TY - JOUR
T1 - TRPM8 polymorphisms associated with increased risk of IBS-C and IBS-M
AU - Henström, Maria
AU - Hadizadeh, Fatemeh
AU - Beyder, Arthur
AU - Bonfiglio, Ferdinando
AU - Zheng, Tenghao
AU - Assadi, Ghazaleh
AU - Rafter, Joseph
AU - Bujanda, Luis
AU - Agreus, Lars
AU - Andreasson, Anna
AU - Dlugosz, Aldona
AU - Lindberg, Greger
AU - Schmidt, Peter T.
AU - Karling, Pontus
AU - Ohlsson, Bodil
AU - Talley, Nicholas J.
AU - Simren, Magnus
AU - Walter, Susanna
AU - Wouters, Mira
AU - Farrugia, Gianrico
AU - D'Amato, Mauro
PY - 2017/9/1
Y1 - 2017/9/1
N2 - 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).
AB - 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).
KW - CONSTIPATION
KW - GENETICS
KW - ION CHANNELS
KW - IRRITABLE BOWEL SYNDROME
KW - POLYMORPHIC VARIATION
UR - http://www.scopus.com/inward/record.url?scp=85006974496&partnerID=8YFLogxK
U2 - 10.1136/gutjnl-2016-313346
DO - 10.1136/gutjnl-2016-313346
M3 - Letter
C2 - 27974553
AN - SCOPUS:85006974496
SN - 0017-5749
VL - 66
SP - 1725
EP - 1727
JO - Gut
JF - Gut
IS - 9
ER -