title: Investigation of epistasis between the serotonin transporter and norepinephrine transporter genes in anorexia nervosa.
abstract: Weight-restored patients with anorexia nervosa (AN) respond favorably to the selective serotonin reuptake inhibitor fluoxetine, which justifies association studies of the serotonin transporter gene (SLC6A4, alias SERT) and AN. Case-control studies suggest that the least transcriptionally active allele of the SERT gene promoter polymorphism (5-HTTLPR) has an increased frequency in AN patients. However, this finding was not replicated with 55 trios (AN child+parents) and the transmission disequilibrium test (TDT). To clarify the role of the 5-HTTLPR in susceptibility to AN, we used the TDT and 106 Australian trios to provide 93% power to detect a genotypic relative risk (GRR) of 2.0. Our results were negative for this GRR (McNemar's chi(2)=0.01, df=1, p=0.921, odds ratio 1.0, 95% CI 0.7-1.5). Additionally, we found no association with AN females, AN subtype, age at onset, or minimum BMI. We then performed the first reported investigation of epistasis between the SERT gene and norepinephrine transporter gene (SLC6A2, alias NET) in AN, as an earlier study suggested that atypical AN responds to the dual serotonin-norepinephrine reuptake inhibitor venlafaxine. We observed no epistasis between the 5-HTTLPR and a polymorphism within the NET gene promoter polymorphic region (NETpPR) (chi(2)=0.48, df=1, p=0.490). Although 5-HTTLPR modulates serotonin reuptake by the serotonin transporter, our analyses provide no evidence that susceptibility to AN is modified by 5-HTTLPR alone, nor in concert with as yet undetermined functional effects of the NETpPR polymorphism.
authors.affiliation: Department of Psychological Medicine, The Children's Hospital at Westmead, Westmead, NSW, Australia. RuthU@chw.edu.au
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Urwin
authors.forename: Bruce H
authors.initials: BH
authors.lastname: Bennetts
authors.forename: Bridget
authors.initials: B
authors.lastname: Wilcken
authors.forename: Pierre J V
authors.initials: PJ
authors.lastname: Beumont
authors.forename: Janice D
authors.initials: JD
authors.lastname: Russell
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nunn
mesh_terms: D000856:Anorexia Nervosa / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D003511:Cyclohexanols / Q000494:pharmacology; D004843:Epistasis, Genetic; D005260:Female; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D026901:Membrane Transport Proteins; D008967:Molecular Biology / Q000379:methods; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010290:Parents; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012306:Risk; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D000069470:Venlafaxine Hydrochloride
chemical_list: D002352:Carrier Proteins; D003511:Cyclohexanols; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D027981:Symporters; D000069470:Venlafaxine Hydrochloride; C493227:SLC6A2 protein, human; C493230:SLC6A4 protein, human