Hunting for genes for hypertension: the Millennium Genome Project for Hypertension

Abstract

The Millennium Genome Project for Hypertension was started in 2000 to identify genetic variants conferring susceptibility to hypertension, with the aim of furthering the understanding of the pathogenesis of this condition and realizing genome-based personalized medical care. Two different approaches were launched, genome-wide association analysis using single-nucleotide polymorphisms (SNPs) and microsatellite markers, and systematic candidate gene analysis, under the hypothesis that common variants have an important role in the etiology of common diseases. These multilateral approaches identified ATP2B1 as a gene responsible for hypertension in not only Japanese but also Caucasians. The high blood pressure susceptibility conferred by certain alleles of ATP2B1 has been widely replicated in various populations. Ex vivo mRNA expression analysis in umbilical artery smooth muscle cells indicated that reduced expression of this gene associated with the risk allele may be an underlying mechanism relating the ATP2B1 variant to hypertension. However, the effect size of a SNP was too small to clarify the entire picture of the genetic basis of hypertension. Further, dense genome analysis with accurate phenotype data may be required.

Animal models for the study of primary and secondary hypertension in humans

“…The millennium genome project for hypertension was initiated in 2000 to identify genetic variants that predispose individuals to hypertension. This has involved a combination of techniques, including a gene linkage approach using single nucleotide polymorphisms, microsatellite markers and systematic candidate gene analysis (66). In parallel with this has been the development of genetic models using different animal species, which have provided insights into the physiological mechanisms of hypertension.…”

Vascular smooth muscle cell phenotype is defined by Ca2+‐dependent transcription factors

“…Although it is unclear how this gene is regulated by Ca 2+ signalling, its mutation leads to excessive proliferation of pulmonary VSMCs, and thereby narrowing of pulmonary arteries . Importantly, the Millennium Genome Project for Hypertension has identified a Ca 2+ ‐ATPase gene ( ATP2B1 ) that confers susceptibility to the development of hypertension . In spontaneously hypertensive rats, the loss of contractile phenotype marker genes is associated with a reduction in the expression of peroxisome proliferator‐activated receptor γ (PPARγ), which inhibits the proliferation and migration of VSMCs .…”

Reduced expression of PMCA1 is associated with increased blood pressure with age which is preceded by remodelling of resistance arteries

“…The results of our study show that changes in the expression of PMCA1, which in younger mice does not significantly influence BP, does so when combined with aging, which is a well‐established risk factor for hypertension and cardiovascular disease (Buford, ). The combination of all loci highly significantly associated with BP in GWAS has been reported to account for only up to 10% of the total estimated genetic component for BP (Tabara et al ., ). Therefore, we propose that some of the ‘missing heritability’ for BP can be derived from an interaction between a genetic factor and aging.…”

“…The results of this study suggest that Atp2b1 may be an important risk factor for the development and progression of hypertension. As even relatively small (5 mmHg) increases in BP are associated with increased risk of adverse cardiovascular events and mortality (Lewington et al ., ; Tabara et al ., ) managing risk factors for hypertension can have a large positive effect on a population's health.…”