Salt Handling And Hypertension

There have been a large number of studies of genes associated with hypertension. It is been estimated that heritability contributes to about 30-35% of blood pressure levels. A high dietary sodium and low potassium intake interact with certain genes to determine blood pressure.

Genome-Wide Association Studies (GWAS) have found a great number of genes associated with hypertension. Most of these genes involve sodium or potassium in one fashion or another. Many of the genes determine either channels that sodium or potassium pass through, transporter proteins for the ions, or ion pumps. A recent review (1) of several salt handling (sodium handling) genes in the kidney was done in 2014.

Kidney Salt Handling

Salt Handling Gene Chart
Genetic Variant Blood Pressure in Red

Each gene for salt handling in the cells of the kidney has rare variants. Although any individual gene variant is rare, there are a fair number of them in total. There are so many that these rare variants are probably what account for the wide variation in blood pressure, and the wide variation in blood pressure's sensitivity to salt (2).

There are two well known inherited syndromes, known as Gitelman's and Bartter's syndromes, which have been proven to be caused by such variants. These salt handling genes affect sodium reabsorption and cause salt wasting by the kidneys.

And they show how there can be a variation in how such genes affect people. Bartter's syndrome causes serious health problems very early. It often presents while the child is still in the womb, and almost always before age 6. Gitelman's causes similar problems, but varies by being less severe. It usually does not present itself until adolescence or early adulthood. In some people it is so mild that it may go undetected.

Other Salt Handling Variants

There are only a few genes involved in these two syndromes. However, there are many other gene variants that affect sodium movement in the cell. There are other genes affecting sodium reabsorption in the kidney. And there are many more that affect potassium in the cell.

These variants have more subtle effects. They probably contribute to the variation in when the salt wasting becomes apparent in these two syndromes. And they would be expected to take longer to have a noticeable effect on health in people without one of the syndromes.

Since each individual gene variant is rare, only about 1% of the population is estimated to be a carrier of any particular variant. However, because there are estimated to be a great number of variants, they are felt to commonly contribute to blood pressure variation. But the result of one of these variants would not be as extreme as occurs in the two known salt wasting syndromes.

Only a few of the gene variants associated with hypertension are felt to cause an increase in gene function. We discussed here one of the variants that increased the function of a potassium channel in certain adrenal gland cells. The original study (3) finding this increase in function stimulated a great deal of research.

The subsequent research resulted in an estimate that 90% of gene variants in channels reduce the function of the channel. This reduction in function is known to result in a reduction in the electrical charge within the involved cells.

Among effects of a reduced charge is slower passage of ions. In the case of kidney cells, the major salt handling variant is involved in the reabsorption of sodium. This slower passage of ions means less reabsorption of sodium by the kidney.

Effect Of Less Salt Reabsorption

When less sodium is reabsorbed, a person is beter protected against a high intake of sodium. These people can eat more sodium before they have a rise in blood pressure. And this protection against hypertension lasts throughout the person's lifetime.

This particular study (1) reviewed 3 genes involved in the sodium reabsorption in the kidney. Each of these 3 genes had a large effect on blood pressure. Depending upon the exact type of effect, there will be a variation in the amount of sodium resorbed, and thus in the susceptibility to high blood pressure. The chart shown above is adapted from (2). It shows the mean systolic blood pressure for those who do not carry one of the variants, and the lower systolic pressure for those who do carry one of the variants.

We discussed a similar gene in the post here about the Sardinian centenarians. Although through a slightly different mechanism, the result of the genetic variation was less sodium reabsorption. This particular gene was present in 14% of the centenarians, which is much higher than the non-variant gene in the general population. In fact it is approximately 14 times as common as the 1% variation estimated for genes of this sort.

Because of this high multiple, it is likely that this gene contributes to the longer functional life found in the Sardinian centenarians. As will be discussed in a future post, the activity of these types of genes is more of a factor contributing to a longer life than is the effect from the pressure itself. The electrical charges within the cell are what matters. The electrical charges determine how your cells function, and thus how well your body functions.

Why Some People Have Less Effect From Salt

Thus we can see that the variability in blood pressure is related to the gene variants in the potassium channels, sodium channels, potassium transporters, and sodium transporters, as well as the sodium potassium pump. The interaction of these cellular structures determines the electrical charges within the cell. If the cells with gene variants are located in the heart, the result is a greater or lesser susceptibility to heart failure, as discussed in this post. If they are in the adrenal gland, they will affect blood pressure as discussed in this post. If they are in the kidney, they will affect sodium reabsorption and thus also affect blood pressure. And if they are located in all cells throughout the body, the results will be determined by the degree to which each cell's function is affected.

If the estimate of 30-35% of blood pressure being genetic is broadly applicable to other functions of the body, then 65-70% of how well your body functions is not genetic. The choices you make in diet, physical activity, and habits (smoking, for example) are more important than genetics.

Too Early For Gene Profiles To Help You

Genetic studies are all in an early stage of application to human health. Although they are consistent with the importance of the potassium sodium ratio in the diet, they need further studies (the usual caveat of the scientist) to show the specifics of the genetic interaction with the dietary potassium sodium ratio. It is doubtful that there will ever be a population study that will show specifically that the potassium sodium ratio has a linear relationship with mortality for hypertension.

Higher Potassium Sodium Ratio Helps

However, multiple epidemiology studies have shown the importance of potassium, and the importance of sodium, in determining blood pressure. There have also been multiple animal studies showing how different levels of potassium and sodium in the diet affect cells in the animals. These types of genetic studies show the variations in cells that can account for the effects in the animals. If more studies are done with pure genetic variants in animals, then the diet can be varied in the genetically variant animals to show a relationship of diet to cellular changes, such as was done in the series of heart failure studies discussed here.

Such studies will make it possible to know how high a potassium sodium ratio you need in your diet to avoid the problems of hypertension. Specific gene combinations can be assessed for the ratio that prevents the electrical charge changes leading to cellular dysfunction. You will be able to adjust your diet to your genetic profile.

It will be unusual that anyone will need more sodium than the present minimal recommendation from the Institute of Medicine. Salt wasting conditions, such as Gitelman's and Bartter's syndromes, would be such a situation, but are quite rare. And they are usually discovered at an early age. Other conditions requiring more sodium are unusual in the absence of disease.

Most people will need a higher potassium sodium ratio in their diet than they get in the typical American diet. But the ratio to protect against the health problems associated with hypertension will vary. Some will only need a slightly higher ratio, and others will need more. But the vast majority will be able to find a ratio in their diet that will protect against hypertension and its potentially devastating effects.
1. Rare mutations in renal sodium and potassium transporter genes exhibit impaired transport function. Welling PA. Curr Opin Nephrol Hypertens. 2014 Jan;23(1):1-8. doi: 10.1097/01.mnh.0000437204.84826.99.

2. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Ji W, Foo JN, O'Roak BJ, Zhao H, Larson MG, Simon DB, Newton-Cheh C, State MW, Levy D, Lifton RP. Nat Genet. 2008 May;40(5):592-9. doi: 10.1038/ng.118. Epub 2008 Apr 6.

3. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Choi M1, Scholl UI, Yue P, Björklund P, Zhao B, Nelson-Williams C, Ji W, Cho Y, Patel A, Men CJ, Lolis E, Wisgerhof MV, Geller DS, Mane S, Hellman P, Westin G, Åkerström G, Wang W, Carling T, Lifton RP. Science. 2011 Feb 11;331(6018):768-72. doi: 10.1126/science.1198785.

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