gut health

pain

GNB3

Can This Gene Worsen GERD Pain? (GNB3)

Written by Carlos Tello, PhD on May 18th, 2020

The GNB3 gene encodes a subunit of G proteins involved in signaling within the gut-brain axis. An overactive variant of this gene has been associated with GERD and the perception of its symptoms. Read below to learn the effects of your GNB3 variant on this condition.

What Is the GNB3 Gene?

The GNB3 gene encodes the beta 3 subunit of a ‘guanine nucleotide-binding protein’, or ‘G protein’ to abbreviate. G proteins bind to specific receptors on the surface of cells to transmit signals that activate different pathways [R, R, R].

The GNB3 subunit is involved in the function of different neurotransmitters such as serotonin. Illustrating the role of this protein in the brain, GNB3 variants have been associated with major depression and response to antidepressant treatment in several studies [R, R, R, R, R, R].

Through other mechanisms, excessive GNB3 activity has been associated with conditions such as high blood pressure, metabolic syndrome, obesity, and type 2 diabetes [R, R, R].

GNB3 and Gastroesophageal Reflux Disease

Gastroesophageal reflux disease (GERD) is a condition that causes stomach acid to rise up into the esophagus. This acid reflux can cause heartburn, bad breath, chest pain, nausea, breathing problems, and even erosion of the teeth [R, R].

GERD occurs when the lower esophageal sphincter, the passage between the esophagus and the stomach, doesn’t close all the way. Risk factors for GERD include pregnancy, diabetes, and certain medications [R].

GNB3 seems to influence GERD pain perception through its involvement in the brain-gut axis. Its overactivation may lower the activation threshold of pain receptors and cause hypersensitivity to acid reflux [R, R].

Indeed, G proteins are known to activate several receptors and messenger proteins that may trigger pain in the upper digestive tract (and other body parts) such as TRPV1, CGRP1, calcitonin, CRF, cholecystokinin, and neurotensin [R, R, R, R, R, R].

The GNB3 gene encodes a subunit of messenger G proteins. GNB3 activity seems to contribute to GERD pain by activating receptors and messenger proteins involved in pain perception.

GNB3 Variants and Digestive Issues

Celiac Disease

The most widely-studied GNB3 polymorphism is rs5443. Its minor allele ‘T’ causes the production of the normal GNB3 subunit plus a shorter alternative version that increases the activation of the G protein. This alternative version may enhance the response to neurotransmitters [R, R, R].

The ‘CT’ genotype was found more frequently than ‘CC’ among GERD patients in a Dutch study of almost 800 people [R].

People with two copies of this variant felt worse GERD symptoms before a treatment with pantoprazole in a multi-center study on Austrian, German, Dutch, Lithuanian, and South African populations. However, the treatment was similarly effective in all genotypes [R].

Similarly, this variant and the minor alleles of two barely-investigated polymorphisms (‘T’ at rs5446 and ‘A’ at rs2301339) were associated with increased perception of GERD symptoms in a study from the US [R].

Other Digestive Issues

The rs5443 polymorphism has also been investigated regarding its role in indigestion. Depending on the study, the ‘T’ variant, the major allele ‘C’, both, or neither of them have been associated with functional dyspepsia [R, R, R, R, R, R, R, R, R].

However, one meta-analysis found the evidence insufficient to link any of the GNB3 genotypes to indigestion and another one only managed to associate the ‘T’ allele with indigestion characterized by pain in the upper stomach (epigastric pain syndrome) [R, R].

Similarly, the ‘T’ variant was associated with IBS in a Greek and a Korean study but not in two other studies on Korean populations. A meta-analysis of these and other studies concluded that this GNB3 polymorphism can’t be associated with IBS [R, R, R, R, R].

A GNB3 variant with increased activity has been associated with increased GERD incidence and symptom perception. In contrast, research has found little or no connection with indigestion and IBS.

Your GNB3 Results for GERD

SNP Summary and Table

Primary SNP: GNB3 rs5443

‘C’ = Normal risk of GERD.
‘T’ = Increased risk of GERD.

