Understanding the role of genetics in hypertension

This editorial refers to ‘Risk for hypertension crosses generations in the community: a multi-generational cohort study’†, by T.J. Niiranen et al., on page 2300. Hypertension is a major modifiable risk factor for renal, cardiovascular, and cerebrovascular disease, and a leading underlying cause of global mortality and morbidity.1 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.2 In this issue of the journal, Niiranen et al. provide an intriguing insight into this topic.3 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. Twin- and 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.4 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.4–6 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 Consortium7 to the more recent reports by Ehret et al.,8 Warren et al.,9 and Hoffman et al.,10 280 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,11 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.9 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.12 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. Validated genetic loci/nearest mapped genes for blood pressure traits identified through genome-wide association studies Validated genetic loci/nearest mapped genes for blood pressure traits identified through genome-wide association studies 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 et al, who report that early (onset before 55 years) rather than late onset of hypertension in first- and second-degree parents is a stronger predictor of the risk of elevated blood pressures values in offspring. From ∼50–55 years, values of systolic blood pressure are known to increase while diastolic blood pressure decreases due to a generalized process of vascular ageing which results from poor ventricular coupling and increased arterial stiffness secondary to arteriosclerosis.13 The risk of elevated values of blood pressure and cardiovascular disease observed after 55 years of age, therefore, are likely to reflect not only genetic influences affecting specific pathways involved in the pathogenesis of the disease, but also the contribution of gene variants regulating the evolution of cellular ageing.14 Genetic discoveries from GWAS now await further inquiry to ascertain whether new mechanisms and pathways for hypertension exist with possibly novel therapeutic targets. The key question remains as to whether we can use this genetic information directly to improve our patient’s care. Currently, the majority of interventions for hypertension are initiated later in life when blood pressure values are already elevated, vessels stiffened, or end-organ damage initiated. We then follow the general approach of prescribing the same sequence of anti-hypertensive drugs for all patients with the disease, based on specific algorithms endorsed by professional societies. Although this approach has the advantage of simplifying treatment decisions, it does not take into account the variable contribution of different biological pathways involved in the pathogenesis of hypertension in any given individual. Screening the human genome for known variants associated with increased risk of hypertension, and combination of this information into genetic risk scores, could provide information not only on an individual’s risk of developing hypertension but also perhaps on which pathways are primarily responsible (Figure 1). This approach could lead to more effective prevention of cardiovascular disease based on: (i) earlier identification of subjects at risk before development of the phenotype; (ii) implementation of aggressive and perhaps targeted lifestyle interventions; and (iii) a more rational and targeted selection of cardiovascular drugs that are likely to be effective and safe for that individual (Figure 1). These concepts are at the foundation of ‘precision medicine’, which is based on identifying pre-symptomatic, high-risk patients with distinct mechanisms of disease and particular responses to treatments15 (Figure 1). As heart disease and hypertension are highly prevalent and have relatively large effects on life expectancy, precision medicine initiatives applied to these diseases might lead to significant public health and economical benefits.16 Although this is an attractive prospective, the value of DNA sequencing for precision medicine in hypertension, as well as in many other complex traits, requires additional important steps before its application to a clinical setting can be considered. From family history to precision medicine. Family history of hypertension could be considered a summary of the whole genetic and environmental influences defining the individual risk of hypertension. However, it does not provide information on the specific environmental or genetic factors affecting the disease risk. A deeper interrogation of the genome and environmental exposure is necessary to provide a more effective risk quantification and to identify the pathophysiological factors affecting the risk. In the near future, adoption of precision medicine initiatives for hypertension could lead to a earlier identification of patients at risk in the pre-clinical phase of the disease. In addition, acting specifically on factors that are more likely to be involved in the disease pathogenesis has the potential to remove non-responders and toxic responders before prescribing medication and to treat with a given drug only responders and patients not predisposed to toxicity. The paper by Niiranen et al. has leveraged the invaluable information on family structure and rich phenotype data from the Framingham cohort to shed some unique insights into transgenerational blood pressure risk. While it may seem a relatively ‘low tech’ approach, the authors have highlighted that simply asking patients about a family history of early-onset hypertension in parents and possibly grandparents could provide the clinician with a valid instrument to identify young patients at potentially higher risk of hypertension due to a shared genetic and environmental background. These individuals, at the very least, should be offered aggressive lifestyle modification and closer monitoring for development of high blood pressure. Perhaps a useful intermediate step while we await the promise of precision medicine. Conflict of interest: none declared.