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Do you think you have NCGS–gluten sensitivity? Proceed with caution in age of mail order genetic tests

| July 6, 2015

Summer gatherings with family and friends often revolve around food, and provide an opportunity to hear everyone’s take about new dietary fads. One such fad obvious to anyone walking the aisles of today’s supermarkets is the avoidance of gluten, even by people who don’t suffer from celiac disease, because they believe they have a gluten-related condition.

Celiac disease is a debilitating, life-threatening condition that is set off by the body’s immune system destroying the inner lining of the small intestine, due to the presence of gluten in the diet. It afflicts an estimated 1 percent of the population, but roughly 18 percent of the population today say they are eating gluten-free. For many such people, the rationale is the presumed presence of a condition known as “non-celiac gluten sensitivity (NCGS)“.

Used sometimes when people experience various non-specific gastro-intestinal symptoms in connection with eating grains and other gluten-containing foods, NCGS is a wishy-washy diagnosis, not an established medical condition like atherosclerosis, lung cancer or for that matter celiac disease. The very same researchers who first proposed the entity NCGS in 2011 based on an initial study, later concluded that NCGS actually doesn’t exist, based on additional research with better statistical power than their earlier study. Rather, the symptoms that many people experience in connection with grainy foods are just plain, old irritable bowel syndrome (IBS), caused by difficulty digesting various kinds of carbohydrates, which thus become fermented by microorganisms in the colon. It’s uncomfortable and can be debilitating, but it’s not caused by the gluten in the grainy foods, and does not involve an immune reaction the way that celiac disease does.

Thus, avoiding foods lacking specifically gluten will not help if you really don’t have celiac disease. And yet, in a recent summer gathering, a mother told me that her child was eating gluten-free after being diagnosed with NCGS in a genetic test.

How could this be? The mother is a pediatric nurse, not a medically illiterate, anti-vaccination science-hater who goes to homeopaths instead of real doctors. People rejecting real medicine, unfortunately, are common where I live, in Portland, Oregon. But such people also would not opt for a genetic test. So what then is going on here?

The answer, it seems, is that we’re in the 23andMe age. People are taking various genetic tests, often paying for them out-of-pocket, and doing it on their own with mail-in kits. And when they get the results, they’re taking them out of the clinical context. It’s happening with many genetic tests, even though the companies (23andMe being the most visible) are careful to post multiple caveats and disclaimers. In the case of gluten sensitivity, the genetic test that people are using to decide they have NCGS is by a company called Nutrigenomix, but the gluten issue is really just one example illustrating a broader problem.

Typically, genetic markers for disease are identified through association studies. The studies are real, they’re scientific, they’re published in good, peer reviewed journals. But, with the exception of a few conditions, such as Huntington disease (where having the gene variant means it’s pretty much 100% that you’ll get sick), the genetic markers are completely meaningless when viewed out of the proper clinical context. They project the possibility of having a condition across the entire population, but say very little about an individual because of the complexity of gene-gene interactions. In other words, except in the cases of Mendelian disorders which alone can lead to a specific disease, they are more entertainment than science. That’s certainly true of NCGS, which even if a real condition would not be linked to one gene. Moreover, proper clinical context requires a thorough patient history and appropriate diagnostic workup.

Shortcuts are bad in medicine

Relying on genetic markers is particularly dangerous when it comes to conditions whose very existence is questionable. One hint that a condition may or may not exist is that it can be diagnosed only as a diagnosis of exclusion. This means that the doctor does a complete workup for a plethora of conditions whose presentation looks similar but that can be detected, or ruled out, with specific tests. Only working through a differential diagnosis, eliminating everything that can be detected in specific tests (or ruled out during the history and physical exam), can a physician diagnose something that does not have a real test.

