Human Chromosome 17 in Essential Hypertension

Clinical Pharmacology, The William Harvey Research Institute Bart's and The London Queen Mary, University of London Charterhouse Square, UK.
Annals of Human Genetics (Impact Factor: 2.21). 04/2003; 67(Pt 2):193-206. DOI: 10.1046/j.1469-1809.2003.t01-1-00002.x
Source: PubMed

ABSTRACT Hypertension affects up to 30% of the adult population in Western societies and is a major risk factor for kidney disease, stroke and coronary heart disease. It is a complex trait thought to be influenced by a number of genes and environmental factors, although the precise aetiology remains unknown at this time. A number of methods have been successfully used to identify mutations that cause Mendelian traits and these are now being applied to the investigation of complex diseases. This review summarises the data gathered, using such approaches, that suggest there is a gene or genes on chromosome 17 causing human essential hypertension.
Studies in rodent models are discussed first, followed by studies of human hypertension that include the investigation of pseudohypoaldosteronism type II, a monogenic trait that manifests with hypertension alongside other phenotypic variables. In addition, candidate gene studies, genome screens and linkage studies based on comparative mapping are outlined. To date no gene has been identified on human chromosome 17 that influences blood pressure and causes human essential hypertension. However, results of ongoing fine mapping and candidate gene studies in both rodents and man are eagerly awaited.

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Available from: Mark Caulfield, Feb 06, 2015
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    • "The human anion exchanger 1 (AEI or SLC4A1) gene is a 911-residue glycoprotein that encodes protein in erythrocytes and basolateral surface of the alpha-intercalated cell in the collecting duct of the kidney 25, 26. Intriguingly, this gene is a possible candidate for essential hypertension as its encoded protein does not only function as chloride/bicarbonate exchanger but also in pathways that regulate blood pressure 27. Besides, Kokubo et al. 28 reported association of SLC4A1 with both blood pressure variation and hypertension. "
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    ABSTRACT: The polygenic nature of essential hypertension and its dependence on environmental factors pose a challenge for biomedical research. We hypothesized that the analysis of gene expression profiles from peripheral blood cells would distinguish patients with hypertension from normotensives. In order to test this, total RNA from peripheral blood cells was isolated. RNA was reversed-transcribed and labeled and gene expression analyzed using significance Analysis Microarrays (Stanford University, CA, USA). Briefly, Significance Analysis Microarrays (SAM) thresholding identified 31 up-regulated and 18 down-regulated genes with fold changes of ≥2 or ≤0.5 and q-value≤5% in expression. Statistically significantly gene ontology (GO) function and biological process differentially expressed in essential hypertension were MHC class II receptor activity and immune response respectively. Biological pathway analysis identified several related pathways which are associated with immune/inflammatory responses. Quantitative Real-Time RT-PCR results were consistent with the microarray results. The levels of C-reactive protein were higher in hypertensive patients than normotensives and inflammation-related genes were increased as well. In conclusion, genes enriched for "immune/inflammatory responses" may be associated with essential hypertension. In addition, there is a correlation between systemic inflammation and hypertension. It is anticipated that these findings may provide accurate and efficient strategies for prevention, diagnosis and control of this disorder.
