Preparation for hypertension specialists:

Abstract

Genomics is a discipline in genetics that applies recombinant DNA, DNA sequencing methods, and bioinformatics to sequence, assemble, and analyze the function and structure of genomes, the complete set of DNA within a single cell of an organism. Research into the genetics of hypertension has now expanded to genomics. Two approaches have dominated this field. One relies on large populations in which the phenotype, hypertension versus no hypertension, or hypertension-relevant phenotypes are compared. Genome-wide association (GWAS) analyses of (>1 million) common variants identify relevant loci and possible genes exerting small effects. Detailed studies on APOL1 and SH2B3 are opening entire new fields of research. Family-based Mendelian studies have identified rare variants that exert very large effects on blood pressure. Mechanistically, these studies have been a bonanza of new information. The approaches are complementary. Genome-wide association studiesEssential (primary) hypertension results from many environmental and genetic factors.Candidate-gene, genome-wide linkage, and genome-wide association studies (GWAS) relying on single-nucleotide polymorphisms (SNPs) have all given insights into genes relevant for essential hypertension. Candidate gene studies have implicated aberrations in aldosterone signaling, catecholamine pathways, ion channel regulation, and inflammatory pathways. For GWAS, massive sample sizes have been used (>80,000 individuals) to find gene loci that exert only modest effects. Memorizing these genes and their variants seems counterproductive since thus far they collectively explain only about 2.5% of blood pressure variation. Nevertheless, ranking all the currently known findings could theoretically produce a genetic risk score indicating a 25% increase in the odds of developing essential hypertension.High-throughput massive parallel sequencing and the plummeting costs (currently about

Genetic Programming of Hypertension

“…Glucocorticoid-remediable aldosteronism, an autosomal dominant disorder, was the first monogenic HTN syndrome to be identified ( 6 ). GRA is caused by a chimeric gene formed from the fusion of the promoter region of the 11 β-hydroxylase gene ( CYP11B1 ) with the coding regions of the aldosterone synthase gene ( CYP11B2 ) on chromosome 8q ( 7 , 8 ). As a result of this chimeric gene, aldosterone production is activated by ACTH and becomes independent of renin regulation ( 7 ).…”

“…The increased salt reabsorption reduces sodium delivery to the cortical collecting duct, facilitating increased potassium absorption and hyperkalemia, which is typical of Gordon syndrome. ROMK channels, which aid in potassium excretion, can also be inhibited by the WNK4 mutation, further causing hyperkalemia ( 8 ). Other metabolic abnormalities in Gordon syndrome include mild hyperchloremic metabolic acidosis, hypercalciuria, low urinary sodium excretion ( 26 ), low serum renin, and varying aldosterone levels.…”