The genetic basis of essential hypertension
ABSTRACT During the last few years the studies on the genetic basis of essential hypertension (EH) have been numerous, allowing however only a partial understanding of the underlying molecular mechanisms. The most used techniques were the candidate gene approach, genome-wide scanning, the intermediate phenotype approach and comparative-genomics in animal models. The renin-angiotensin-aldosterone system may play a prominent role in the genesis of hypertension, and polymorphisms of the genes coding for angiotensinogen, angiotensin-converting enzyme, angiotensin II type 1 and 2 receptors, and aldosterone synthase have been widely studied. Other mechanisms may involve the KLK 1 gene of tissue kallikrein, gene variants of endothelial nitric oxide synthase and polymorphisms of the endothelin-1 gene. Finally, a number of studies have highlighted the potential contribution of polymorphisms of genes coding for inflammatory cytokines, adrenergic receptors and intracellular G proteins, which can activate Na+/K+ exchangers. Further important information might derive from proteomic analysis and the study of mitochondrial genome. Overall, results have often been discordant, sometimes suggesting a different expression of the same gene variants in different populations. EH is a highly polygenic condition, caused by the combination of small changes in the expression of many genes, in conjunction with a variable collection of environmental factors.
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ABSTRACT: The Gln(27)Glu polymorphism but not the Arg(16)Gly polymorphism of the beta2-adrenergic receptor (ADRB2) gene appears to be associated with a broad range of aging-associated phenotypes, including cancers at different sites, myocardial infarction (MI), intermittent claudication (IC), and overall/healthy longevity in the Framingham Heart Study Offspring cohort. The Gln(27)Gln genotype increases risks of cancer, MI and IC, whereas the Glu(27) allele or, equivalently, the Gly(16)Glu(27) haplotype tends to be protective against these diseases. Genetic associations with longevity are of opposite nature at young-old and oldest-old ages highlighting the phenomenon of antagonistic pleiotropy. The mechanism of antagonistic pleiotropy is associated with an evolutionary-driven advantage of carriers of a derived Gln(27) allele at younger ages and their survival disadvantage at older ages as a result of increased risks of cancer, MI and IC. The ADRB2 gene can play an important systemic role in healthy aging in evolutionary context that warrants exploration in other populations.Mechanisms of ageing and development 05/2010; 131(5):338-45. DOI:10.1016/j.mad.2010.04.001 · 3.51 Impact Factor
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ABSTRACT: We explored the interaction of 6 candidate genetic mutations in essential hypertension (EH). The mutations AGT M235T, ACE I/D, eNOS Glu298Asp, ET-2 A985G, ANP T2238C, and NPRC A-55C were detected using a genechip microarray in 100 patients with EH and 97 controls from the Han population living in the Yunnan Province of China. Risks of EH were evaluated with respect to a combination of these genotypes. Interactions were analyzed using multifactor dimensionality reduction (MDR). P values were corrected using Bonferroni's adjustment. Results showed that CC genotype frequencies for NPRC A-55C (0.540) in EH were significantly higher than those in controls (0.237, Pc < 0.01; odds ratio (OR) = 3.777; 95% confidence interval (CI) = 2.050-6.960). The OR for NPRC A-55C CC combined with ET-2 A985G GG increased to 4.673 and to 5.529 when the MT genotype of AGT M235T, the EE genotype of eNOS Glu298Asp, the GG genotype of ET-2 A985G, and the CC genotype of NPRC A-55C were combined. MDR showed that ET-2/NPRC is the best model (OR = 4.002; 95%CI = 2.1597-7.4159). The CC genotype for NPRC A-55C and the G allele for ET-2 A985G were associated with susceptibility to EH. Although the contributions of the candidate genes differ, they may have cooperative effects on conferring risk for EH. Moreover, potential gene-gene interactions were found between ET-2 A985G and NPRC A-55C in EH.Genetics and molecular research: GMR 01/2014; 13(4):8385-95. DOI:10.4238/2014.October.20.14 · 0.85 Impact Factor
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ABSTRACT: Aim: Nitric oxide (NO) plays a major role in the regulation of vascular tone. Production of NO can be influenced by polymorphisms of the endothelial NO synthase (eNOS) gene, which may be associated with the pathogenesis of essential hypertension (EHT). Therefore, eNOS gene intron 4 a/b variable number of tandem repeats (VNTR) and intron 23 polymorphisms were investigated in patients with EHT living in a central area of Turkey. Materials and methods: The study was performed in 91 patients (34 M, 57 F) with EHT, aged 38-76 years, and 75 age-and sex-matched healthy controls (35 M, 40 F). eNOS gene polymorphisms were detected by polymerase chain reaction method. Results: There was no significant difference between the G-allele frequency of the G10-T polymorphism in intron 23 and intron 4 a/b VNTR polymorphism of the eNOS gene in EHT patients and in the controls. Conclusion: eNOS gene intron 4 a/b VNTR and intron 23 gene polymorphisms were not associated with EHT patients living in a central area of Turkey. Further studies are needed to investigate whether these 2 polymorphisms of the eNOS gene could represent useful genetic markers for indentifying individuals at risk of developing EHT. Key words: Essential hypertension, eNOS gene polymorphisms, Intron 4 a/b VNTR, Intron 23 Esansiyel hipertansiyon hastalarında eNOS gen intron 4 a/b VNTR ve intron 23 polimorfizimlerinin araştırılması Amaç: Nitrik oksit (NO), vasküler tonusun düzenlenmesinde önemli bir rol oynar. NO'in üretimi esansiyel hipertansiyon (EHT)'un patogenezi ile ilişkili olan endotelyal NO sentaz (eNOS) gen polimorfizimlerinden etkileniyor olabilir. Bundan dolayı, çalışmamızda Türkiye'nin orta bölgesinde yaşayan EHT hastalarında eNOS gen intron 4 a/b değişken sayıdaki ardışık tekrarlar (VNTR) ve intron 23 gen polimorfizimleri araştırıldı. Yöntem ve gereç: Çalışma 38-76 yaşları arasındaki 91 EHT hastası (34 E, 57 K) ile uygun yaş ve cinsiyette 75 sağlıklı kontrol (35 E, 40 K) vakası üzerinde gerçekleştirildi. eNOS gen polimorfizmleri polimeraz zincir reaksiyon metodu ile belirlendi. Bulgular: EHT hastaları ile kontrollerin eNOS gen intron 23 G10-T polimorfizminin G-allel sıklığı ile intron 4 a/b VNTR polimorfizimleri arasında önemli bir fark bulunamadı. Sonuç: eNOS geni intron 4 a/b VNTR ve intron 23 polimorfizimleri Türkiye'nin orta bölgesinde yaşayan EHT hastaları ile ilişkili değildir. EHT gelişme riski olan kişilerin tanınmasında eNOS genindeki bu iki polimorfizmin faydalı birer genetik markır olup olmayacağının anlaşılması için daha ileri çalışmalara ihtiyaç vardır.