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TRPM8 polymorphisms associated with increased risk of IBS-C and IBS-M
  1. Maria Henström1,
  2. Fatemeh Hadizadeh1,2,
  3. Arthur Beyder3,
  4. Ferdinando Bonfiglio1,4,
  5. Tenghao Zheng1,
  6. Ghazaleh Assadi1,
  7. Joseph Rafter1,
  8. Luis Bujanda4,
  9. Lars Agreus5,
  10. Anna Andreasson5,6,
  11. Aldona Dlugosz7,
  12. Greger Lindberg7,
  13. Peter T Schmidt7,
  14. Pontus Karling8,
  15. Bodil Ohlsson9,
  16. Nicholas J Talley10,
  17. Magnus Simren11,
  18. Susanna Walter12,
  19. Mira Wouters13,
  20. Gianrico Farrugia3,
  21. Mauro D'Amato4,14,15,16
  1. 1Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
  2. 2School of Nutrition, Isfahan University of Medical Sciences, Isfahan, Iran
  3. 3Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA
  4. 4Department of Gastrointestinal and Liver Diseases, BioDonostia Health Research Institute, San Sebastian, Spain
  5. 5Division for Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
  6. 6Stress Research Institute, Stockholm University, Stockholm, Sweden
  7. 7Department of Medicine, Karolinska Institutet, Center for Digestive Diseases, Karolinska University Hospital Huddinge, Stockholm, Sweden
  8. 8Division of Medicine, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
  9. 9Department of Internal Medicine, Lund University, Skåne University Hospital, Sweden
  10. 10Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia
  11. 11Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  12. 12Division of Neuro and Inflammation Science, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
  13. 13Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven University, Leuven, Belgium
  14. 14BioCruces Health Research Institute, Bilbao, Spain
  15. 15IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
  16. 16Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
  1. Correspondence to Professor Mauro D'Amato, BioDonostia Health Research Institute, Donostia University Hospital, Paseo Dr Begiristain s/n, San Sebastian E-200014, Spain; mauro.damato{at}biodonostia.org

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Recently in Gut, genetic variation affecting ion channels activity has been highlighted in relation to bowel function and the biology of stool frequency.1 It is also known that 2% of patients with IBS carry functional missense mutations in the voltage-gated channel NaV1.5 (SCN5A gene).2 Hence, channelopathies represent potential abnormalities underlying GI dysfunction and IBS. We inspected data from our previous genome-wide association study (GWAS) of IBS,3 in relation to 27 genes whose ion channel products contribute to GI sensorimotor development and function, visceral sensation and GI motility (see online supplementary table S1). Significant (uncorrected) results were detected for four genes (calcium voltage-gated channels CACNA1A and CACNA1E, and transient receptor potential channels TRPV3 and TRPM8; see online supplementary figure S1), which were selected for replication analyses in an independent set of IBS cases (N=386) and controls (N=357) (see online supplementary material methods). A sex-adjusted logistic regression analysis of genotype data from this cohort (see online supplementary material methods) detected significant associations for TRPM8, and a meta-analysis of GWAS and replication yielded (i) strongest evidence of association at this locus, (ii) no statistical heterogeneity (Cochran's Q test p>0.05) and (iii) same direction of genetic risk effects in the two studies (table 1). Rome III IBS-subtype information available for the replication cohort revealed TRPM8 single nucleotide polymorphisms (SNP) to impact IBS risk exclusively in the IBS-C and IBS-M types, with strongest evidence obtained from their combined analysis (table 1). This prompted us to investigate the relationship between TRPM8 and GI motility in the Population-based Colonoscopy study (PopCol),4 focusing on IBS-free individuals (N=120) who kept weekly records of their defaecation episodes based on the Bristol Stool Form Scale (BSFS; see online supplementary material methods). A Spearman correlation analysis revealed all IBS-C/M risk alleles to be consistently associated with harder stools, showing progressively decreasing frequencies from lower to upper average BSFS quartile groups, while opposite results were obtained for protective alleles (figure 1).

Table 1

Associations between IBS, IBS subtypes and TRPM8 SNPs

Figure 1

Correlation between TRPM8 genotype and average Bristol Stool Form Scale (BSFS) scores. Left: Spearman correlation statistics. Right: frequency of TRPM8 alleles across BSFS quartile groups (alleles from each SNP are colour-coded as in the table on the left).

Dysregulated transient receptor potential (TRP) channel activity has been associated to IBS and constipation, and peppermint oil (which contains the TRPM8 activator menthol as its biologically active ingredient) is reported to induce symptoms relief in patients with IBS and to exert spasmolytic effects and inhibition of GI contractility.5–7 TRPM8 SNP associations with slower colonic transit, constipation and IBS may thus result from allele-specific effects on TRPM8 function (due to coding variants) and/or expression (due to regulatory variants) in the GI tract. In the meta-analysis, strongest association and IBS-C/M risk effects were observed for two SNPs (rs10166942 and rs2362290; table 1) mapping in the promoter region of the gene where transcriptional regulation takes place. These markers are computationally predicted to alter the transcription factor (TF) binding at the corresponding DNA sites and, in addition to expected transcription-related activities, pathway analysis of this TF pool yielded ‘abnormal hepatobiliary system’ as the top scoring mammalian phenotype (see online supplementary material methods and table S2). Additional pathway analyses of TRPM8 coexpressed genes (see online supplementary material methods), returned ‘bile secretion’, ‘bile acid and bile salt transport’ and ‘bile acid metabolic process’ as the main biological processes (see online supplementary table S3). These are potentially important observations, since the mechanisms regulating TRPM8 expression are poorly characterised, and alterations of bile acid synthesis and metabolism are implicated as causative mechanisms linked to constipation and IBS.8

In summary, we identify TRPM8 polymorphisms that associate with slower colonic transit rates and increased risk of IBS with constipation (IBS-C and IBS-M). These results may contribute to identifying subsets of patients with IBS for improved therapeutic precision, and provide novel opportunities for mechanistic investigation of IBS symptom generation.

References

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Footnotes

  • Contributors MH, AB, GF and MD: study concept and design; TZ, JR, LB, LA, AA, AD, GL, PTS, PK, BO, NJT, MS and SW: characterisation of study individuals, acquisition of data; GA: genotyping; MH, FH, FB and MD: statistical analyses; MH, AB, MW, GF and MD: analysis and interpretation of data; MH, AB, GF and MD: drafting of the manuscript, with critical revision for important intellectual content by all other authors.

  • Funding This work was supported by grants from The Swedish Research Council (VR 2013-3862) and the Department of Health of the Basque Government (2015111133) to MD. MD and GF are the recipients of a KI-Mayo Collaborative Research Grant for the study of genetic channelopathies in IBS.

  • Competing interests None.

  • Ethics approval Karolinska Institutet Ethics Review Board

  • Provenance and peer review Not commissioned; internally peer reviewed.

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