Genetic architecture of ambulatory blood pressure in the general population: insights from cardiovascular gene-centric array.
Genetic architecture of ambulatory blood pressure in the general population: insights from cardiovascular gene-centric array.
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DOI：
10.1161/hypertensionaha.110.155721
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发表时间：
2010-12
期刊：
影响因子：
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通讯作者：
Samani NJ
中科院分区：
文献类型：
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作者：
Tomaszewski M;Debiec R;Braund PS;Nelson CP;Hardwick R;Christofidou P;Denniff M;Codd V;Rafelt S;van der Harst P;Waterworth D;Song K;Vollenweider P;Waeber G;Zukowska-Szczechowska E;Burton PR;Mooser V;Charchar FJ;Thompson JR;Tobin MD;Samani NJ
血压的遗传决定因素定义不清。我们进行了大规模的基因中心分析，以确定与动态收缩压和舒张压相关的基因座和途径。我们测量了来自520个白色欧洲核心家庭的2020名个体的24小时动态血压（GRAPHIC研究），并使用Illumina HumanCVD BeadChip阵列对其DNA进行基因分型，该阵列包含>2000个心血管候选基因座中的约50000个单核苷酸多态性。我们发现MTHFR和CLCN 6启动子区域的rs 13306560多态性与平均24小时舒张压之间存在强相关性-rs 13306560的每个次要等位基因拷贝与平均24小时舒张压降低2.6 mmHg相关（P=1.2×10−8）。在对来自GRAPHIC研究、CoLaus研究和西里西亚心血管研究的8129例受试者进行的联合分析中，rs 13306560也与门诊舒张压相关（P=5.4×10−6）。在GRAPHIC研究中，对基因本体定义的通路中的变体与平均24小时血压之间的关联进行的额外分析表明，细胞存活控制信号级联可能在血压调节中发挥作用。在显示与平均24小时血压至少存在名义关联的多态性中，罕见变异（次要等位基因频率<0.05）也有显著的过度代表性，表明其相当大比例的遗传性可能由罕见等位基因解释。通过对动态血压的大规模基因中心分析，我们确定了MTHFR/CLNC 6位点的一种新变体与舒张压的相关性，并为血压的遗传结构提供了新的见解。
Genetic determinants of blood pressure are poorly defined. We undertook a large-scale gene-centric analysis to identify loci and pathways associated with ambulatory systolic and diastolic blood pressure. We measured 24-hour ambulatory BP in 2020 individuals from 520 white European nuclear families (the GRAPHIC Study) and genotyped their DNA using the Illumina HumanCVD BeadChip array which contains approximately 50000 single nucleotide polymorphisms in >2000 cardiovascular candidate loci. We found a strong association between rs13306560 polymorphism in the promoter region of MTHFR and CLCN6 and mean 24-hour diastolic blood pressure - each minor allele copy of rs13306560 was associated with 2.6 mmHg lower mean 24-hour diastolic blood pressure (P=1.2×10−8). rs13306560 was also associated with clinic diastolic blood pressure in a combined analysis of 8129 subjects from the GRAPHIC Study, the CoLaus Study and the Silesian Cardiovascular Study (P=5.4×10−6). Additional analysis of associations between variants in Gene Ontology-defined pathways and mean 24-hour blood pressure in the GRAPHIC Study showed that cell survival control signalling cascades could play a role in blood pressure regulation. There was also a significant over-representation of rare variants (minor allele frequency <0.05) amongst polymorphisms showing at least nominal association with mean 24-hour blood pressure indicating that a considerable proportion of its heritability may be explained by uncommon alleles. Through a large scale gene-centric analysis of ambulatory blood pressure, we identified an association of a novel variant at the MTHFR/CLNC6 locus with diastolic blood pressure and provided new insights into the genetic architecture of blood pressure.