TY - JOUR
T1 - Genetic architecture of ambulatory blood pressure in the general population
T2 - insights from cardiovascular gene-centric array
AU - Tomaszewski, Maciej
AU - Debiec, Radoslaw
AU - Braund, Peter S
AU - Nelson, Christopher P
AU - Hardwick, Robert
AU - Christofidou, Paraskevi
AU - Denniff, Matthew
AU - Codd, Veryan
AU - Rafelt, Suzanne
AU - van der Harst, Pim
AU - Waterworth, Dawn
AU - Song, Kijoung
AU - Vollenweider, Peter
AU - Waeber, Gerard
AU - Zukowska-Szczechowska, Ewa
AU - Burton, Paul R
AU - Mooser, Vincent
AU - Charchar, Fadi J
AU - Thompson, John R
AU - Tobin, Martin D
AU - Samani, Nilesh J
PY - 2010/12
Y1 - 2010/12
N2 - 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 blood pressure in 2020 individuals from 520 white European nuclear families (the Genetic Regulation of Arterial Pressure of Humans in the Community Study) and genotyped their DNA using the Illumina HumanCVD BeadChip array, which contains ≈ 50 000 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 mm Hg 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 Genetic Regulation of Arterial Pressure of Humans in the Community 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 Genetic Regulation of Arterial Pressure of Humans in the Community Study showed that cell survival control signaling cascades could play a role in blood pressure regulation. There was also a significant overrepresentation of rare variants (minor allele frequency: < 0.05) among 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.
AB - 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 blood pressure in 2020 individuals from 520 white European nuclear families (the Genetic Regulation of Arterial Pressure of Humans in the Community Study) and genotyped their DNA using the Illumina HumanCVD BeadChip array, which contains ≈ 50 000 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 mm Hg 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 Genetic Regulation of Arterial Pressure of Humans in the Community 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 Genetic Regulation of Arterial Pressure of Humans in the Community Study showed that cell survival control signaling cascades could play a role in blood pressure regulation. There was also a significant overrepresentation of rare variants (minor allele frequency: < 0.05) among 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.
KW - Blood Pressure/genetics
KW - Blood Pressure Monitoring, Ambulatory
KW - Chloride Channels/genetics
KW - Cohort Studies
KW - Female
KW - Gene Frequency
KW - Genetic Association Studies
KW - Genetic Loci
KW - Genotype
KW - Humans
KW - Hypertension/epidemiology
KW - Male
KW - Methylenetetrahydrofolate Reductase (NADPH2)/genetics
KW - Middle Aged
KW - Oligonucleotide Array Sequence Analysis
KW - Polymorphism, Single Nucleotide
KW - Prevalence
KW - Promoter Regions, Genetic
KW - United Kingdom/epidemiology
KW - Whites/genetics
KW - Young Adult
U2 - 10.1161/HYPERTENSIONAHA.110.155721
DO - 10.1161/HYPERTENSIONAHA.110.155721
M3 - Article
C2 - 21060006
SN - 0194-911X
VL - 56
SP - 1069
EP - 1076
JO - Hypertension (Dallas, Tex. : 1979)
JF - Hypertension (Dallas, Tex. : 1979)
IS - 6
ER -