Blood pressure genetics: from candidate genes to genome-wide association studies
Date
2011-04-05
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Abstract
Vererõhu geneetilise tausta selgitamiseks valiti välja 160 kandidaatgeeni, milledes oli Lõuna-Saksa populatsioonis genotüpiseeritud 2411 geneetilist polümorfismi. Genotüpiseeritud variandid katavad uuritud geene ebaühtlaselt. Rangetele statistiliste olulisuse kriteeriumitele vastavaid vererõhku mõjutavaid geneetilisi variante kandidaatgeenides ei tuvastatud, kuigi leptiini retseptori (LEPR) ja prostaglandiin E retseptor 3 (PTGER3) geenides olevad variandid omavad võimalikku seost vererõhuga. Samuti viitavad töö tulemused inimeste elustiili (suitsetamine, alkoholi tarbimine ja kehamassiindeks) koosmõjule geneetiliste teguritega. Töö tulemuste kinnitamiseks on tugevaimad leitud seosed kontrollitud ka Eesti ja Inglismaa päritoluga valimites.
Täiendavalt analüüsiti mikroRNAde võimalikku mõju vererõhu kandidaatgeenide avaldumisele. Bioinformaatiline analüüs näitas, et ükski mikroRNA ei ole pühendatud spetsiifiliselt vererõhku mõjutavate geenide regulatsioonile. Samas, katsed rakukultuuris näitasid, et mikroRNAd miR-124 ja miR-135a on võimelised vähendama valgu sünteesi mineralokortikoidi retseptori (NR3C2) geenilt. Mineralokortikoidi retseptor (aldosterooni retseptor) on oluline komponent reniin-angiotensiin-aldosteroon süsteemis, mis on üks põhilisi vererõhu regulatsiooni mehhanisme.
Töö teine osa andis panuse ülegenoomsesse assotsiatsiooniuuringusse leidmaks seoseid geneetiliste variantide ja inimese vererõhu vahel. Analüüsiti 395912 geneetilist varianti Lõuna-Saksa populatsioonis. Tulemused kombineeriti andmetega lisaindiviididest samast populatsioonist ning Eestist ja Inglismaalt pärit valimitest. Leiti mitmeid potentsiaalseid vererõhku mõjutavaid variante, milledest tugevaimad asuvad kaderiin 13 (CDH13) ja anoktamiin 3 (ANO3) geenide ümbruses. Kaderiin 13 on adiponektiini retseptor ja hea funktsionaalne kandidaat osalemaks vererõhu regulatsioonis.
In order to clarify the genetic causes of human blood pressure variation, 160 candidate genes containing 2411 polymorphisms genotyped in a Southern German population were selected. The genotyped polymorphisms cover the selected genes unevenly. No polymorphisms were found to satisfy strict statistical criteria for association with blood pressure, but the leptin receptor (LEPR) and prostaglandin E receptor 3 (PTGER3) genes contained variants with potential effect on blood pressure. The results also point to interactions of genetic and life-style factors in blood pressure determination. The strongest discovered associations were additionally explored in samples from Estonia and UK. In addition, the potential influence of microRNAs on the expression of blood pressure candidate genes was analyzed. Bioinformatic analysis revealed that no microRNAs were specifically devoted to the regulation of blood pressure determining genes. Cell culture experiments on the other hand demonstrated that microRNAs miR-124 and miR-135a are able to down-regulate the translation of the mineralocorticoid receptor (NR3C2) gene. The mineralocorticoid receptor (aldosterone receptor) is an important component in the renin-angiotensin-aldosterone system, which is one of the principal blood pressure regulation mechanisms. The second part of the work contributed to a genome-wide association study to find associations between genetic variants and human blood pressure. The study explored 395912 genetic polymorphisms in a Southern German population. The results were combined with data from additional individuals from the same population and samples from Estonia and UK. Several potential blood pressure altering variants were discovered, the strongest of which are located near cadherin 13 (CDH13) and anoctamine 3 (ANO3) genes. Cadherin 13 is the adiponectin receptor and a good functional candidate for involvement in blood pressure regulation.
In order to clarify the genetic causes of human blood pressure variation, 160 candidate genes containing 2411 polymorphisms genotyped in a Southern German population were selected. The genotyped polymorphisms cover the selected genes unevenly. No polymorphisms were found to satisfy strict statistical criteria for association with blood pressure, but the leptin receptor (LEPR) and prostaglandin E receptor 3 (PTGER3) genes contained variants with potential effect on blood pressure. The results also point to interactions of genetic and life-style factors in blood pressure determination. The strongest discovered associations were additionally explored in samples from Estonia and UK. In addition, the potential influence of microRNAs on the expression of blood pressure candidate genes was analyzed. Bioinformatic analysis revealed that no microRNAs were specifically devoted to the regulation of blood pressure determining genes. Cell culture experiments on the other hand demonstrated that microRNAs miR-124 and miR-135a are able to down-regulate the translation of the mineralocorticoid receptor (NR3C2) gene. The mineralocorticoid receptor (aldosterone receptor) is an important component in the renin-angiotensin-aldosterone system, which is one of the principal blood pressure regulation mechanisms. The second part of the work contributed to a genome-wide association study to find associations between genetic variants and human blood pressure. The study explored 395912 genetic polymorphisms in a Southern German population. The results were combined with data from additional individuals from the same population and samples from Estonia and UK. Several potential blood pressure altering variants were discovered, the strongest of which are located near cadherin 13 (CDH13) and anoctamine 3 (ANO3) genes. Cadherin 13 is the adiponectin receptor and a good functional candidate for involvement in blood pressure regulation.
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Keywords
dissertatsioonid, bioloogia, genoomid, vererõhk, populatsioonigeneetika, Eesti, Inglismaa, population genetics, blood pressure, genes, polymorphism, Estonia, Great Britain