title: Serotonin (5-HT) receptor 5A sequence variants affect human plasma triglyceride levels.
abstract: Neurotransmitters such as serotonin (5-hydroxytryptamine, 5-HT) work closely with leptin and insulin to fine-tune the metabolic and neuroendocrine responses to dietary intake. Losing the sensitivity to excess food intake can lead to obesity, diabetes, and a multitude of behavioral disorders. It is largely unclear how different serotonin receptor subtypes respond to and integrate metabolic signals and which genetic variations in these receptor genes lead to individual differences in susceptibility to metabolic disorders. In an obese cohort of families of Northern European descent (n = 2,209), the serotonin type 5A receptor gene, HTR5A, was identified as a prominent factor affecting plasma levels of triglycerides (TG), supported by our data from both genome-wide linkage and targeted association analyses using 28 publicly available and 12 newly discovered single nucleotide polymorphisms (SNPs), of which 3 were strongly associated with plasma TG levels (P < 0.00125). Bayesian quantitative trait nucleotide (BQTN) analysis identified a putative causal promoter SNP (rs3734967) with substantial posterior probability (P = 0.59). Functional analysis of rs3734967 by electrophoretic mobility shift assay (EMSA) showed distinct binding patterns of the two alleles of this SNP with nuclear proteins from glioma cell lines. In conclusion, sequence variants in HTR5A are strongly associated with high plasma levels of TG in a Northern European population, suggesting a novel role of the serotonin receptor system in humans. This suggests a potential brain-specific regulation of plasma TG levels, possibly by alteration of the expression of HTR5A.
authors.affiliation: Human and Molecular Genetics Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: E M
authors.initials: EM
authors.lastname: Smith
authors.forename: T M
authors.initials: TM
authors.lastname: Baye
authors.forename: J V
authors.initials: JV
authors.lastname: Eckert
authors.forename: L J
authors.initials: LJ
authors.lastname: Abraham
authors.forename: E K
authors.initials: EK
authors.lastname: Moses
authors.forename: A H
authors.initials: AH
authors.lastname: Kissebah
authors.forename: L J
authors.initials: LJ
authors.lastname: Martin
authors.forename: M
authors.initials: M
authors.lastname: Olivier
mesh_terms: D015331:Cohort Studies; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011985:Receptors, Serotonin / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D014280:Triglycerides / Q000097:blood*
chemical_list: D011985:Receptors, Serotonin; D014280:Triglycerides; C078730:serotonin 5 receptor
references.citation: J Neurosci. 1995 May;15(5 Pt 1):3526-38
references.pmid: 7751928
references.citation: Am J Hum Genet. 1998 May;62(5):1198-211
references.pmid: 9545414
references.citation: Mol Cell Biol. 1991 Apr;11(4):1883-93
references.pmid: 2005886
references.citation: Hum Genet. 2005 Oct;117(6):545-57
references.pmid: 16021472
references.citation: Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14478-83
references.pmid: 11121050
references.citation: Am J Hum Genet. 1998 Jul;63(1):259-66
references.pmid: 9634505
references.citation: Hum Mol Genet. 2000 May 22;9(9):1315-20
references.pmid: 10814713
references.citation: Neurosci Biobehav Rev. 2001 Mar;25(2):167-74
references.pmid: 11323081
references.citation: J Lipid Res. 2005 Mar;46(3):432-8
references.pmid: 15604520
references.citation: N Engl J Med. 1993 Apr 22;328(16):1150-6
references.pmid: 8455681
references.citation: BMC Med Genet. 2007 Sep 19;8 Suppl 1:S17
references.pmid: 17903299
references.citation: J Psychiatr Res. 2004 Jul-Aug;38(4):371-6
references.pmid: 15203288
references.citation: Nat Genet. 2009 Jan;41(1):56-65
references.pmid: 19060906
references.citation: Am J Hum Genet. 2004 Jan;74(1):106-20
references.pmid: 14681826
references.citation: Nucleic Acids Res. 2002 Jun 15;30(12):e53
references.pmid: 12060691
references.citation: J Lipid Res. 2004 Apr;45(4):610-5
references.pmid: 14754912
references.citation: Genome Res. 2005 Feb;15(2):269-75
references.pmid: 15687290
references.citation: Am J Hum Genet. 2000 Apr;66(4):1237-45
references.pmid: 10729112
references.citation: Neuropharmacology. 1999 Aug;38(8):1083-152
references.pmid: 10462127
references.citation: Nat Genet. 2009 Jan;41(1):25-34
references.pmid: 19079261
references.citation: Nat Genet. 2009 Feb;41(2):157-9
references.pmid: 19151714
references.citation: Brain Res. 2008 Oct 21;1236:140-4
references.pmid: 18755168
references.citation: Obes Res. 1995 Nov;3 Suppl 4:471S-476S
references.pmid: 8697045
references.citation: Hum Biol. 2005 Oct;77(5):541-59
references.pmid: 16596940
references.citation: Genomics. 2006 Oct;88(4):407-14
references.pmid: 16713172
references.citation: Nat Genet. 2008 Feb;40(2):189-97
references.pmid: 18193044
references.citation: Nat Genet. 2005 Nov;37(11):1234-41
references.pmid: 16227999
references.citation: Nat Biotechnol. 2003 Jun;21(6):673-8
references.pmid: 12730666
references.citation: Cell Mol Neurobiol. 2009 Mar;29(2):157-68
references.pmid: 18773289
references.citation: Nat Genet. 2008 Feb;40(2):161-9
references.pmid: 18193043
references.citation: Am J Epidemiol. 1987 Feb;125(2):308-18
references.pmid: 3812436
references.citation: Diabetologia. 2000 Mar;43(3):373-6
references.pmid: 10768099
references.citation: Nat Genet. 2009 Jan;41(1):18-24
references.pmid: 19079260
references.citation: J Lipid Res. 2010 Apr;51(4):701-8
references.pmid: 19965593
references.citation: Neuropsychopharmacology. 1999 Aug;21(2 Suppl):91S-98S
references.pmid: 10432494