Population Frequency

Almost 36% of the world population carries at least one copy of the minor ‘T’ allele. Surprisingly, this allele is the major variant in people of African (73% of carriers) and East Asian (52% of carriers) descent. Indeed, the ‘TT’ genotype is the most common one (56%) in African Americans as opposed to European Americans (only 10%).

SNP Table

variant	genotype	frequency	risk allele
rs5443

Recommendations

Lifestyle

Weight Loss

Obesity is considered a significant risk factor for the development of GERD. Importantly, the ‘T’ variant of rs5443 is associated with being overweight or obese, and may contribute to GERD through this effect [R, R, R, R].

Being overweight or obese are well-known GERD triggers. The risk variant of GNB3 may further worsen this condition by promoting weight gain. Losing weight helps reduce GERD symptoms and may be especially recommended in people with this variant.

Supplements

Bitters

In one observational study, 50 patients with acid reflux were given an Ayurvedic syrup called Acidinol for 4 weeks. This multi-herbal formula with bitters such as neem (Azadirachta indica), relieved symptoms of heartburn, stomach pain, bloating, nausea, indigestion, and loss of appetite in over 75% of patients [R].

Interestingly, the risk variant of GNB3 promotes the activity of G proteins, including those that activate the receptors for bitter taste. This means that this variant may further enhance the positive effects of bitters on digestive function. However, more research is needed [R, R, R].

CBD

Activation of cannabinoid CB1 receptors prevented the relaxation of the lower esophageal sphincter in human and animal studies, and even prevented GERD in dogs. Although CBD blocks rather than activating this receptor, it may indirectly contribute to its activation by preventing the breakdown of anandamide [R, R, R, R, R].

Importantly, both CBD and G proteins interact with the pain-involved TRPV1 receptor. While G proteins stimulate it and increase pain perception, CBD makes it less sensitive to stimuli that may trigger pain [R, R, R].

Supplementing with bitters and CBD may help reduce GERD symptoms, including pain perception.

Carlos Tello

PhD

Carlos received his PhD and MS from the Universidad de Sevilla.

Carlos spent 8 years in the laboratory investigating mineral transport in plants. He then started working as a freelancer, mainly in science writing, editing, and consulting. Carlos is passionate about learning the mechanisms behind biological processes and communicating science to both academic and lay audiences. He strongly believes that scientific literacy is crucial to maintaining a healthy lifestyle and avoiding falling for scams.

Disclaimer

The information on this website has not been evaluated by the Food & Drug Administration or any other official medical body. This information is presented for educational purposes only, and may not be used to diagnose or treat any illness or disease.

Also keep in mind that the “Risk Score” presented in this post is based only on a select number of SNPs, and therefore only represents a small portion of your total risk as an individual. Furthermore, these analyses are based primarily on associational studies, which do not necessarily imply causation. Finally, many other (non-genetic) factors can also play a significant role in the development of a disease or health condition — therefore, carrying any of the risk-associated genotypes discussed in this post does not necessarily mean you are at increased risk of developing a major health condition.

Always consult your doctor before acting on any information or recommendations discussed in this post — especially if you are pregnant, nursing, taking medication, or have been officially diagnosed with a medical condition.

More gut health blogs

Could This Gene Be Linked To Gut Inflammation? (ATG16L1) Could This Gene Play A Role In Inflammatory Bowel Disease? (STAT3) How Do Your Genes Respond to Dietary Fat? (TCF7L2) Do Your Genes Favor the Mediterranean Diet? (TCF7L2) How Does this Serotonin Receptor Affect Gut Inflammation? (HTR3E) The Impact of a Serotonin Receptor on IBS-D (HTR3A) How Can Neurotrophins Affect Gut Inflammation? (BDNF) Could Your IBS Symptoms Be Caused by an Enzyme Deficiency? (SI) What is the Connection Between β-Klotho and Gut Inflammation? (KLB) Can This Gene Worsen Gut Inflammation? (NOS2)

Content

What Is the GNB3 Gene? GNB3 Variants and Digestive Issues Your GNB3 Results for GERD

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