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Genotypic and Phenotypic Heterogeneity—Hurdles and
Opportunities in the Quest for Hypertension-Related Genes
Theodore A. Kotchen1
Although family studies suggest that hypertension heritability is in the range of 30–40%, genome-wide association
studies in large populations have identified specific genetic
variants that account for only 3–4% of blood pressure variability and hypertension.1 It is likely that a myriad of issues
contribute to this “heritability gap”2 (Table 1). Furthermore,
as articulated by Pickering over half a century ago, “..the
practice of making a sharp distinction between normal and
pathologically high pressure is entirely arbitrary and is in
the nature of artifact. Essential hypertension represents the
upper end of a distribution curve showing continuous variation, with no definite evidence of two populations.3”
In this issue of AJH, Jones et al. report preliminary results
of a study that focuses on specific hypertension phenotypes
in Africans.4 Six targeted candidate genes associated with
low-renin resistant hypertension were sequenced in Black
CYP11B2 was sequenced if the aldosterone level was
high (n = 9; primary aldosteronism phenotype); SCNN1b,
NEDD4l, GRK4, UMOD, and NPPA genes were sequenced
if the aldosterone level was low (n = 9; Liddle syndrome
phenotype). Several variants of these genes were found,
including some previously reported to be associated with
hypertension. As the authors indicate, a major weakness of
the study is the small sample size. Other weaknesses include
absence of patients with “normal” aldosterone, normal and
high renin hypertensive patients, and normotensive controls.
The strength of the study is the strategy of genotyping in patients with focused hypertension phenotypes.
Hypertension is not a homogenous disorder, and hypertension mechanisms differ among subgroups of patients. For
example, in the 1970s, based on standardized measurements
of plasma renin activity, Laragh et al. proposed a vasoconstrictor-volume hypothesis for understanding and treating
hypertension.5 Although acceptance of renin-guided treatment of hypertension is limited, the attempt to direct antihypertensive therapy to a specific physiological phenotype is an
important concept. Other researchers have documented the
value of noninvasive hemodynamic monitoring as a guide to
selecting an initial antihypertensive agent.
The results of the Jones report suggest that the search for
hypertension-related genes will benefit by “physiologic profiling.” To date, the most successful strategies for identifying
genetic variants contributing to hypertension have focused
on physiologic pathways known to be involved in blood pressure regulation. The rare monogenic forms of hypertension
have identified genetic variants involved in the regulation of
sodium excretion. In Jones’ preliminary study, the functional
relevance of the identified variants was not evaluated.
Because of their high incidence of hypertension and
hypertension-related cardiovascular/renal disease, African
Americans have been a focus of genome-wide association
studies. A distinct difference between the genetic architecture of Africans and African Americans is European
admixture in African Americans, ranging from 10 to 20%,
as estimated by a number of studies.6 Several genetic signals
have been found in African Americans that are associated
with systolic or diastolic blood pressure.7 Prominent signals
have been described in pathways of biologic relevance to
blood pressure regulation and hypertension. However, replication has been a challenge, possibly due, at least in part, to
heterogeneity of both the study populations and the hypertension phenotype.8
Another strength of the Jones report is its basis on Africans.
Genetic studies in African populations may be particularly
informative because of their complex history and high level
of genetic diversity.9,10 Modern humans originated in Africa
~200,000 years ago and spread across the globe within the
past ~100,000 years. Thus, modern humans have existed
continuously in Africa longer than in any other geographic
region and have maintained large population sizes, resulting
in high levels of genetic diversity, including more than 2,000
distinct ethnolinguistic groups.11 Genetic variation is greatest in populations of recent African ancestry. Consequently,
studies in African populations are likely to increase the yield
of rare variants and narrow the large chromosomal regions
Correspondence: Theodore A. Kotchen (
1Department of Medicine, Medical College of Wisconsin, Milwaukee,
Wisconsin, USA. Initially submitted January 23, 2017; date of first revision January 25,
2017; online publication February 28, 2017.
© American Journal of Hypertension, Ltd 2017. All rights reserved.
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466 American Journal of Hypertension 30(5) May 2017
Table 1. Potential contributors to the “heritability gap” of hypertension
Genetic heterogeneity within and across populations
Different hypertension phenotypes
The likelihood that multiple independent genetic variants each account for only small blood pressure variability
Epigenetic (environmental and lifestyle) modifications of gene expression
Lability of blood pressure
Rare variants that are poorly detected by existing genotyping arrays
Low power to detect gene–gene interactions
Inflated estimates of heritability
of association identified in “younger” populations, due to
extended linkage disequilibrium.
New funding opportunities are becoming available for
genomic research in Africa. For example, in 2010, NIH and
Welcome Trust, in partnership with the African Society of
Human Genetics, introduced a plan to support genomic
research in Africa—The Human Hereditary and Health (H3)
in Africa initiative.12 H3 Africa has been useful in leveraging
additional funding from local sources. These initiatives have
the potential to stimulate genomic research in Africa that
will contribute to the understanding of the genetic determinants of hypertension.
The author declared no conflict of interest.
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American Journal of Hypertension 30(5) May 2017 467
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