Gene Finding Could Help Show Who Really, Really Needs To Cut Down On Salt

Just about all of us need to cut down on the salt we eat, according to public health guidelines. But some of us — those with high blood pressure that is sensitive to salt — really need to cut down.

New research out in the journal Physiological Genomics suggests that DNA analyses may come to help identify which Americans with high blood pressure have a form sensitive to salt, thus making it worth extra effort to maintain a low-salt diet.

I spoke with Boston University associate professor of pharmacology Richard Wainford about the study. Our edited conversation:

Let's begin with how incredibly prevalent both high blood pressure and salt sensitivity are.

With the recent changes in the guidelines on what level of high blood pressure equals hypertension, staggeringly, one in two U.S. adults have high blood pressure. It's an astounding number.

And what's even more interesting is this phenomenon of salt sensitivity: You and I could go out for lunch and one of us is likely to be salt-sensitive. That means that when we eat our lunch, which is loaded with salt, in one of us, the blood pressure will go up. You'd be termed salt-sensitive. The other person will be salt-resistant. In the person who has salt sensitivity of blood pressure, what they eat causes a short spike in blood pressure. This can lead to damaging cardiovascular events, and over time, hypertension, which is the number one non-communicable cause of mortality in the world.

When people are salt-sensitive, do we generally know it?

The honest answer to that is no. It's incredibly time-consuming and challenging to tell who is salt-sensitive and who is salt-resistant. Your clinician can't do a quick test. The gold standard involves administering high and then low dietary sodium intake in controlled settings for a three-week period, and measuring their blood pressure response to changes in salt intake.  Clinically, that's not a good tool.

Fifty percent of people who have high blood pressure were termed salt-sensitive under the old guidelines. That number may increase. So it's a huge public health issue. The CDC are aware of it. One of the staggering numbers is: the American Heart Association has guidelines of how much salt we should eat. Would you believe that 99.9 percent of Americans exceed that every single day? Over a lifetime, we're all eating more salt than is being recommended for us.

So if I could say,  I've got a very easy, rapid way to tell if you're salt-sensitive or not, it would aid the clinical diagnosis, and also the way that we treat hypertension.

So ideally, you could check my genes and say, oh, I see you're overwhelmingly likely to be salt-sensitive?

That's the goal. And the federal government is actually encouraging research into this area. My goal would be, based on what we build in the future, I could do a blood draw, we send your blood away the same as we do to screen for cholesterol, and we'd also screen for a mutation in this gene. If you were positive,  we would have a very strong indication based on our data with this one gene, that there's a strong chance you're going to be salt-sensitive.

So how would you sum up what you are reporting in this paper?

What we are reporting is a way to identify a specific subset of patients who are salt-sensitive.

And how did you get there?

I'm very interested in integrative whole physiology --  how does our body work? How does our body respond to challenges? And we know so little about salt. We don't know how the body truly senses salt. We don't know how it's handled,  where it goes.

So I started off my research in that: I was interested in high blood pressure, I'm interested in dietary salt intake. Some basic animal studies we've conducted over the last five years have shown that this protein that I'm studying — a G-protein signaling protein in the brain --  responds to salt intake in animals.

It's incredible. If you have a salt-resistant animal, if you give them dietary salt, this protein's expression level goes up in a specific brain region to help remove salt from the body. If you reduce dietary salt, the animal decreases this protein to retain the salt in the body. And we studied this protein across salt-resistant animals, but I wanted to know whether alterations or changes in this protein are present in humans. And do they tie in to the phenomenon of salt sensitivity?

So how did you move to humans?

The key was a big Japanese hypertension study, the Millennium Hypertension Study, where they found that a mutation in a gene that makes the protein that I'm studying was associated with the development of hypertension. But there was no link to salt sensitivity of blood pressure in this study.

So I needed to find a different resource, and I was fortunate enough to find a study called the Genetic Epidemiology of the Salt Sensitivity of Blood Pressure Study that was conducted many years ago in a Chinese Han population, in which we knew the salt sensitivity of blood pressure. I was able to access the genetic data that was generated in that study and look for mutations in this new protein that I discovered impacted salt sensitivity in animals.

We wanted to see, if you have a mutation in this gene  -- the GNAI2 gene that encodes the G-Alpha12 protein -- does it appear in people who are salt sensitive more frequently than people who aren't? And that was the analysis we did. We discovered that if you have mutations in this GNAI2 gene, your odds of being salt-sensitive are much greater. And 33 percent of patients who are defined as salt sensitive had this mutation. So it appears to be a pretty strong association going on there.

We have a new NIH grant funded on this work that will be running through the next few years. The caveat to the data is that it was conducted in a Chinese Han population, which doesn't represent the population we have in America particularly well. So I'm using  genetic material from a different patient cohort containing the melting pot of America — with African-American ancestry, with Caucasian ancestry, Asian-American ancestry — to validate our findings in US patients.

So to sum up?

One really easy way to translate this would be: in our study, if you have this mutation in our gene of interest, you're three times more likely to be salt sensitive than patients that don't have the mutation. So you are at greater danger of being salt sensitive and the associated adverse cardiovascular outcomes.

And in the future, that could help us avoid those adverse outcomes?

Correct.  Currently, clinicians do not have an empirical way to say, "You are actually salt-sensitive." And reducing your dietary salt intake is actually harder than it sounds. I believe the power of this is that it has the potential to give the clinician a yes or no answer, and can help make a patient say, "Hey, you know what, maybe I really do need to crack down and change this, because I have this gene mutation."