May 11, 2009 (San Francisco, California) — Two international research projects have identified more than a dozen different genetic variants associated with blood pressure and hypertension [1,2]. The teams, working independently as well as in concert, identified regions near 13 genes, including genes not previously implicated in blood pressure, according to researchers.
The new data were presented here last week at the American Society of Hypertension 2009 Scientific Meeting and published online May 10, 2009 in Nature Genetics by Drs Daniel Levy (National Heart, Lung, and Blood Institute, Framingham, MA) and Christopher Newton-Cheh (Massachusetts General Hospital, Boston, MA).
"We know that blood pressure is highly heritable," Levy told heartwire . "It runs in families, but the search for genes that contribute to interindividual variation in blood pressure has come up with very few successes to date. Most of the success comes from studying families who have very unusual Mendelian forms of high or very low blood pressure, and these are almost invariably due to abnormalities in genes that are involved in the way the kidney handles salt."
The CHARGE Consortium
In the search for these elusive blood pressure-related genes, Levy and colleagues performed a genomewide association study of individuals in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. The project included 29 136 white men and women from the Framingham Heart Study, Atherosclerosis Risk in Communities study, Cardiovascular Health Study, Rotterdam Study, Rotterdam Extension Study, and Age, Gene/Environment Susceptibility Reykjavik Study.
Investigators genotyped approximately 500 000 common single nucleotide polymorphisms (SNPs) across the entire genome, and then, using patterns of linkage disequilibrium identified in the HapMap project, they were able to impute the identity of roughly 2.5 million additional SNPs.
Conducting a genomewide association study meta-analysis across those six studies, the researchers identified a number of highly suggested regions for systolic and diastolic pressure and hypertension. Working with the Global Blood Pressure Genetics (BPGen) study, the consortium led by Newton-Cheh, the group identified four genetic variants for systolic blood pressure (ATP2B1, CYP17A1, PLEKHA7, and SH2B3), six variants for diastolic blood pressure (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, and ULK4), and one for hypertension (ATP2B1).
The investigators then created a weighted systolic and diastolic risk score based on the number of alleles individuals carried. Both systolic and diastolic blood pressure increased in a stepwise manner with higher risk scores, with a systolic blood pressure range of 10 mm Hg and diastolic blood pressure range of 5 mm Hg. This type of variation in blood pressure is sufficient to have an effect on cardiovascular disease events, said Levy.
"The individual variance contributes only a small amount of interindividual variation in blood pressure, about 1 mm Hg per risk allele, but there clearly were aggregate effects due to the presence of multiple risk alleles in individuals," he said. "People who were dealt a very good hand had much lower blood pressure on average, and those who were dealt a bad hand had much higher blood pressure."
During his presentation, Levy pointed out that the identified ATP2B1 gene encodes PMCA1, a plasma membrane enzyme involved in calcium transport, and that CACNB2 also encodes part of a calcium-channel protein. SH2B3 is involved in the human immune response and has previously been linked with autoimmune diseases, while CYP17A1 encodes an enzyme necessary for steroid production.
BPGen Consortium
Similar to the CHARGE consortium, the BPGen researchers tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34 433 subjects of European ancestry. The analysis included patients from 17 population-based or case-control studies in the BPGen consortium.
After identifying a number of possible SNPs influencing systolic and diastolic blood pressure, they genotyped the 12 gene variants with the strongest signals in more than 71 000 additional individuals of European descent and in 12 300 people of Indian-Asian ancestry. In addition, the group exchanged their results with the CHARGE consortium.
The BPGen investigators identified an association with systolic and diastolic blood pressure and genetic variants in eight regions near the following genes: CYP17A1, CYP1A2, FGF5, SH2B3, MTHFR, c10orf107, ZNF652, and PLCD3.
Like Levy, Newton-Cheh noted that the effect size associated with individual genes was small, responsible for variations in systolic and diastolic blood pressure of 1 mm Hg and 0.5 mm Hg, respectively.
"I think it raises the question of what is the value of common variants with weak effects," he said. "Clearly, individually, each one of these variants cannot improve risk prediction. I think it remains to be shown whether an additive approach, taking the 13 variants between the two papers, results in a clinically meaningful improvement in predicted risk. It may be that the blood-pressure cuff is the best way to prevent risk associated with hypertensive outcomes, but the advantage of identifying variants that were previously unrecognized can't be overstated."
To heartwire , Levy said identifying the new genes would help expand researchers' understanding of the biology of blood-pressure regulation. A reasonable speculation, he added, could see the information used in the future to identify high-risk individuals before they develop hypertension, specifically at a time when approaches to treatment and prevention are most likely to succeed.
Both Levy and Newton-Cheh said the two studies were massive undertakings, involving collaboration with centers and colleagues from around the world. The BPGen consortium, for example, included 159 investigators from 93 centers in the US and Europe.
Source : http://www.medscape.com/viewarticle/702680?sssdmh=dm1.470812&src=nldne
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