Genomics, the Mind, and the Gut

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 158^th 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.