Genetic architecture of ambulatory blood pressure in the general population: insights from cardiovascular gene-centric array.
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.
Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester, UK. njs@le.ac.uk
Maciej
M
Tomaszewski
Radoslaw
R
Debiec
Peter S
PS
Braund
Christopher P
CP
Nelson
Robert
R
Hardwick
Paraskevi
P
Christofidou
Matthew
M
Denniff
Veryan
V
Codd
Suzanne
S
Rafelt
Pim
P
van der Harst
Dawn
D
Waterworth
Kijoung
K
Song
Peter
P
Vollenweider
Gerard
G
Waeber
Ewa
E
Zukowska-Szczechowska
Paul R
PR
Burton
Vincent
V
Mooser
Fadi J
FJ
Charchar
John R
JR
Thompson
Martin D
MD
Tobin
Nilesh J
NJ
Samani
D001794:Blood Pressure / Q000235:genetics*; D018660:Blood Pressure Monitoring, Ambulatory; D018118:Chloride Channels / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D056426:Genetic Loci; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D011401:Promoter Regions, Genetic; D006113:United Kingdom / Q000453:epidemiology; D044465:White People / Q000235:genetics; D055815:Young Adult
C097539:CLCN6 protein, human; D018118:Chloride Channels; D042965:Methylenetetrahydrofolate Reductase (NADPH2)