Evaluating the association of transient receptor potential cation channel subfamily A member 1 gene polymorphisms with pain sensitivity: Results from an adaptive recall by genotype study

Objective:
This prospective, double-blind, adaptive recall-by-genotype study assessed the effects of nonsynonymous variation in transient receptor potential ankyrin 1 (TRPA1) on thermal and mechanical detection and pain thresholds before and after topical application of the TRPA1 agonist cinnamaldehyde.

Methods:
Five putative gain-of-function TRPA1 variants were assessed within the ALSPAC cohort (aged 27–30). After accounting for linkage disequilibrium, 3 TRPA1-allele groups were considered for recruitment with the reference alleles considered as a control. An interim cohort was recruited, per protocol, from homozygous carriers of a group (rs7819749) with an equal number of controls (N = 15/group).

Results:
Interim analysis demonstrated a lower heat pain threshold of 2.4°C (d = 0.6) suggestive of a TRPA1 gain-of-function, with a predicted 80% statistical power at full enrolment, thus recruitment continued for rs7819749. At full enrolment (N = 99), there was no observed effect of rs7819749 on heat pain threshold or any other nociceptive modality in naïve or cinnamaldehyde-sensitised skin. The lack of heat hyperalgesia was replicated in a population sample having quantitative sensory test data, the TwinsUK cohort. As expected, topical cinnamaldehyde induced a robust flare and a reduction in heat pain threshold (P < 0.05), but in contrast to previous reports, it did not alter cold pain threshold, nor did it produce mechanical hyperalgesia.

Conclusion:
The novel adaptive study design successfully balanced a 20% risk of incorrect interim assessment while optimising the power to observe sensory changes using small cohorts. Post-hoc simulation confirmed that the correct decision to terminate the study of a particular variant was performed in over 94% of permutations at our chosen interim point (N = 15).