Genomics, the Mind, and the Gut

An analysis of 2 trials

By Joshua Z. Goldenberg, ND

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Reference

Han CJ, Kohen R, Jun S, et al. COMT Val158Met polymorphism and symptom improvement following a cognitively focused intervention for irritable bowel syndrome. Nurs Res. 2017;66(2):75-84.

Design

Secondary genomic analysis of 2 previous randomized controlled trials comparing a nurse-delivered cognitive behavioral therapy (CBT) package to usual care for irritable bowel syndrome (IBS)

Participants

A combined 172 participants (from 2 previous studies) who had been diagnosed with IBS and for whom catechol-O-methyltransferase (COMT) genetic data was available. The sample was 87% female; 29% of participants had constipation-predominant IBS, 54% had diarrhea-predominant IBS, 11% had a mixed presentation, and 6% had an unknown IBS subtype.

Study Parameters Assessed

IBS symptoms, psychological distress, quality of life, and cognitive beliefs about IBS

Intervention

Nurse-delivered, IBS-focused CBT package. This included self-work on a CBT for IBS workbook1 and checking in with nurses throughout the study for 8 to 9 sessions (60-minute sessions) over 10 to 12 weeks. The concepts covered included recognizing dietary triggers, relaxation techniques, problem-solving, revising false beliefs, managing pain, and practicing good sleep habits.

Primary Outcome Measures

Percentage of days with moderate-severe levels of abdominal pain or discomfort, depression, anxiety, and feeling stressed; secondary measures included daily gastrointestinal symptoms, Brief Symptom Inventory (retrospective assessment of psychological distress), IBS-QoL scale (quality of life), and cognitive scale for functional bowel disorders (cognitive beliefs about IBS).

Symptoms were measured 1 month before baseline, with assessments conducted at 3 and 6 months post-baseline.

Key Findings

The researchers found that COMT status was statistically significantly associated with the benefit derived from the CBT package. Specifically, those with at least 1 copy of the val158met version of the single nucleotide polymorphism (SNP) saw more improvement in their anxiety, stress, abdominal distension, constipation, and retrospective psychological distress at 3 months. This effect was not seen at the 6-month mark.

Practice Implications

Catechol-O-methyltransferase (COMT) is an important enzyme involved in the degradation of the neurotransmitters dopamine and adrenaline. Val158met is a common COMT variant, a single nucleotide polymorphism (SNP) where the variant allele encodes for methionine instead of valine at the 158th amino acid position. This results in a functional difference in the COMT enzyme resulting in a 30% drop in enzymatic activity.2 The status of one’s COMT alleles (wild type or variant) has previously been associated with the efficacy of CBT interventions.3,4

The researchers found that COMT status was statistically significantly associated with the benefit derived from the CBT package.

Genomic medicine has come under criticism5 for the generally minimal clinical effects of single SNPs. For this reason many genomic medicine researchers now turn toward genetic risk scores composed of a portfolio of SNPs.6 However, COMT is an exception in that it is often still viewed individually and, because of its connection to dopamine levels, is often considered with psychological interventions.

Two previous studies have shown that a nurse-delivered cognitive behavioral therapy (CBT) package is effective for IBS.7,8 But the question remained: Does one’s COMT status modulate the effect of this CBT approach in patients with IBS?

In this paper, the authors found that a packaged CBT program for IBS was effective when compared to usual care and it was most effective for patients with at least one Val allele of the common val158met COMT SNP. The current study found that this allele is most associated with improvement in anxiety and stress, abdominal distension, constipation, and retrospective psychological distress.

In general, this was a well-conducted study. It is registered on the US National Library of Medicine’s website ClinicalTrials.gov, which decreases the risk of selective outcome reporting bias. There are some limitations of the study as well. They didn’t use standard IBS scales, which makes it difficult to understand the magnitude of effect, and they only looked at people with European American genetic ancestry. They did this to avoid potential bias issues inherent in genomic medicine research but it does limit the external validity when trying to apply the results to patients with other genetic lineages.

As discussed above, the magnitude of the effect modulation based on COMT status in this study is hard to gauge, so recommending genetic testing based on this data alone may be overreach. However, despite this, I do find this study clinically useful. Many of my patients have already had their COMT status identified via commercially available genetics companies. When I am already considering a CBT intervention for an IBS patient because the clinical scenario suggests a strong psychological component, knowing they have a Val allele may help inform my treatment decision. If that is the case it is simple enough to direct the patient to the workbook used to deliver this particular CBT package, which is easily available in book and eBook form.1

Detailed background on SNPs, genomic medicine, and a video version of this review are available here

About the Author

Joshua Z Goldenberg, ND is a researcher, teacher, registered naturopathic doctor, and founder of Dr. Journal Club, LLC. He is most passionate about the interplay of evidence and clinical practice.

Goldenberg is an active researcher with numerous publications in high impact scientific journals such as JAMA, Annals of Internal Medicine and The Cochrane Library. His research focus includes irritable bowel syndrome, probiotics, evidence-informed practice, and research methodology. He is currently Research Investigator at the Bastyr University Research Institute and Visiting Research Scholar at the University of Technology Sydney. He has presented nationally and internationally on evidence-based medicine as well as probiotics and research methodology. His probiotics work has been highlighted by the BBC, The New York Times, The Seattle Times, Prevention Magazine, and Fox News.

Goldenberg is a passionate educator and currently is faculty for the Academy of Integrative Health and Medicine’s Interprofessional Fellowship in Integrative Health and Medicine, where he teaches critical evaluation of the literature and evidence-informed practice. He is past adjunct faculty at Bastyr University, his alma mater, in which he enrolled after receiving honors and distinction in molecular biology from the University of Pennsylvania. He also guest lectures widely.

To watch a free video review of this research article check out www.DrJournalClub.com/NMJ/.

References

  1. Barney P, Weisman P, Jarrett M, Levy R, Heitkemper M. Master Your IBS: An 8-Week Plan to Control the Symptoms of Irritable Bowel Syndrome. Bethesda, MD: AGA Press; 2010.
  2. Lachman HM, Papolos DF, Saito T, et al. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics. 1996;6(3):243-250.
  3. Carroll KM, Herman A, DeVito EE, Frankforter TL, Potenza MN, Sofuoglu M. Catehol-o-methyltransferase gene Val158met polymorphism as a potential predictor of response to computer-assisted delivery of cognitive-behavioral therapy among cocaine-dependent individuals: preliminary findings from a randomized controlled trial. Am J Addict. 2015; 24(5):443-451.
  4. Lonsdorf TB, Rück C, Bergström J, et al. The COMTval158met polymorphism is associated with symptom relief during exposure-based cognitive-behavioral treatment in panic disorder. BMC Psychiatry. 2010;10(1):99.
  5. Cooke Bailey JN, Igo RP. Genetic risk scores. Curr Protoc Hum Genet. 2016;91:1.29.1-1.29.9.
  6. Knowles JW, Zarafshar S, Pavlovic A, et al. Impact of a genetic risk score for coronary artery disease on reducing cardiovascular risk: a pilot randomized controlled study. Front Cardiovasc Med. 2017;4:53.
  7. Jarrett ME, Cain KC, Barney PG, et al. Balance of autonomic nervous system predicts who benefits from a self-management intervention program for irritable bowel syndrome. J Neurogastroenterol Motil. 2016;22(1):102-111.
  8. Jarrett ME, Cain KC, Burr RL, Hertig VL, Rosen SN, Heitkemper MM. Comprehensive self-management for irritable bowel syndrome: randomized trial of in-person vs. combined in-person and telephone sessions. Am J Gastroenterol. 2009;104(12):3004-3014.