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Association of distinct α2 adrenoceptor and serotonin transporter polymorphisms with constipation and somatic symptoms in functional gastrointestinal disorders
  1. H J Kim1,
  2. M Camilleri1,
  3. P J Carlson1,
  4. F Cremonini1,
  5. I Ferber1,
  6. D Stephens1,
  7. S McKinzie1,
  8. A R Zinsmeister2,
  9. R Urrutia1
  1. 1Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) Program, Gastroenterology Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
  2. 2Department of Health Sciences Research, Division of Biostatistics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
  1. Correspondence to:
    Professor M Camilleri
    Mayo Clinic, Charlton 8-110, 200 First St SW, Rochester, MN 55905, USA;


Background: The role of genetics in the phenotypic manifestations of irritable bowel syndrome (IBS) is unclear. Our aims were: (1) to compare the prevalence of polymorphisms of alpha 2 (α2) adrenoceptors, norepinephrine transporter, and serotonin transporter protein (soluble carrier protein member 4 (SLC6A4)) promoter in patients with lower functional gastrointestinal disorders (FGID) and in healthy controls; and (2) to test associations of these genetic variations with symptoms of IBS and high somatic symptom scores.

Methods: Validated bowel and somatic symptom questionnaires characterised the phenotype: 90 with IBS constipation (IBS-C), 128 IBS diarrhoea, 38 IBS alternating bowel function, and 20 chronic abdominal pain. Logistic regression analyses assessed associations of different polymorphisms for α2 adrenoceptor and SLC6A4 with IBS or chronic abdominal pain phenotypes and high somatic score.

Results: Two distinct polymorphisms independently appeared to be associated with the phenotype IBS-C: α2C Del 322–325 (odds ratio (OR) 2.48 (95% confidence interval (CI) 0.98, 6.28); p = 0.05) and α2A −1291 (C→G) (OR 1.66 (95% CI 0.94, 2.92); p = 0.08) relative to wild-type. Overall, the α2C Del 322–325 polymorphism (alone or combined with other polymorphisms) was also significantly associated with a high somatic symptom score (OR 2.2 (95% CI 1.06, 4.64); p = 0.03). Combinations of polymorphisms were also associated with high somatic scores.

Conclusion: Functionally distinct α2A and α2C adrenoceptor and serotonin transporter polymorphisms are associated with constipation and high somatic symptoms in patients with lower functional gastrointestinal disorders, although the strength of the genetic contribution to the phenotype is unclear.

  • genotype
  • somatic symptoms
  • irritable bowel syndrome
  • irritable bowel syndrome phenotype
  • IBS, irritable bowel syndrome
  • IBS-C, irritable bowel syndrome with predominant constipation
  • IBS-D, irritable bowel syndrome with predominant diarrhoea
  • FGID, functional gastrointestinal disorders
  • FC, functional constipation
  • FD, functional diarrhoea
  • CAP, chronic abdominal pain
  • SoSc, somatic symptom score
  • NET, norepinephrine transporter
  • 5-HT, 5-hydroxytryptamine (serotonin)
  • SERT, serotonin transporter
  • SERT-P, serotonin transporter promoter
  • SLC6A4, solute carrier family 6 (neurotransmitter transporter, serotonin), member 4
  • α2C Del 322–325, deletion in third intracellular loop of α2C adrenoceptor protein
  • α2ALys251, a cytosine to guanine transversion at position 753 that changes amino acid 251 of the third intracellular loop of the α2A adrenoceptor from asparagine to lysine
  • α2A −1291 (C→G), cytosine to guanine transversion in promoter of α2A receptor protein
  • OR, odds ratio
  • PCR, polymerase chain reaction

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