Genetic polymorphisms of eNOS (-786T/C, Intron 4b/4a &amp; 894G/T) and its association with asymptomatic first degree relatives of coronary heart disease patients

Kumar, G. Rajesh; Spurthi, Kondapalli Mrudula; Kumar, G. Kishore; Aiyengar, Tupurani Mohini; Padala, Chiranjeevi; Shyamala, Nivas; Cingeetham, Anuradha; Banapuram, Swathi; Sahu, Sushanta Kumar; Ali, Altaf; Rani, H. Surekha

doi:10.1016/j.niox.2016.09.001

Cited by 11 publications

(5 citation statements)

References 29 publications

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“…Haplotype differences between ethnicities may underlie disparities in susceptibility to a variety of diseases involving alterations in NO formation and could thus also explain ethnic differences in MIS-C incidence [ 93 ]. While the C-b-Asp haplotype may enhance eNOS expression and NO production, the C–4b–Glu haplotype is associated with lower NO formation in healthy Caucasian and African Americans, but also in CAD in patients and their first-degree relatives [ 98 – 100 ]. NOS3 haplotype-related variability in vasculoprotective NO bioavailability may consequently affect NLRP3 regulation and be the tipping point for MIS-C development (Fig.…”

Section: The No Genetic Pathway To Mis-cmentioning

confidence: 99%

“…The implicated risk haplotypes were overwhelmingly composed of variant alleles coding for RAAS hyperactivity and eNOS inhibition, confirmed by higher ACE activity and lower NO levels in plasma [ 144 ]. The C–4b–Glu haplotype associated with lower NO formation, together with relevant alleles of FGF23 and members of the RAAS, could be a causative haplotype in children with MIS-C (Table 3 ) [ 98 , 99 ]. Similar genetic cluster findings have been reported in SARS-CoV-2, thus haplotypes with the above effects, together with an age-dependent loss of EPO protection, might induce higher levels of NLRP3 and result in MIS-C in genetically susceptible children [ 107 ].…”

Section: Gene Clusters Predisposing For Mis-cmentioning

confidence: 99%

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A protective erythropoietin evolutionary landscape, NLRP3 inflammasome regulation, and multisystem inflammatory syndrome in children

Papadopoulos

Papadopoulou

2022

Human Cell

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The low incidence of pediatric severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and the associated multisystem inflammatory syndrome (MIS-C) lack a unifying pathophysiological explanation, impeding effective prevention and therapy. Activation of the NACHT, LRR, and PYD domains-containing protein (NLRP) 3 inflammasome in SARS-CoV-2 with perturbed regulation in MIS-C, has been reported. We posit that, early age physiological states and genetic determinants, such as certain polymorphisms of renin-angiotensin aldosterone system (RAAS) molecules, promote a controlled RAAS hyperactive state, and form an evolutionary landscape involving an age-dependent erythropoietin (EPO) elevation, mediating ancestral innate immune defenses that, through appropriate NLRP3 regulation, mitigate tissue injury and pathogen invasion. SARS-CoV-2-induced downregulation of angiotensin-converting enzyme (ACE)2 expression in endothelial cells (EC), impairment of endothelial nitric oxide (NO) synthase (eNOS) activity and downstream NO bioavailability, may promote a hyperactive RAAS with elevated angiotensin II and aldosterone that, can trigger, and accelerate NLRP3 inflammasome activation, while EPO-eNOS/NO abrogate it. Young age and a protective EPO evolutionary landscape may successfully inhibit SARS-CoV-2 and contain NLRP3 inflammasome activation. By contrast, increasing age and falling EPO levels, in genetically susceptible children with adverse genetic variants and co-morbidities, may lead to unopposed RAAS hyperactivity, NLRP3 inflammasome dysregulation, severe endotheliitis with pyroptotic cytokine storm, and development of autoantibodies, as already described in MIS-C. Our haplotype estimates, predicted from allele frequencies in population databases, are in concordance with MIS-C incidence reports in Europeans but indicate lower risks for Asians and African Americans. Targeted Mendelian approaches dissecting the influence of relevant genetic variants are needed.

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Section: The No Genetic Pathway To Mis-cmentioning

confidence: 99%

Section: Gene Clusters Predisposing For Mis-cmentioning

confidence: 99%

A protective erythropoietin evolutionary landscape, NLRP3 inflammasome regulation, and multisystem inflammatory syndrome in children

Papadopoulos

Papadopoulou

2022

Human Cell

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“…Определение маркеров эндотелиальной дисфункции при ИБС у жителей Астраханского региона установило преобладание 4b/4а генотипа данного гена среди обследованных с указанным заболеванием [16]. В исследовании Kumar GR (2016) аналогичные результаты: именно гетерозиготный генотип имел большую распространенность в группе пациентов с ИБС, чем в группе здоровых респондентов [17]. Наличие ассоциаций 4b/4а полиморфизма гена NOS3 с риском развития ИБС на примере африканской популяции подтвердил мета-анализ, проведенный Yang Y, еt al.…”

