Genes involved in cardiovascular traits: detection of genetic variation in Estonian and Czech populations
Date
2010-10-20
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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.
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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Keywords
doktoritööd, bioloogia, geenid, DNA, südame-veresoonkonna haigused