Genetic Risk of Diverticular Disease Predicts Early Stoppage of Nicorandil

Abstract

Gastrointestinal fistulation has been widely reported as an adverse effect of nicorandil therapy in Europe. People who have underlying diverticular disease are most at risk of this side effect. In Western countries, diverticular disease is highly prevalent and can be clinically silent. This study aimed to identify diverticular disease genetic risk scores (GRSs) associated with early nicorandil stoppage, a surrogate marker for drug intolerance. A case‐control study was carried out on 1,077 patients from the Genetics of Diabetes Audit and Research Tayside Scotland (GoDARTS) database. Cases were defined as having < 9 nicorandil prescriptions with no identifiable reason for stopping (n = 230). Controls had either ≥ 9 prescriptions, treatment continuation to death/study end or stoppage post‐myocardial infarction. Two diverticular GRSs were created and used in logistic regression models. Isosorbide mononitrate was used as a control analysis. Patients with a raised diverticular GRS, based on 23 replicable loci, had increased risk of stopping nicorandil therapy early (univariate (odds ratio (OR) 2.26; P = 0.04], multivariate (OR 3.96; P = 0.01)). Similar trends were noted when using the full 42 variant diverticular score but statistical significance was not reached. The isosorbide control analysis did not reach statistical significance. Our analysis demonstrates a novel positive association between a raised diverticular GRS and early stoppage of nicorandil therapy.

A Systematic Review and Analysis of the Use of Polygenic Scores in Pharmacogenomics

“…Of the two studies that examined antihypertensives responses, only one study reported a significant association; however, the base cohort that was used to inform the PGS was small ( n = 248) 58,59 . Finally, significant associations were reported for a PGS derived from a GWAS of QRS duration (electrical heart pattern) and Brugada syndrome/response to the antiarrhythmic agent ajmaline, 60 as well as for a diverticular disease PGS and nicorandil intolerance ( Table ) 61 …”

“…58,59 Finally, significant associations were reported for a PGS derived from a GWAS of QRS duration (electrical heart pattern) and Brugada syndrome/response to the antiarrhythmic agent ajmaline, 60 as well as for a diverticular disease PGS and nicorandil intolerance (Table S5). 61 A number of conditions were covered in the remaining 14 publications included in this review. Three articles examined PGSs in the context of the treatment of inflammatory bowel disease, with one of these studies reporting a significant association between…”

Nicorandil‐induced colovesical fistula in a patient with diverticular disease

“…12,14 Advances in pharmacogenetics have shown that people with a high genetic risk of diverticular disease are more likely to stop nicorandil therapy early. 15 This provides an insight to future strategies aimed at tailoring antianginal treatment based on individual patient risk of adverse drug effects.…”

“…Epidemiological studies have predicted the heritability of diverticular disease to be up to 50% with an increased prevalence of diverticula noted in monozygotic co‐twins compared to dizygotic co‐twins 12,14 . Advances in pharmacogenetics have shown that people with a high genetic risk of diverticular disease are more likely to stop nicorandil therapy early 15 . This provides an insight to future strategies aimed at tailoring antianginal treatment based on individual patient risk of adverse drug effects.…”

Precision Medicine and Adverse Drug Reactions Related to Cardiovascular Drugs

“…Pharmacogenomics provides a potential strategy to identify those at increased risk of diverticular disease prior to commencement of anti-anginal medication, without the expense and risk of a colonoscopy. A recent study identified in a genotyped cohort that the genetic risk of diverticular disease predicted early stoppage of nicorandil, which was used as a surrogate marker of nicorandil intolerance [30]. They utilised a previous genome-wide association study (GWAS) which identified SNPs associated with diverticular disease.…”