    International journal of medical sciences 02/2011; 8(2):168-79. · 2.00 Impact Factor
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    • "Estimates from the studies of familiar aggregation indicate that approximately 30% of blood pressure variance is due to a genetic component [1]. Human Chr17 harbors genes possibly playing an important role in blood pressure regulation [2]. Multiple evidence from the genetic analysis of hypertensive rats indicates that genes on Chr10, syntenic to human Chr17, might be implicated in the aetiology of hypertension [3,4]. "
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    ABSTRACT: Human linkage and animal QTL studies have indicated the contribution of genes on Chr17 into blood pressure regulation. One candidate gene is PNMT, coding for phenylethanolamine-N-methyltransferase, catalyzing the synthesis of epinephrine from norepinephrine. Fine-scale variation of PNMT was screened by resequencing hypertensive (n = 50) and normotensive (n = 50) individuals from two European populations (Estonians and Czechs). The resulting polymorphism data were analyzed by statistical genetics methods using Genepop 3.4, PHASE 2.1 and DnaSP 4.0 software programs. In silico prediction of transcription factor binding sites for intron 1 was performed with MatInspector 2.2 software. PNMT was characterized by minimum variation and excess of rare SNPs in both normo- and hypertensive individuals. None of the SNPs showed significant differences in allelic frequencies among population samples, as well as between screened hypertensives and normotensives. In the joint case-control analysis of the Estonian and the Czech samples, hypertension patients had a significant excess of heterozygotes for two promoter region polymorphisms (SNP-184; SNP-390). The identified variation pattern of PNMT reflects the effect of purifying selection consistent with an important role of PNMT-synthesized epinephrine in the regulation of cardiovascular and metabolic functions, and as a CNS neurotransmitter. A striking feature is the lack of intronic variation. In silico analysis of PNMT intron 1 confirmed the presence of a human-specific putative Glucocorticoid Responsive Element (GRE), inserted by Alu-mediated transfer. Further analysis of intron 1 supported the possible existence of a full Glucocorticoid Responsive Unit (GRU) predicted to consist of multiple gene regulatory elements known to cooperate with GRE in driving transcription. The role of these elements in regulating PNMT expression patterns and thus determining the dynamics of the synthesis of epinephrine is still to be studied. We suggest that the differences in PNMT expression between normotensives and hypertensives are not determined by the polymorphisms in this gene, but rather by the interplay of gene expression regulators, which may vary among individuals. Understanding the determinants of PNMT expression may assist in developing PNMT inhibitors as potential novel therapeutics.
    BMC Medical Genetics 02/2007; 8(1):47. DOI:10.1186/1471-2350-8-47 · 2.08 Impact Factor
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    ABSTRACT: Südameveresoonkonna haigusi (SVH) peetakse tänapäeva lääne ühiskonna üheks sagedasemaks enneaegse surma põhjustajaks. Vastuvõtlikust SV haiguste suhtes on sõltuv pärilikkusest kuid ka elustiilist ja keskkonnast tulenevatest teguritest. Olulist rolli mängivad see juures ülekaalulisus, vähene füüsiline aktiivsus, liigne soola- ja alkoholitarbimine ning suitsetamine. Perekondadel põhinevad ja kaksikute uuringud on näidanud, et SVH pärilik komponent võib olla väga varieeruv. Lisaks keskkonnast tingitud riskiteguritele on geneetilised uuringute tulemusena tuvastanud, et erinevate SVHte vormide kujunemiseni võivad viia mutatsioon(id), mis esinevad ühes geenis (üksiku geeni ehk monogeenne vorm) kui ka mitmed mutatsioonid erinevates geenides (multigeenne vorm) korraga. Levinumad on neist multigeensed vormid, mis teevad haiguse kujunemisel osalevate mutatsioonide leidmise protsessi keeruliseks ja aeganõudvaks tegevuseks. Inimeste haigustega seotud geene ning nendes esinevate mutatsioonide leidmiseks on läbi aegade kasutatud genoomis esinevaid kindlaid geneetilisi piirkondi ehk markereid. Neist kõige levinumad on ühe nukleotiidsed polümorfismid (ÜNPd). ÜNPdel põhinevaid tänapäeval laialdast kasutust leidnud üle kogu genoomi analüüsid, mille tulemusena on kaardistatud mitmeid sh. SVHte kujunemisel osalevaid DNA lookusi. Kuid lisaks ÜNPdele, esineb genoomis ka veel teisi pikemaid geneetilisi markereid nagu insertsioonid ja deletsioonid (indelid) ning mille rolli inimese haiguste kujunemisel