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Looking for love in all the wrong places.—

Recorded by Johnny Lee

The sequencing of the human nuclear genome was a marvelous scientific feat. Many clinicians and scientists involved in hypertension research sensed a mood of exhilaration that finally the genetics of hypertension would be revealed and that the gene(s) in-part responsible for this greatest of cardiovascular health problems would be revealed.

Thus, some of the largest “fishing expeditions” known to science were carried out without much to show for it. There is nothing inherently wrong with a fishing expedition provided one can identify the fish for which one is looking. Therein lies the rub. The disease hypertension is usually identified for population studies by an increase in the biomarker, blood pressure. The signal is captured by a snapshot recorded in one setting, ie, the clinic. This continuous variable, which is not only a biomarker, but a vital sign as well, is perhaps not suited to distinguish completely the hypertension phenotype.

An example of such a large study was the genome-wide association study of blood pressure and hypertension.1 Data collected from 29,136 patients identified 13 SNPs for systolic blood pressure, 20 for diastolic blood pressure, and 10 for hypertension (blood pressure again?). This search was not driven by a hypothesis for particular genes.

A slightly different approach was used by a group of Chinese investigators.2 Realizing that hypertension is multifactorial and associated with endothelial dysfunction and oxidative stress, these investigators examined the potential for mitochondrial DNA mutation in a cohort of matrilineal hypertension. Oxidative stress might result from abnormalities in mitochondrial respiration, eg, uncoupling of pathways for adenosine triphosphates synthesis. Mitochondrial abnormalities have been found in both human and experimental hypertension.

A total of 106 patients from a large Chinese family underwent clinical genetic, molecular, and biochemical evaluation. Fifteen of 24 adult matrilineal relatives exhibited a wide range of severity in hypertension. Mutational analysis of their mitochondrial genomes identified a novel homoplasmic m.4263A>G mutation in MT-T1, which codes for mitochondrial tRNA for isoleucine. The mutation was located at the processing site for the tRNAIle 5′ end precursor. Impaired mitochondrial capacity was demonstrated by malate/glutamate-promoted respiration, succinate/glycerol-33-phosphate–promoted respiration, or N,N,N′,N′-tetramethyl-p-phenylenediamine/ascorbate–promoted respiration and the increasing level of reactive oxygen species in lymphoblastoid cell lines carrying the 4263A>G mutation.

This targeted study that had a more highly refined phenotype and was tied to a pathophysiological mechanism is the prototype of studies that are likely to increase our understanding of the genetic and environmental factors responsible for hypertension and associated abnormalities. Mitochondrial abnormalities have already been linked to the cardiometabolic syndrome. In a superb editorial accompanying this paper, Marian states, “The strength of the study is in robust multilevel mechanistic characterizations of biological and functional significance of the mutated mtDNA. In this aspect, the study is exemplary.”3

If the problem of hypertension is to be solved there must be involvement of clinician-scientists and continued phenotypic refinement. For the elimination of the consequences of hypertension, it is likely that treatment will begin before there is any increase in systemic arterial blood pressure.

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