Friday, February 19, 2016

Rare Diseases and the Quantitative Traits of Common Diseases

"Only theory can tell us what to measure and how to interpret it." - Albert Einstein

Though hypertension influences the development of a great many serious co-morbidities (e.g., renal failure, stroke, heart failure), those of us inclined to dwell on technicalities will insist that hypertension is not a disease; it is a physiologic measurement. Hypertension occurs when our blood pressure rises above a certain quantitative threshold, but there is no specific pathologic finding that characterizes hypertension; nor is there a specific clinical phenotype that tells us that an individual with hypertension is ill. It is best to think of hypertension as a quantitative trait that signals a complex problem.

What is the quantitative measure of hypertension? Definitions vary, but an often-used cut-off is a systolic blood pressure exceeding 140 mm Hg, or a diastolic pressure exceeding 90 mm Hg. It is estimated that 25% of adults and over one billion people worldwide are hypertensive (1), (2). Because high blood pressure is a quantitative trait, and not a disease, the majority of the occurrences of hypertension cannot have a monogenic cause. Theory, strengthened by empiric observations, informs us that quantitative traits have multi-factorial causes, and that inherited quantitative traits have non-Mendelian inheritance. The non-Mendelian origin of inherited quantitative traits has been recognized since the early studies of RA Fisher, in 1919 (3), (4), (5). Research scientists could have saved themselves a great deal of effort, over the past few decades, searching for a specific genetic cause for commonly occurring cases of hypertension, had they simply recognized that hypertension is a quantitative trait, not a disease.

We typically find that hypertension co-occurs with rare diseases such as fibromuscular dysplasia, hyperaldosteronism, and various channelopathies; and common diseases such as metabolic syndrome, stroke, and left ventricular hyperplasia. Fibromuscular dysplasia is a rare condition of arteries wherein pathological growth of the artery's muscular wall produces a functional narrowing of the artery at the dysplastic site. Fibromuscular dysplasia occurs most often in young-to-middle aged women, but cases have occurred at every age and in either gender. Its cause is unknown. When fibromuscular dysplasia occurs in a renal artery, the blood flow to the kidney distal to the point of narrowing is reduced, thus producing an orchestrated physiological response of the renin-angiotensin-aldosterone system that produces hypertension.

Here is how the renin-angiotensin-aldosterone system works. Specialized cells located at the root of the glomeruli (i.e., the juxtaglomerular cells) release renin into the general circulation when the blood pressure drops. Renin is involved in a pathway that produces a powerful vasoconstrictor (i.e., angiotensin II) in the lungs. This same vasoconstrictor stimulates the adrenal cortex to secrete aldosterone (part of the mineralcorticoid system), which causes the kidney to increase its absorption of sodium and water; thus increasing the volume of fluid in the body. Increased blood volume produces an increase in blood pressure. In summary, when fibromuscular dysplasia reduces the blood floow to the kidney, the kidney responds as if there were a system-wide drop in blood pressure, setting into motion a two connected pathways that increase blood pressure. Because the hypertensive response does not "turn off" the localized hypotensive effect of fibromuscular dysplasia, the renin-angiotensin-aldosterone response stays "on" permanently, contributing to ever-worsening hypertension.

Observations of hypertension resulting from fibromuscular dysplasia of the renal artery, would suggest that variants of any components of the renin, angiotensin, or aldosterone system could contribute to quantitative alterations in blood pressure. As it happens, most of the rare monogenic and Mendelian forms of hypertension are associated with proteins involved, in one way or another, with the transport of electrolytes in the renal tubules, resulting in increased retention of sodium and to an increased volume of body fluid, and the enlistment of the mineralcorticoid system (6), (7), (8), (9), (1).

Rare causes of hypertension dovetail with medically proven methods for treating and preventing common hypertension. Standard therapies for treating hypertension include drugs that target the angiotensin pathway (i.e., angiotensin converting enzyme inhibitors, angiotensin receptor blockers, renin inhibitors, and diuretics. The mainstay of prevention is dietary salt reduction (10).

Genome wide association studies have yielded several dozen genes associated with commonly occurring hypertension (11), (2). These associated genes seem to account for a very small portion of the occurences of hypertension in the general population (11). The function of the majority of the associated genes is unknown at present.

There are numerous genetic and environmental causes of hypertension, targeting a wide variety of cellular pathways and anatomic sites. As examples, the different causes of hypertension may include: over-activity of the renin-angiotensin system; defects at various sites of the renal tubule, arterial wall pathology; and increased salt consumption. Regardless of the underlying cause of hypertension, all inherited and acquired forms of the disease produce hypertension through the same, final pathway: increased net salt balance, leading to increased intravascular volume, leading to augmented cardiac output, leading to elevated blood pressure (1). Because all causes of hypertension produce an increase in net salt balance, almost all individuals with hypertension will respond to treatment with diuretics such as hydrochlorothiazide or furosemide, that reduce the reabsorption of sodium in the kidneys. A common, final mechanism accounting for all causes of hypertension, is an example of disease convergence. Disease convergence is an extremely important concept, as it provides an opportunity to treat many different diseases with a single medication, if they converge to the same pathway.

Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.

- Jules Berman (copyrighted material)

key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, common diseases, hypertension, jules j berman


[1] Lifton RP, Gharavi AG, Geller DS. Molecular Mechanisms of Human Hypertension. Cell 104:545-556, 2001

[2] International Consortium for Blood Pressure Genome-Wide Association Studies. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478:103-109, 2011.

[3] Fisher, RA. The correlation between relatives on the supposition of Mendelian inheritance. Trans R Soc Edinb 52:399-433, 1918.

[4] Ward LD, Kellis M. Interpreting noncoding genetic variation in complex traits and human disease. Nature Biotechnology 30:1095-1106, 2012.

[5] Visscher PM, McEvoy B, Yang J. From Galton to GWAS: quantitative genetics of human height. Genet Res 92:371-379, 2010.

[6] Lifton RP. Molecular genetics of human blood pressure variation. Science 272:676-680, 1996.

[7] Wilson FH, Kahle KT, Sabath E, Lalioti MD, Rapson AK, Hoover RS, et al. Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. Proc Natl Acad Sci USA. 2003 100:680-684, 2003.

[8] Bahr V, Oelkers W, Diederich S. Monogenic hypertension. Journal Med Klin (Munich) 98:208-217, 2003.

[9] Warnock DG. Liddle syndrome: genetics and mechanisms of Na+ channel defects. Am J Med Sci 322:302-307, 2001.

[10] Hideaki Nakagawa H, Katsuyuki Miura K. Salt reduction in a population for the prevention of hypertension.Environ Health Prev Med 9:123-129, 2004.

[11] Cowley AW Jr, Nadeau JH, Baccarelli A, Berecek K, Fornage M, Gibbons GH, et al. Report of the National Heart, Lung, and Blood Institute Working Group on epigenetics and hypertension. Hypertension 59:899-905, 2012