Section: Discussionunclassified

Associations of genetic markers of the sympathoadrenal system and endothelial dysfunction with coronary heart disease on the example of a small Shoriya population

et al. 2018

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Цель. Установить ассоциации полиморфизмов генов-кандидатов, кодирующих компоненты эндотелиальной (NOS3, MTHFR) и симпатоадреналовой систем (ADRB1, ADRА2B) с ишемической болезнью сердца (ИБС) в когорте малочисленной популяции Горной Шории. Материал и методы. Проведено клинико-эпидемиологическое исследование в районах Горной Шории (п. Ортон, п. Усть-Кабырза, п. Шерегеш, г. Таштагол). Анализ факторов риска включал: учет возраста, пола, показателя индекса массы тела, окружности талии, наличие/отсутствие артериальной гипертензии (АГ), курения, наличия нарушений липидного и углеводного обменов. Диагноз ИБС выставлялся на основании трех эпидемиологических критериев: кодирования электрокардиограммы по Миннесотскому коду, опросника Rose и инфаркта миокарда в анамнезе. Обследуемым проведено молекулярногенетическое тестирование. Выделение ДНК из крови проводилась методом фенол-хлороформной экстракции. Статистическая обработка проводилась с помощью программ "STATISTICA 6.1" (StatSoft Inc., США) и SNPStats. Результаты. Распространенность ИБС в когорте шорцев составила 9,7%. Результаты нашего исследования установили взаимосвязь генетических маркеров симпатоадреналовой и эндотелиальной систем с коронарным атеросклерозом в коренной малочисленной популяции шорцев. С высоким риском развития атеросклеротической болезни сердца ассоциировался генотип 4b/4a гена NOS3 (ОШ 2,57; 95% ДИ (1,12-5,86), р=0,026) по доминантному типу наследования. Установлена взаимосвязь генотипа Т/Т гена MTHFR c ИБС по рецессивному типу наследования (ОШ 13,28; 95% ДИ (1,79-98,40), р=0,024). Заключение. Благодаря генетическим исследованиям, появляется реальная возможность не только проводить точную молекулярную диагностику, но и определять предрасположенность человека к тому или иному заболеванию. Выявление генетической предрасположенности к ИБС, может быть проведено задолго до появления клинических симптомов, что позволяет эффективно предупреждать её развитие или отодвигать сроки манифестации.

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“…Firstly, only one polymorphism site was analyzed in the current study, and the interaction between G894T and other polymorphism sites in eNOS has not been investigated. Previous studies have indicated that additional polymorphism sites in eNOS, including rs2070744 T786C and eNOS4a/4b 27 bp variable number tandem repeat, may also be associated with CHD (22,36,37); therefore, whether the G894T polymorphism may lead to CHD via combined action with other polymorphism sites in eNOS requires further investigation. Additionally, the mechanism was analyzed by a bioinformatics tool and, although structural alterations were identified, the effect of these structural alterations on eNOS activity requires verification, which may illustrate the association between the G894T polymorphism and the risk of CHD more clearly.…”

Section: Discussionmentioning

confidence: 99%

The association between an endothelial nitric oxide synthase gene polymorphism and coronary heart disease in young people and the underlying mechanism

et al. 2017

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With the development of molecular biological technology, the association between genes and diseases has drawn increasing attention of researchers; the endothelial nitric oxide synthase (eNOS) gene has been reported to be a candidate gene for cardiovascular disease (CHD). The present study aimed to investigate the association between a polymorphism of eNOS and the risk of CHD in young people (≤40 years old), in addition to the underlying mechanism. A total of 234 cases of CHD in young individuals were collected as the CHD group and 228 cases of healthy individuals as the control group. Peripheral blood was collected and the genotype of the eNOS G894T polymorphism was identified by polymerase chain reaction-restriction fragment length polymorphism, the gene frequency was calculated and the distributions of genotype and allele frequency between the two groups were compared. Bioinformatics tools were employed to analyze the differences in the local protein structures of the eNOS G894T polymorphism and the biological mechanism was preliminary discussed. The results demonstrated that there were significant differences in the distribution of genotype frequency and allele frequency of the eNOS G894T gene polymorphism between the CHD group and control group (P<0.05). The risk of CHD in GT and TT genotypes were higher compared with the GG genotype (P<0.05). The G894T polymorphism led to Glu298Asp mutation of encoded protein, which is within the active site of eNOS, and partial structures of the protein were converted from random coil to α‑helix. In conclusion, the eNOS G894T gene polymorphism was associated with the occurrence and development of CHD in young people. The potential mechanism is that the G894T polymorphism leads to altered protein structure, which affects the function of eNOS in generating nitric oxide and cardiovascular diastole. The results of the present study suggested a potential target gene for the prevention and treatment of CHD in young people (≤40 years old).

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Genetic polymorphisms of eNOS (-786T/C, Intron 4b/4a & 894G/T) and its association with asymptomatic first degree relatives of coronary heart disease patients

Cited by 11 publications

References 29 publications

A protective erythropoietin evolutionary landscape, NLRP3 inflammasome regulation, and multisystem inflammatory syndrome in children

A protective erythropoietin evolutionary landscape, NLRP3 inflammasome regulation, and multisystem inflammatory syndrome in children

Associations of genetic markers of the sympathoadrenal system and endothelial dysfunction with coronary heart disease on the example of a small Shoriya population

The association between an endothelial nitric oxide synthase gene polymorphism and coronary heart disease in young people and the underlying mechanism

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