Precision Pathology

The original article can be found published in SA Medicine, March 2019.

By: Shelly Gunn, MD PhD

Chances are you’ve noticed the growing number of gluten free food choices when shopping at your local grocery store or dining at a favorite restaurant. Clearly supply is increasing to meet a certain demand, but what is motivating consumers to adopt a non-grain based diet? We know that approximately 1% of the world population is afflicted with pathology proven celiac disease, but the ubiquity of gluten free options clearly appeals to a broader population. Many US consumers, savvy about health and wellness, proactively reduce gluten consumption
based on directives from the wellness ‘self help’ literature, or as a reaction to peer and family pressure. However, a growing number of individuals, eager to learn their genetic predisposition for developing gluten intolerance disorder, are opting for DNA-based Gluten ID testing. Who can benefit from knowing their unique inherited susceptibility to gluten intolerance? The answer
is virtually everyone. In fact, universal screening for gluten sensitivity has been on the table for decades but in this new era of personalized medicine, we finally have the laboratory tools to
make it a reality.

The Backstory: Gluten, the major storage protein in wheat, was first introduced into the human diet around 10,000 years ago when the Paleolithic period menu of hunted meats and
gathered fruits was replaced by farmed, grain-based nutrition. Due to the inherent stability of wheat, it became a valuable nonperishable exchange commodity soon spreading via trade
routes around the globe. However, a small percentage of the human population was unable to consume wheat without experiencing gastrointestinal (GI) symptoms. The earliest reports of
diarrhea and malabsorption from wheat consumption were reported by the celebrated Greek physician Aretaeus of Cappadocia 2000 years ago. He described the malady as “koiliakos”
meaning “abdominal” from which the term “celiac” was later derived. In the late 19th century celiac disease (CD) from wheat consumption was documented in the in the Northern European
medical literature. By the 1990’s, CD had come to be recognized as a worldwide disease entity affecting approximately 1% of the population in gluten-consuming countries.

The Molecule: Comprised of long strands of protein chains, the gluten molecule cannot be completely broken down by human digestive enzymes. Thus the stable attributes of wheat that
made it such a valuable exchange commodity in the ancient world are also a major reason why wheat consumption can trigger symptoms of gluten intolerance. Once gluten enters the human gut it remains there for many hours, long enough for the immune system to mount a response against specific regions of the protein chains. However, this strong immune reaction occurs only in individuals who have inherited the genes coding for the specific immune cell receptors capable of recognizing gluten proteins. Gluten does not evoke the same reaction in individuals who lack genes encoding these immune cell receptors. This explains why, even in ancient times, only a subset of the population has been reported to develop GI symptoms from gluten consumption.

Gluten Genetics: Using molecular genetic laboratory techniques, we can identify an individual’s inherited susceptibility to gluten intolerance. DNA-based testing will identify the
presence or absence of the genes encoding the gluten recognition immune cell receptors, HLA-DQ2 and DQ8. The receptors are comprised of two protein chains, alpha and beta,
(encoded by genes DQA1 and DQB1 respectively) that can be inherited from the same or different parents. An estimated 30% of the human population carries combinations of the DQ2
and DQ8 gluten intolerance susceptibility genes. Within this population of genetically susceptible individuals there is a spectrum of elevated risk for developing severe celiac disease
accompanied by 50% or 100% chance of transmitting combinations of these genes to future generations. Conversely, individuals lacking DQ2/DQ8 gene combinations have virtually no risk
for development of celiac disease and 0% transmission risk.

Celiac Disease Testing: Prior to the Precision Medicine era, clinical laboratory testing for celiac disease (the most extreme expression of gluten intolerance) has primarily been
performed at the protein (not DNA) level. Antibody-based tests including tTG-IgA and IgA Endomysial antibody (EMA) remain the mainstays for laboratory diagnosis because they are
quick and accurate in acutely ill patients who have been consuming gluten in their diet. However, in individuals with celiac disease who are on a gluten free diet and asymptomatic
family members, antibody testing often gives false results because gluten antibodies are not being produced by the immune system. DNA testing thus provides a stable alternative to
antibody testing and only needs to be performed once in a person’s lifetime to provide accurate, unchanging results. DNA test results are often included with findings from antibody
testing, clinical presentation, and small bowel biopsy to help make the diagnosis of celiac disease. The high negative predictive value of DNA test results essentially rules out the
diagnosis of celiac disease in individuals lacking the DQ2 and DQ8 genes.

Non-celiac Gluten Sensitivity (NCGS): For some individuals with symptoms of gluten intolerance, genetic testing results are negative for DQ2 and/or DQ8 genes. The good news for
those with NCGS is their chances of developing severe celiac disease requiring small bowel biopsy is less than 1%. In addition, these individuals have 0% chance of transmitting DQ2 and
DQ8 genes to their children. However, these positive factors do not diminish the reality of their gluten-related symptoms or detract from the importance of a gluten free diet as a path to
wellness. DQ2 and DQ8 positivity has been well documented in the medical literature as a reliable biomarker for celiac disease susceptibility, but emerging protein and genetic
biomarkers may one day be clinically available for NCGS. Additionally, NCGS individuals may have a wheat allergy (WA) caused by an IgE mediated immune reaction to gluten as opposed
to the celiac specific T cell attack on the gut. Gluten is the least digestible, most immunogenic protein in the human diet so it comes as no surprise that the human immune system has
multiple ways to recognize and mount a targeted response against the gluten proteins. Human tissues including the gut, thyroid, and musculoskeletal system are often in the line of fire and
suffer collateral damage through molecular mimicry when normal tissues are mistaken for gluten proteins.

The Path to Wellness: Anyone with unexplained GI symptoms, autoimmune disease, brain fog, chronic fatigue syndrome or known celiac disease in a first degree relative could
potentially benefit from knowing their Gluten ID. In the direct to consumer (DTC) era of genetics, DQ2/DQ8 testing can be performed with cheek swab kits purchased online and
results reported directly to the individual. However for purposes of wellness planning, it is desirable that DQ2/DQ8 test results be included in the medical record. Therefore, Gluten ID
testing is optimally ordered and performed by physicians such as family practice or functional medicine, rheumatologists, and gastroenterologists so it can be integrated into the patient’s
preventive medicine and wellness plan. Gluten intolerance is best viewed on a spectrum of risk, and those with the highest risk have increased incentive to be cautious about how much
of a highly immunogenic protein they introduce into their digestive system. Celiac and autoimmune diseases can be silent for many years, just like a glass gradually filling with water.
However, as a glass overflows suddenly, so do celiac and autoimmune disease symptoms often present without warning. Therefore, the path to wellness begins with knowledge about
each person’s unique genetic predisposition to gluten intolerance and continues through a lifetime of steps taken towards reducing risk and promoting health. In the era of personalized
medicine, this pathway empowers each individual to know their susceptibility and transmission risk for celiac disease in order to appropriately minimize gluten consumption and maximize a
lifetime of wellness.

(c) 2018 Targeted Genomics, San Antonio TX. All rights reserved.