Hypertension: Essential No More?
The publication on September 11, 2011 of two important studies (1,2) on the genetics of hypertension prompt the question: Can we really say that hypertension is “essential”?
Dr Eric Topol from Scripps Research Institute,La Jolla , CA
It had been estimated that around 30% of variation in blood pressure is due to genetic factors. These newer studies might result in an upward revision of this estimate as we gain a greater understanding of the role of genetic factors in these established and novel pathways involved in the regulation of blood pressure.
I would recommend that you read the article by Claire Hastie in the International Journal of Hypertension. She discusses the arguments supporting a genetic basis for hypertension and the GWAS approach to this problem. Hastie makes the point that multiple studies support a genetic basis for hypertension. These include data demonstrating that hypertension is about twice as common in individuals who have one or two hypertensive parents, and blood pressure is more closely correlated in monozygotic than dizygotic twins. Other analyses adding to the evidence for a genetic basis include studies of rare monogenic forms of hypertension associated with major defects in renal salt handling, as well as family aggregation studies indicating the presence of a heritable component.
Some basic information about GWAS:
The genes identified included three in the cyclic guanosine monophosphate (cGMP) system, involved in the excretion of salt and the relaxation of blood vessels. Six of the loci included genes that had already been linked with high blood pressure – GUCY1A3–GUCY1B3, NPR3–C5orf23, ADM, FURIN–FES, GOSR2, and GNAS–EDN3. The study initially found links with people of European ancestry, but further research showed connections in individuals of East Asian, South Asian or African ancestries.
The study in Nature Genetics was a GWAS approach to pulse pressure (PP) and mean arterial pressure (MAP). They examined over 110000 subjects and identified four new pulse pressure loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new mean arterial pressure loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN).
What are the implications of these results? The most important is that studies to identify new disease causing pathways can begin. This will provide considerable new information on the pathophysiology of hypertension. These studies might also broaden our understanding of the inter-connection of various pathways in the regulation of hypertension. For example, in the Nature Genetics study, three of the new variants, which influence pulse pressure, appeared to have opposite effects on systolic and diastolic BP. The other important implication of these studies is the power of collaboration: starting fromm the collaborative work that embodied the Human Genome Project and the International HapMap Project these projects demonstrate the benefit of networks of centers and investigators working together.
Bottom Line: Are we ready to drop the term "Essential Hypertension"? No, but GWAS studies like the ones published in Nature and Nature Genetics are breakthroughs that should transform our understanding of some of the pathways that lead to hypertension.
References
1. The International Consortium for Blood Pressure Genome-Wide Association Studies. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 2011; DOI:10.1038/nature10405.
2. Wain LV, Verwoert GC, O'Reilly PF, et al. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. Nature Genetics 2011; DOI:10.1038/ng.922.
Dr Eric Topol from Scripps Research Institute,
It had been estimated that around 30% of variation in blood pressure is due to genetic factors. These newer studies might result in an upward revision of this estimate as we gain a greater understanding of the role of genetic factors in these established and novel pathways involved in the regulation of blood pressure.
I would recommend that you read the article by Claire Hastie in the International Journal of Hypertension. She discusses the arguments supporting a genetic basis for hypertension and the GWAS approach to this problem. Hastie makes the point that multiple studies support a genetic basis for hypertension. These include data demonstrating that hypertension is about twice as common in individuals who have one or two hypertensive parents, and blood pressure is more closely correlated in monozygotic than dizygotic twins. Other analyses adding to the evidence for a genetic basis include studies of rare monogenic forms of hypertension associated with major defects in renal salt handling, as well as family aggregation studies indicating the presence of a heritable component.
Some basic information about GWAS:
- GWAS stands for genome-wide association study.
- GWAS entails an examination of an individual’s genome. A comparison is made of cases (with a particular trait or disease) versus controls (those without the trait or disease). Briefly, each subject in the study provides a sample of cells, e.g., swabs of cells from the inside of the cheek. DNA is extracted from these cells, and spread on gene chips and the DNA is sequenced. These chips are read into computers, where they can be analyzed with sophisticated bioinformatic techniques. Variations in single nucleotides (or single nucleotide polymorphisms (SNP’s)) are identified.
- Two methods are used to search for disease-associated mutations: hypothesis-driven and non-hypothesis driven methods. Hypothesis-driven methods start with the hypothesis that a particular gene may be associated with a particular disease and then seeks to find an association. Non-hypothesis-driven studies scan the entire genome and then looks for those genes demonstrating an association. GWAS analyses are generally non-hypothesis-driven. If certain genetic variations are found to be significantly more frequent in people with the disease compared to people without disease, the variations are said to be "associated" with the disease.
- Surprisingly, most of the SNP variations associated with disease are not in the region of DNA that codes for a protein. Instead, they are usually in the large non-coding regions on the chromosome between genes, or in the intron sequences that are edited out of the DNA sequence when proteins are processed. These are presumably sequences of DNA that control other genes, but usually, their protein function is not known.
The genes identified included three in the cyclic guanosine monophosphate (cGMP) system, involved in the excretion of salt and the relaxation of blood vessels. Six of the loci included genes that had already been linked with high blood pressure – GUCY1A3–GUCY1B3, NPR3–C5orf23, ADM, FURIN–FES, GOSR2, and GNAS–EDN3. The study initially found links with people of European ancestry, but further research showed connections in individuals of East Asian, South Asian or African ancestries.
The study in Nature Genetics was a GWAS approach to pulse pressure (PP) and mean arterial pressure (MAP). They examined over 110000 subjects and identified four new pulse pressure loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new mean arterial pressure loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN).
What are the implications of these results? The most important is that studies to identify new disease causing pathways can begin. This will provide considerable new information on the pathophysiology of hypertension. These studies might also broaden our understanding of the inter-connection of various pathways in the regulation of hypertension. For example, in the Nature Genetics study, three of the new variants, which influence pulse pressure, appeared to have opposite effects on systolic and diastolic BP. The other important implication of these studies is the power of collaboration: starting fromm the collaborative work that embodied the Human Genome Project and the International HapMap Project these projects demonstrate the benefit of networks of centers and investigators working together.
Bottom Line: Are we ready to drop the term "Essential Hypertension"? No, but GWAS studies like the ones published in Nature and Nature Genetics are breakthroughs that should transform our understanding of some of the pathways that lead to hypertension.
References
1. The International Consortium for Blood Pressure Genome-Wide Association Studies. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 2011; DOI:10.1038/nature10405.
2. Wain LV, Verwoert GC, O'Reilly PF, et al. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. Nature Genetics 2011; DOI:10.1038/ng.922.
