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Hypertension is a major modifiable risk factor for renal, cardiovascular, and cerebrovascular disease, and a leading underlying cause of global mortality and morbidity. Incremental advances in our understanding of blood pressure have highlighted its complex pathophysiology, whereby genetic and environmental factors combine with a plethora of physiological pathways and mechanisms ultimately to yield the phenotype. While epidemiological studies have improved our understanding of environmental factors in relation to blood pressure, especially with regards to diet and exercise, the exact role of genetics in this setting has been challenging to tease apart from the shared environment often found in families and communities. In this issue of the journal, Niiranen et al. provide an intriguing insight into this topic. Using blood pressure data systematically acquired across three generations of the Framingham Heart Study, the authors showed that higher blood pressure, not only in parents, but also in grandparents, is associated with risk of the same condition in the third-generation individuals. Specifically, a family history of hypertension developed before 55 years of age represents the strongest risk factor for high blood pressure in the offspring, independently of several measured environmental factors known to influence the risk of hypertension, including levels of physical activity, dietary sodium, and alcohol intake. Importantly, the fact that grandparental hypertension confers risk in grandchildren and that only 10% of the grandchildren had last reported living in Framingham, suggests that the impact of shared environment here is likely to be low, making the genetic effect perhaps more apparent. There are of course limitations in the approach which the authors describe, but overall these data support the concept of genetic predisposition to hypertension. Understanding these genetic factors has been a key challenge facing investigators over time. Twinand family-based studies have indicated that as much as 30–50% of the variance in blood pressure readings may be heritable, while a growing list of rare disorders have led to the identification of clear and causal Mendelian mutations. At a population level, however, the smooth Gaussian distribution of blood pressure suggests that these mutations are unlikely to play a major role and that, if anything, multiple genetic effects, each of a small size, are likely to be contributing to or adding susceptibly to high blood pressure levels. With the advent of the genomic era, it is now generally accepted that the most common form of hypertension is a complex trait with a polygenic basis and environmental influences that may also exert effects through epigenetic changes which could even be transmitted across generations. The completion of the Human Genome Project and HapMap initiatives yielded a multitude of genome-wide association studies (GWAS) that have sought to discover these common genetic variants. From the early and negative GWAS for hypertension within the Wellcome Trust Case Control Consortium to the more recent reports by Ehret et al., Warren et al., and Hoffman et al., 280 genetic variants have been associated with risk of high blood pressure, as well as other traits such as coronary artery disease, for which hypertension may be on the causal pathway (Table 1). Although the contribution of each single nucleotide polymorphism (SNP) to systolic and diastolic blood pressure values is typically very small, when combined together their cumulative impact is more revealing. For example, in the recent report by Warren et al., a combination of multiple SNPs in a risk score accounted for a difference in systolic blood pressure values up to 10 mmHg between individuals. Despite this, the combined contribution of these multiple genetic variants to heritability estimates remains lower than expected, leading to questions about ‘missing’ heritability. This, however, is not unique to hypertension and is seen in other complex traits such as coronary disease. Although it is expected that many more as yet undiscovered loci will contribute to explain the missing heritability, it has been postulated that, at least in part, this discordance could also be related to an overestimation of initial hereditary estimates as well as phenotypic pleiotropy. Phenotype is of course as critical as genotype in these studies. As with other traits, premature onset of a condition is often considered to be more specific and genetically driven than environment or lifestyle factors. This is also supported by the findings from Niiranen

Understanding the role of genetics in hypertension