Sardinia has a Blue Zone, made famous by Dan Buettner for its high percentage of centenarians. Due to its long-standing isolation, low immigration rate, and fairly uniform lifestyle, Sardinia is a great location to study genetic traits associated with longevity. There have been multiple studies of older Sardinians, including studies of the genetics of hypertension. Many genes affect hypertension. As discussed here, a Genome-Wide Association Study (GWAS) is a screening method to look for possible genes associated with a disease. It is especially helpful for diseases involving multiple genes, such as hypertension.
However, it only shows an association. After screening, other methods are needed to determine if and how a gene affects a disease. A recent article (1) used some of these other methods to show that a particular sodium reabsorption gene (ATP1A1) that was not found by GWAS was involved in hypertension in older men in Sardinia.
Sodium Reabsorption Gene
Primary hypertension is divided into 2 large categories – salt sensitive and non-salt-sensitive. In salt sensitive hypertension small increases in sodium in the body lead more easily to hypertension. The kidneys play a large role in hypertension because they reabsorb sodium. The reabsorption may lead to more sodium in the body.
In this recent study, researchers showed a major influence on blood pressure from a change in a gene (ATP1A1) that is involved in regulating the reabsorption of sodium by certain cells in the kidney. This sodium reabsorption gene is also involved in maintaining the sodium potassium balance in the cells that line blood vessels. When there is imbalance, the vessel lining cells become stiffer.
This particular gene is a gene that regulates the sodium potassium ATPase pump. The sodium potassium ATPase pump comes in several variations, but there is only one variation found in these particular kidney cells and in the blood vessel lining cells. Thus when this gene is affected, it has a major effect on how much sodium is reabsorbed by the kidneys and how stiff the blood vessels are. If the effect is to slow down the pump, less sodium is reabsorbed in the kidney, and the effect on blood pressure of excessive sodium in the diet will be less.
The researchers studied several hundred of the older men and women in Sardinia for two forms of this gene. They looked at 678 older (> 60 years old) Sardinians and determined the difference in blood pressure in those with the common form of the gene, and those with a variant of the gene. In women the difference in the sodium reabsorption gene produced no difference in blood pressure. But in the men there was a large difference in blood pressure.
After finding that those men who had the variant had lower blood pressure (12mm Hg systolic and 6 mm Hg diastolic) than those with the usual gene, the researchers checked that the common gene and its variant both were functional. They used the two variations in cell lines grown in tissue culture. They found that both gene variations were functional.
Then they raised mice with the altered gene, and found a difference in blood pressure compared to those mice with the unaltered gene. Those with the altered gene produced 58% less protein from the gene, and had much lower blood pressure (17 mm Hg lower systolic).
Although this gene is not the only cause of high blood pressure, this study shows that a change in this sodium reabsorption gene will cause a change in blood pressure in humans, as well as mice. This is the kind of confirmational experiment that is needed when association studies are done on human populations.
Not Just Another Association Study
By testing a hypothesis with experiments, fewer misinterpretations of association studies will occur. In this case, the researchers saw an association of different blood pressure levels with two variations in a gene in humans. They tested the hypothesis that the two variations of the gene affected blood pressure differently. First they isolated the different variations of the gene and showed that both variations were functional. Then they showed that the uncommon variation slowed sodium reabsorption by certain kidney cells. Finally they showed that the two different variations of the gene had the same effect on blood pressure in mice as in humans.
So we have another piece of evidence showing the importance of the potassium sodium ratio in hypertension. The model proposed by Dr Guyton, discussed here, and now in medical textbooks, has another piece supporting it.
In this particular case, the study shows the importance of the sodium potassium pump in the kidney to maintain a proper level of sodium, and to prevent too much sodium from accumulating in the body. This study provides another piece of evidence that the accumulation of sodium in the body leads to hypertension, and that the potassium sodium ratio is important for blood pressure.
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1. A Functional 12T-Insertion Polymorphism in the ATP1A1 Promoter Confers Decreased Susceptibility to Hypertension in a Male Sardinian Population. Herrera VL, Pasion KA, Moran AM, Zaninello R, Ortu MF, Fresu G, Piras DA, Argiolas G, Troffa C, Glorioso V, Masala W, Glorioso N, Ruiz-Opazo N. PLoS One. 2015 Jan 23;10(1):e0116724. doi: 10.1371/journal.pone.0116724. eCollection 2015.