were sometimes chalky and rough surfaced. Enam+/- Ambn+/- enamel was thin and rough, in part due to ectopic mineralization, but also underwent accelerated attrition. CONCLUSION:Novel ENAM mutations causing AI were identified, raising to 22 the number of ENAM variations known to cause AI. The severity of the enamel phenotype in Enam+/- Ambn+/- double heterozygous mice is caused by composite digenic effects. Digenic inheritance should be explored as a cause of AI in humans.

Project description:IntroductionAdvancing understanding of key factors that determine the magnitude of the hemostatic response may facilitate the identification of individuals at risk of generating an occlusive thrombus as a result of an atherothrombotic event such as an acute Myocardial Infarction (MI). While fibrinogen levels are a recognized risk factor for MI, the association of thrombotic risk with other coagulation proteins is inconsistent. This is likely due to the complex balance of pro- and anticoagulant factors in any individual.MethodsWe compared measured levels of pro- and anticoagulant proteins in plasma from 162 patients who suffered an MI at an early age (MI <50 y) and 186 age- and gender-matched healthy controls with no history of CAD. We then used the measurements from these individuals as inputs for an established mathematical model to investigate how small variations in hemostatic factors affect the overall amplitude of the hemostatic response and to identify differential key drivers of the hemostatic response in male and female patients and controls.ResultsPlasma from the MI patients contained significantly higher levels of Tissue Factor (P = 0.007), the components of the tenase (FIX and FVIII; P < 0.0001 for both) and the prothrombinase complexes (FX; P = 0.003), and lower levels of Tissue Factor Pathway Inhibitor (TFPI; P = 0.033) than controls. The mathematical model, which generates time-dependent predictions describing the depletion, activation, and interaction of the main procoagulant factors and inhibitors, identified different patterns of hemostatic response between MI patients and controls, and additionally, between males and females. Whereas, in males, TF, FVIII, FIX, and the inhibitor TFPI contribute to the differences seen between case and controls, and in females, FII, FVIII, and FIX had the greatest influence on the generation of thrombin. We additionally show that further donor stratification may be possible according to the predicted donor response to anticoagulant therapy.ConclusionsWe suggest that modeling could be of value in enhancing our prediction of risk of premature MI, recurrent risk, and therapeutic efficacy.

Project description:BackgroundPreclinical data suggest that an acute inflammatory response following myocardial infarction (MI) accelerates systemic atherosclerosis. Using combined positron emission and computed tomography, we investigated whether this phenomenon occurs in humans.Methods and resultsOverall, 40 patients with MI and 40 with stable angina underwent thoracic 18F-fluorodeoxyglucose combined positron emission and computed tomography scan. Radiotracer uptake was measured in aortic atheroma and nonvascular tissue (paraspinal muscle). In 1003 patients enrolled in the Global Registry of Acute Coronary Events, we assessed whether infarct size predicted early (≤30 days) and late (>30 days) recurrent coronary events. Compared with patients with stable angina, patients with MI had higher aortic 18F-fluorodeoxyglucose uptake (tissue-to-background ratio 2.15±0.30 versus 1.84±0.18, P<0.0001) and plasma C-reactive protein concentrations (6.50 [2.00 to 12.75] versus 2.00 [0.50 to 4.00] mg/dL, P=0.0005) despite having similar aortic (P=0.12) and less coronary (P=0.006) atherosclerotic burden and similar paraspinal muscular 18F-fluorodeoxyglucose uptake (P=0.52). Patients with ST-segment elevation MI had larger infarcts (peak plasma troponin 32 300 [10 200 to >50 000] versus 3800 [1000 to 9200] ng/L, P<0.0001) and greater aortic 18F-fluorodeoxyglucose uptake (2.24±0.32 versus 2.02±0.21, P=0.03) than those with non-ST-segment elevation MI. Peak plasma troponin concentrations correlated with aortic 18F-fluorodeoxyglucose uptake (r=0.43, P=0.01) and, on multivariate analysis, independently predicted early (tertile 3 versus tertile 1: relative risk 4.40 [95% CI 1.90 to 10.19], P=0.001), but not late, recurrent MI.ConclusionsThe presence and extent of MI is associated with increased aortic atherosclerotic inflammation and early recurrent MI. This finding supports the hypothesis that acute MI exacerbates systemic atherosclerotic inflammation and remote plaque destabilization: MI begets MI.Clinical trial registrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT01749254.

