TY - JOUR
T1 - Loci influencing blood pressure identified using a cardiovascular gene-centric array
AU - Ganesh, Santhi K
AU - Tragante, Vinicius
AU - Guo, Wei
AU - Guo, Yiran
AU - Lanktree, Matthew B
AU - Smith, Erin N
AU - Johnson, Toby
AU - Castillo, Berta Almoguera
AU - Barnard, John
AU - Baumert, Jens
AU - Chang, Yen-Pei Christy
AU - Elbers, Clara C
AU - Farrall, Martin
AU - Fischer, Mary E
AU - Franceschini, Nora
AU - Gaunt, Tom R
AU - Gho, Johannes M I H
AU - Gieger, Christian
AU - Gong, Yan
AU - Isaacs, Aaron
AU - Kleber, Marcus E
AU - Mateo Leach, Irene
AU - McDonough, Caitrin W
AU - Meijs, Matthijs F L
AU - Mellander, Olle
AU - Molony, Cliona M
AU - Nolte, Ilja M
AU - Padmanabhan, Sandosh
AU - Price, Tom S
AU - Rajagopalan, Ramakrishnan
AU - Shaffer, Jonathan
AU - Shah, Sonia
AU - Shen, Haiqing
AU - Soranzo, Nicole
AU - van der Most, Peter J
AU - Van Iperen, Erik P A
AU - Van Setten, Jessica
AU - Van Setten, Jessic A
AU - Vonk, Judith M
AU - Zhang, Li
AU - Beitelshees, Amber L
AU - Berenson, Gerald S
AU - Bhatt, Deepak L
AU - Boer, Jolanda M A
AU - Boerwinkle, Eric
AU - Burkley, Ben
AU - Burt, Amber
AU - Chakravarti, Aravinda
AU - Chen, Wei
AU - Hofker, Marten H
AU - CARDIOGRAM
AU - METASTROKE
AU - Keating, Brendan J.
AU - Asselbergs, Folkert W.
PY - 2013/4/15
Y1 - 2013/4/15
N2 - Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
AB - Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
KW - Adult
KW - Aged
KW - Blood Pressure/genetics
KW - Cardiovascular Diseases/genetics
KW - Chromosome Mapping
KW - Cohort Studies
KW - European Continental Ancestry Group/genetics
KW - Female
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Genotype
KW - Humans
KW - Male
KW - Middle Aged
KW - Polymorphism, Single Nucleotide
U2 - 10.1093/hmg/dds555
DO - 10.1093/hmg/dds555
M3 - Article
C2 - 23303523
SN - 0964-6906
VL - 22
SP - 1663
EP - 1678
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 8
ER -