title: Effect of endocannabinoid degradation on pain: role of FAAH polymorphisms in experimental and postoperative pain in women treated for breast cancer.
abstract: Fatty acid amide hydrolase (FAAH) metabolizes the endocannabinoid anandamide, which has an important role in nociception. We investigated the role of common FAAH single-nucleotide polymorphisms (SNPs) in experimentally induced and postoperative pain. One thousand women undergoing surgery for breast cancer participated in the study. They were tested for cold (n = 900) and heat pain (n = 1000) sensitivity. After surgery, their pain intensities and analgesic consumption were carefully registered. FAAH genotyping was performed using MassARRAY platform and genome-wide chip (n = 926). Association between 8 FAAH SNPs and 9 pain phenotypes was analyzed using linear regression models. The results showed that carrying 2 copies of a missense variant converting proline at position 129 to threonine (rs324420) resulted in significantly lower cold pain sensitivity and less need for postoperative analgesia. More specifically, rs324420 and another highly correlated SNP, rs1571138, associated significantly with cold pain intensity (corrected P value, 0.0014; recessive model). Patients homozygous for the minor allele (AA genotype) were less sensitive to cold pain (β = -1.48; 95% CI, -2.14 to -0.8). Two other SNPs (rs3766246 and rs4660928) showed nominal association with cold pain, and SNPs rs4141964, rs3766246, rs324420, and rs1571138 nominal association with oxycodone consumption. In conclusion, FAAH gene variation was shown to associate with cold pain sensitivity with P129T/rs324420 being the most likely causal variant as it is known to reduce the FAAH enzyme activity. The same variant showed nominal association with postoperative oxycodone consumption. Our conclusions are, however, limited by the lack of replication and the results should be replicated in an independent cohort.
authors.affiliation: Departments of Anaesthesiology, Intensive Care, and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Department of Molecular Genetics, Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Cajanus
authors.forename: Emil J
authors.initials: EJ
authors.lastname: Holmström
authors.forename: Maija
authors.initials: M
authors.lastname: Wessman
authors.forename: Verneri
authors.initials: V
authors.lastname: Anttila
authors.forename: Mari A
authors.initials: MA
authors.lastname: Kaunisto
authors.forename: Eija
authors.initials: E
authors.lastname: Kalso
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000581:Amidohydrolases / Q000235:genetics*; D001943:Breast Neoplasms / Q000601:surgery; D016009:Chi-Square Distribution; D015331:Cohort Studies; D063388:Endocannabinoids / Q000378:metabolism*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D006930:Hyperalgesia / Q000235:genetics; D008875:Middle Aged; D010147:Pain Measurement; D017288:Pain Threshold; D010149:Postoperative Pain / Q000209:etiology* / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055815:Young Adult; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D063388:Endocannabinoids; D000099252:Fatty Acid Amide Hydrolases