Project description:ObjectiveTo evaluate the magnitude of the association between risk factors and premature myocardial infarction (MI) (men aged 18-55 years; women aged 18-65 years).Patients and methodsWe searched MEDLINE and other databases from inception through April 30, 2020, as well as bibliography of articles selected for data extraction. We selected observational studies reporting the magnitude of the association of at least 1 risk factor (demographic characteristics, lifestyle factors, clinical risk factors, or biomarkers) with premature MI and a control group. Pooled risk estimates (random effects) from all studies unadjusted and adjusted for risk factors were reported as summary odds ratios (ORs) with 95% CIs.ResultsFrom 35,320 articles of 12.7 million participants, we extracted data on 19 risk factors from 77 studies across 58 countries. Men had a higher risk of premature MI (OR, 2.39; 95% CI, 1.71 to 3.35) than did women. Family history of cardiac disease was associated with a higher risk of premature MI (OR, 2.67; 95% CI, 2.29 to 3.27). Major modifiable risk factors associated with higher risk were current smoking (OR, 4.34; 95% CI, 3.68 to 5.12 vs no/former), diabetes mellitus (OR, 3.54; 95% CI, 2.69 to 4.65), dyslipidemia (OR, 2.94; 95% CI, 1.76 to 4.91), and hypertension (OR, 2.85; 95% CI, 2.48 to 3.27). Higher body mass index carried higher risk (OR, 1.46; 95% CI, 1.24 to 1.71 for ≥25 kg/m2 vs <25 kg/m2). Biomarkers associated with 2- to 3-fold higher risk were total cholesterol levels greater than 200 mg/dL, triglyceride levels higher than 150 mg/dL, and high-density lipoprotein cholesterol levels less than 60 mg/dL (to convert to mmol/L, multiply by 0.0259).ConclusionMajor risk factors for premature MI are mostly amenable to patient, population, and policy level interventions. Mild elevations in body mass index and triglyceride levels were associated with higher risk, which has implications for the growing worldwide epidemic of cardiometabolic diseases.

Project description:Background Evaluating premature (<65 years of age) mortality because of acute myocardial infarction (AMI) by demographic and regional characteristics may inform public health interventions. Methods and Results We used the Centers for Disease Control and Prevention's WONDER (Wide-Ranging Online Data for Epidemiologic Research) death certificate database to examine premature (<65 years of age) age-adjusted AMI mortality rates per 100 000 and average annual percentage change from 1999 to 2019. Overall, the age-adjusted AMI mortality rate was 13.4 (95% CI, 13.3-13.5). Middle-aged adults, men, non-Hispanic Black adults, and rural counties had higher mortality than young adults, women, NH White adults, and urban counties, respectively. Between 1999 and 2019, the age-adjusted AMI mortality rate decreased at an average annual percentage change of -3.4 per year (95% CI, -3.6 to -3.3), with the average annual percentage change showing higher decline in age-adjusted AMI mortality rates among large (-4.2 per year [95% CI, -4.4 to -4.0]), and medium/small metros (-3.3 per year [95% CI, -3.5 to -3.1]) than rural counties (-2.4 per year [95% CI, -2.8 to -1.9]). Age-adjusted AMI mortality rates >90th percentile were distributed in the Southern states, and those with mortality <10th percentile were clustered in the Western and Northeastern states. After an initial decline between 1999 and 2011 (-4.3 per year [95% CI, -4.6 to -4.1]), the average annual percentage change showed deceleration in mortality since 2011 (-2.1 per year [95% CI, -2.4 to -1.8]). These trends were consistent across both sexes, all ethnicities and races, and urban/rural counties. Conclusions During the past 20 years, decline in premature AMI mortality has slowed down in the United States since 2011, with considerable heterogeneity across demographic groups, states, and urbanicity. Systemic efforts are mandated to address cardiovascular health disparities and outcomes among nonelderly adults.

Dataset Information

Digenic mutations on SCAP and AGXT2 predispose to premature myocardial infarction.

Publications

Digenic mutations on <i>SCAP</i> and <i>AGXT2</i> predispose to premature myocardial infarction.

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