on oluliselt vähem uuritud. Kirjeldades geneetilist varieeruvust mitmetes inimese SVHte kandidaatgeenides selgus, et DNA järjestuse varieeruvus geenide regulatoorsetes piirkondades, nagu seda on promootorid ja evolutsiooniliselt konserveerunud mittekodeerivad piirkonnad, on suhteliselt madal. Vähene varieeruvus geenide funktsiooni mõjutavates alades annab alust arvata, et uuritud geenide roll SVH kujunemisel ei sõltu mitte ainult nendes leiduvate polümorfismide poolt, vaid ilmselt hoopis keerulisemas koostöös individuaalsete ekspressiooni reguleerivate üksustega. Uuringute käigus tuvastasin ühe konserveerunud indiviiditi väga varieeruva piirkonna, inimese SVH kandiaatgeenis. Leitud piirkonnas esines mitmeid eri pikkusega seni varasemalt kirjeldamata indeleid. Šimpansi, reesusmakaagi ja inimese vastavate genoomipiirkondade võrdlemisel selgus veel, et tegemist on inimese spetsiifilise deletsiooniga. Läbi viidud assotsiatsioonianalüüs kahes Ida-Euroopa populatsioonis näitas seost uuritud geeni sagedasema variandi, 14bp indeli, kandjastaatuse ja suurenenud CAD haigestumise riski vahel tšehhi valimis. Risk oli veelgi kõrgem metaboolse sündroomiga koronaartõvega patsientidel. Lisaks esines seos ka 14bp indel variandi ja triglütseriidide tasemete vahel tšehhidel ning 14bp indel variandi ja HR ja LDL tasemete vahel mõlema valimi (tsehhid ja eestlased) tervetel kontrollidel. Nii käesolev töö kui ka mõned varasemad tööd on näidanud, et seni vähe uuritud geneetilised variandid, nagu indelid võivad omada palju olulisemat rolli inimeste komplekshaiguste (nagu SVHd) kujunemisel kui seni arvatud. Cardiovascular diseases (CVD) are known as one of the main causes of premature deaths and disability in Western societies. CVDs are complex diseases influenced by the interplay of multiple genes as well as controllable (diet, exercise, stress) and uncontrollable (age, sex, family history) including environmental determinants. To date there are many genetic loci already known to have an impact on the etiology of CVD causing both monogenic and complex forms of the disease. In case of monogenic forms a single alteration in the gene may lead to the disease manifestation whereas in complex forms more than one gene has an impact to the disease phenotype. Genetic studies focused on families and twin cohorts have been previously shown that the approximate inheritance of CVD may range from 17% up to 66%. Despite of the great knowledge of the loci leading to the susceptibility to CVD, still many loci are remained to be described. To find these genomic regions a wide range of genetic markers are widely used. The most common markers in the genome are single nucleotide polymorphisms (SNPs). SNPs located in the regulatory or protein coding region may have an impact on gene function and thereby lead to the disease development. But there are also other genetic markers in the genome, like short insertions and deletions, which may have even higher impact on diseases development than previously expected. Studying variation pattern of CVD candidate genes in two population sample of European descent showed low genetic variation along regulatory regions (for example promoters, conserved non-coding regions) of the studied genes. This phenomenon indicates that the function of these genes is not determined only by the variations in these regions but with the complex interplay with other transcription regulators. Interestingly, during the variation detection one hypervariable genomic fragment in human CVD candidate gene was found. This region included multiple indel variations with the range of 5bp up to 43bp in size. Comparison of this region against chimpanzee and rhesus macaque revealed that the most common variant, 14p indel was human-specific deletion located in intronic CNR of NCX1 gene. In association study of two CVD phenotypes (coronary artery disease (CAD) and essential hypertension (EH)) this indel variant showed significant association with coronary artery disease and was even higher between the indel variant and among patients additionally diagnosed with metabolic syndrome in Czech population. A suggestive evidence of association with indel variant and serum triglyceride levels was observed in Czechs as well as with indel variant and heart rate and LDL levels in healthy control individuals among both (Czechs and Estonians) cohorts. Current research, as well as other recent studies have shown that non-SNP variations are a substantial source of polymorphism in humans and may have even larger role in complex disease (like CVD) than previously thought.
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