Moreover, there are good diagnoses of exclusion as well as bad ones. An example of a good diagnosis of exclusion is something like decompression sickness (DCS). There’s not one single test that actually can prove a person has DCS, but if you get sick within 24 hours of SCUBA diving, you then need a very thorough medical history and physical exam, a close look at your dive profile, and sometimes a few tests to rule out, one-by-one, a myriad of other conditions that can make it look as if you might have DCS –only then can a DCS diagnosis be established. But at that point it’s a good diagnosis, because there’s no doubt that DCS really exists. We know it because of real studies with instruments, but they’re not the kind of instruments that can be used practically for clinical studies.

Related article:  Low-gluten, high-fiber wheat varieties may begin to hit the market next year

With gluten, on the other hand, there’s a definite test for celiac disease. The patient eats gluten on purpose for a few weeks, then gets an endoscope inserted through the mouth, esophagus and stomach and into the small intestine, and a tissue biopsy is taken and analyzed. But there is no test at all for gluten sensitivity that’s not celiac disease. The Nutrigenomix genetic test, which costs $280, is actually a test for several different gene variants associated with celiac disease. Based on how many of these variants your cells have, the company gives you a result in the form of low, medium, or high risk for “gluten sensitivity”, and by that they mean celiac disease. As stated on the Nutrigenomix site in the brochure for the test:

Research has shown that the human leukocyte antigen (HLA) gene is the most important genetic predictor of gluten intolerance. Approximately, 99% of people with celiac disease and 60% of those with NCGS have the DQ2 or DQ8 risk version of the HLA gene, compared to only 30% of the general population.

That means couple of things. First of all, since the genetic markers being used to assess risk are in 30 percent of the general population, it means you can have those genetic variants and not be sick. Second, the sickness that they’re talking about in terms of risk is celiac disease, not NCGS. The latter they do mention in a very careful way, namely:

Celiac disease represents the most severe form of gluten intolerance and affects about 1 percent of the population. Another 5 percent of the population may have non-celiac gluten sensitivity (NCGS), which results in various gastrointestinal problems and other health issues.

So the company is straightforward in its representations. What’s happened is that people are assuming the genetic risk for celiac disease should have some implication vis-à-vis the risk for developing a non-celiac condition. In other words, if you test positive for a few of markers in the Nutrigenomix test leading them to tell you that your risk is medium for celiac disease, or if you test positive for all of them so they they tell you you’re high risk, yet the endoscopic biopsy testing reveals that you do not have celiac disease, the human mind has a tendency to think that the truth for you is in the middle; in this case, that you must have some less severe gluten-related condition. But there’s no scientific rationale for this kind of thinking.

The existence of NCGS is highly debated, but, even among experts who do think that it should be an official diagnosis, the distinction from celiac disease is that NCGS is characterized by a lack an an immune response. In celiac disease, the immune response is what causes all of the pathology and it’s also what’s related to the genetic markers in the Nutrigenomix test.

The gluten issue discussed here is just one example to illustrate a broader issue regarding how seriously you should take results of genetic tests that have been developed based on association studies. The answer is not very seriously, or at least don’t start changing around your lifestyle simply because of a worrisome test result. As the most widely-used genetic testing company, 23andMe, states clearly in their consent form:

You should not change your health behaviors solely on the basis of information from 23andMe….For most common diseases, the genes we know about are only responsible for a small fraction of the risk. There may be unknown genes, environmental factors, or lifestyle choices that are far more important predictors. If your data indicate that you are not at elevated genetic risk for a particular disease or condition, you should not feel that you are protected. The opposite is also true; if your data indicate you are at an elevated genetic risk for a particular disease or condition, it does not mean you will definitively develop the disease or condition.

And the same is true for pretty much any genetic test that you take.

David Warmflash is an astrobiologist, physician, and science writer. Follow @CosmicEvolution to read what he is saying on Twitter.

The GLP featured this article to reflect the diversity of news, opinion and analysis. The viewpoint is the author’s own. The GLP’s goal is to stimulate constructive discourse on challenging science issues.

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