title: Polymorphisms of serotonin receptor 2A and 2C genes and COMT in relation to obesity and type 2 diabetes.
abstract: BACKGROUND
  Candidate genes of psychological importance include 5HT2A, 5HT2C, and COMT, implicated in the serotonin, noradrenaline and dopamine pathways, which also may be involved in regulation of energy balance. We investigated the associations of single nucleotide polymorphisms (SNPs) of these genes with obesity and metabolic traits.
  
  
  RESULTS
  In a population of 166 200 young men examined at the draft boards, obese men (n = 726, BMI> or =31.0 kg/m(2)) and a randomly selected group (n = 831) were re-examined at two surveys at mean ages 46 and 49 years (S-46, S-49). Anthropometric, physiological and biochemical measures were available. Logistic regression analyses were used to assess age-adjusted odds ratios. No significant associations were observed of 5HT2A rs6311, 5HT2C rs3813929 and COMT rs4680 with obesity, except that COMT rs4680 GG-genotype was associated with fat-BMI (OR = 1.08, CI = 1.01-1.16). The SNPs were associated with a number of physiological variables; most importantly 5HT2C rs3813929 T-allele was associated with glucose (OR = 4.56, CI = 1.13-18.4) and acute insulin response (OR = 0.65, CI = 0.44-0.94) in S-49. COMT rs4680 GG-genotype was associated with glucose (OR = 1.04, CI = 1.00-1.09). Except for an association between 5HT2A rs6311 and total-cholesterol at both surveys, significant in S-46 (OR = 2.66, CI = 1.11-6.40), no significant associations were observed for the other phenotypes. Significant associations were obtained when combined genotype of 5HT2C rs3813929 and COMT rs4680 were examined in relation to BMI (OR = 1.12, CI = 1.03-1.21), fat-BMI (OR = 1.22, CI = 1.08-1.38), waist (OR = 1.13, CI = 1.04-1.22), and cholesterol (OR = 5.60, CI = 0.99-31.4). Analyses of impaired glucose tolerance (IGT) and type 2 diabetes (T2D) revealed, a 12.3% increased frequency of 5HT2C rs3813929 T-allele and an 11.6% increased frequency of COMT rs4680 GG-genotype in individuals with IGT or T2D (chi(2), p = 0.05 and p = 0.06, respectively). Examination of the combined genotypes of 5HT2C and COMT showed a 34.0% increased frequency of IGT or T2D (chi(2), p = 0.01).
  
  
  CONCLUSIONS
  The findings lend further support to the involvement of serotonin, noradrenaline and dopamine pathways on obesity and glucose homeostasis, in particular when combined genotype associations are explored.
authors.affiliation: Institute of Preventive Medicine, Copenhagen University Hospital, Centre for Health and Society, Copenhagen, Denmark. SI@ipm.regionh.dk
authors.forename: Sofia I I
authors.initials: SI
authors.lastname: Kring
authors.forename: Thomas
authors.initials: T
authors.lastname: Werge
authors.forename: Claus
authors.initials: C
authors.lastname: Holst
authors.forename: Søren
authors.initials: S
authors.lastname: Toubro
authors.forename: Arne
authors.initials: A
authors.lastname: Astrup
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.forename: Thorkild I A
authors.initials: TI
authors.lastname: Sørensen
mesh_terms: D002394:Catechol O-Methyltransferase / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005951:Glucose Tolerance Test; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics*; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics*
chemical_list: D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D002394:Catechol O-Methyltransferase
references.citation: Curr Drug Targets. 2005 Mar;6(2):201-13
references.pmid: 15777190
references.citation: Lancet. 2002 Jun 15;359(9323):2086-7
references.pmid: 12086765
references.citation: Ann Hum Genet. 1999 Jul;63(Pt 4):329-40
references.pmid: 10738544
