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GEN News Highlights : Sep 12, 2011

Studies Identify Multiple Loci Associated with Blood Pressure and Cardiovascular Disease

Consortium carried out GWAS meta-analyses and GWAS validation studies on over 200,000 people.

Two published papers by The International Consortium for Blood Pressure Genome-Wide Association Studies (ICBP-GWAS) report on the identification of new gene loci associated with hypertension and other cardiovascular risk factors including left ventricular wall thickness, stroke, coronary artery disease, pulse pressure, and mean arterial pressure.

The consortium carried out a meta-analysis of data from 29 studies involving some 70,000 individuals of European ancestry. Their initial findings for blood pressure were then confirmed through a three-stage validation experiment in over 133,000 additional people.

The researchers identified independent SNPs at 28 loci that are significantly associated with systolic blood pressure (SBP), diastolic blood pressure (DBP), or both. Of these, 16 were novel and 22 of the loci did not contain genes that were a priori strong biological candidates. The findings relating to blood pressure and cardiovascular disease risk are described in Nature, in a paper titled “Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.”

In an offshoot of the same GWAS analyses, the researchers looked for loci specifically associated with pulse pressure (PP) and mean arterial pressure (MAP). These results, which were validated in a separate GWAS stage including over 74,000 individuals, highlighted four new gene regions associated with PP, two associated with MAP, and one associated with both. The data is reported in Nature Genetics in a paper titled “Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.”

Among the DBP and SBP genes identified at the genome-wide significant loci, only CYP17A1, which has previously been implicated in  congenital adrenal hyperplasia and hypertension, is known to harbor rare variants that have large effects. The effects of the other loci were small on an individual basis.

Most of the 28 SBP and DBP loci were found to harbor multiple genes. Several loci did, nevertheless, contain highly plausible biological candidates, the researchers note. These include the NPPA and NPPB genes encoding precursors for atrial- and B-type natriuretic peptides. Previous work has identified SNPs “modestly correlated with our index SNP at this locus,” which are associated with plasma ANP, BNP, and blood pressure, the authors admit.

Two other loci harbor the genes NPR3 and GUCY1A3 and GUCY1B3. NPR3 knockout mice exhibit low blood pressure, and knockout animals deficient in either GUCY1A3 and GUCY1B3 display hypertension. Another locus contains ADM—encoding adrenomedullin—which has natriuretic, vasodilatory, and blood-pressure-lowering properties. Several of the highlighted loci were separately found to be associated with blood pressure among individuals of non-European ancestry.

The investigations focused on PP and MAP started with a meta-analysis of the same GWAS studies analyzed for the SBT and DBP research. It also conducted validation discovery studies in additional cohorts. Although none of the genes in the newly identified regions associated with PP represents a strong candidate for blood pressure regulation, several are implicated in mechanisms that may influence blood pressure, the researchers note.

The most significant association with PP was identified within a putative mRNA clone spanning a region upstream of PIK3CG and which has previously been associated with mean platelet volume, platelet count, and platelet aggregation, although the prior study highlighted a different SNP in the same region. The top-ranking PP-related SNP is located downstream of a gene associated with acute myeloid leukemia and upstream of PDGFRA, which encodes a cell surface receptor for members of the PDGF family involved in kidney development. Variants in PDGFRA have been associated with red blood cell count and other haematological indices, the team notes.

Of the two MAP loci, one lies upstream of ADRB1, which encodes the beta-1 adrenergic receptor, polymorphisms in which have been associated with resting heart rate, response to beta blockers, and hypertension. The second spans a region encompassing the top-ranking SNP, which lies within an intron of MAP4, which encodes microtubule-associated protein 4. The locus associated with both PP and MAP traits (2q24.3 near FIGN) has recently been associated with SBP in east Asians.

“Pulse pressure is a marker of the stiffness of the arteries that carry blood pressure from the heart round the body,” comments Imperial College London’s Paul Elliott, Ph.D., co- author on the Nature Genetics paper. “Our results could help our understanding about the genetic mechanisms underlying relationships of pulse pressure with risk of heart disease and stroke.”