references.citation: BMC Genet. 2007 Oct 16;8:70
references.pmid: 17937824
references.citation: Ann Hum Genet. 2006 May;70(Pt 3):293-303
references.pmid: 16674552
references.citation: J Psychiatr Res. 2003 May-Jun;37(3):193-220
references.pmid: 12650740
references.citation: Int Rev Psychiatry. 2007 Oct;19(5):523-30
references.pmid: 17896232
references.citation: Hum Genet. 2007 Aug;122(1):41-9
references.pmid: 17497175
references.citation: Pharmacol Rev. 1999 Dec;51(4):593-628
references.pmid: 10581325
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2005 Jul;29(6):1021-8
references.pmid: 15953671
references.citation: Lancet. 2007 Jan 6;369(9555):71-7
references.pmid: 17208644
references.citation: BMJ. 1989 Sep 23;299(6702):767-70
references.pmid: 2508915
references.citation: Psychopharmacology (Berl). 2003 Apr;167(1):72-8
references.pmid: 12632246
references.citation: Ann N Y Acad Sci. 2002 Jun;967:571-5
references.pmid: 12079891
references.citation: Pharmacogenet Genomics. 2008 Feb;18(2):153-9
references.pmid: 18192901
references.citation: Int J Obes (Lond). 2005 Jun;29(6):624-31
references.pmid: 15824752
references.citation: Anesthesiology. 2008 Jul;109(1):137-48
references.pmid: 18580184
references.citation: J Neurosci. 2004 Jun 9;24(23):5331-5
references.pmid: 15190105
references.citation: Science. 2005 Jan 21;307(5708):375-9
references.pmid: 15662002
references.citation: Curr Drug Targets. 2004 Apr;5(3):221-40
references.pmid: 15058309
references.citation: Metabolism. 2008 May;57(5):708-11
references.pmid: 18442637
references.citation: Diabet Med. 2005 Sep;22(9):1199-205
references.pmid: 16108849
references.citation: World Health Organ Tech Rep Ser. 1995;854:1-452
references.pmid: 8594834
references.citation: Am J Physiol. 1990 Oct;259(4 Pt 2):R829-35
references.pmid: 2221150
references.citation: Diabetologia. 2007 Sep;50(9):1880-1888
references.pmid: 17624514
references.citation: Lancet. 2001 Feb 3;357(9253):354-7
references.pmid: 11210998
references.citation: Genet Res. 2005 Dec;86(3):223-31
references.pmid: 16454861
references.citation: Nature. 2000 Apr 6;404(6778):661-71
references.pmid: 10766253
references.citation: Obes Res. 2002 Jul;10(7):585-9
references.pmid: 12105278
references.citation: Obes Facts. 2008;1(3):138-45
references.pmid: 20054173
references.citation: N Engl J Med. 2005 Nov 17;353(20):2121-34
references.pmid: 16291982
references.citation: Med Hypotheses. 2004;62(6):976-9
references.pmid: 15142660
references.citation: Ann Hum Genet. 2006 Mar;70(Pt 2):262-76
references.pmid: 16626336
references.citation: Brain Res Mol Brain Res. 2004 Aug 23;127(1-2):39-47
references.pmid: 15306119
references.citation: Eur J Pharmacol. 2008 May 6;585(1):38-49
references.pmid: 18407262
references.citation: Am J Epidemiol. 1996 Aug 1;144(3):207-13
references.pmid: 8686689
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2004 Apr 1;126B(1):124-7
references.pmid: 15048662
references.citation: Mol Psychiatry. 2007 Aug;12(8):707-47
references.pmid: 17549063
references.citation: Neuroimage. 2008 Apr 15;40(3):1175-80
references.pmid: 18291676
references.citation: Ann Med. 2001 Nov;33(8):534-41
references.pmid: 11730160
references.citation: Obesity (Silver Spring). 2008 Jun;16(6):1363-9
references.pmid: 18356831
references.citation: Biometrics. 1976 Sep;32(3):599-606
references.pmid: 963173
references.citation: Diabetologia. 2003 Jan;46(1):3-19
references.pmid: 12637977
references.citation: Am J Psychiatry. 2003 Jan;160(1):90-9
references.pmid: 12505806
references.citation: Diabetes Care. 2007 Feb;30(2):257-62
references.pmid: 17259491
references.citation: Diabetologia. 2000 Mar;43(3):373-6
references.pmid: 10768099