Serotonin (5-HT) receptor 5A sequence variants affect human plasma triglyceride levels.
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.
Zhang
Y
Y
Human and Molecular Genetics Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Smith
E M
EM
Baye
T M
TM
Eckert
J V
JV
Abraham
L J
LJ
Moses
E K
EK
Kissebah
A H
AH
Martin
L J
LJ
Olivier
M
M
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*
D011985:Receptors, Serotonin; D014280:Triglycerides; C078730:serotonin 5 receptor
J Neurosci. 1995 May;15(5 Pt 1):3526-38
7751928
Am J Hum Genet. 1998 May;62(5):1198-211
9545414
Mol Cell Biol. 1991 Apr;11(4):1883-93
2005886
Hum Genet. 2005 Oct;117(6):545-57
16021472
Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14478-83
11121050
Am J Hum Genet. 1998 Jul;63(1):259-66
9634505
Hum Mol Genet. 2000 May 22;9(9):1315-20
10814713
Neurosci Biobehav Rev. 2001 Mar;25(2):167-74
11323081
J Lipid Res. 2005 Mar;46(3):432-8
15604520
N Engl J Med. 1993 Apr 22;328(16):1150-6
8455681
BMC Med Genet. 2007 Sep 19;8 Suppl 1:S17
17903299
J Psychiatr Res. 2004 Jul-Aug;38(4):371-6
15203288
Nat Genet. 2009 Jan;41(1):56-65
19060906
Am J Hum Genet. 2004 Jan;74(1):106-20
14681826
Nucleic Acids Res. 2002 Jun 15;30(12):e53
12060691
J Lipid Res. 2004 Apr;45(4):610-5
14754912
Genome Res. 2005 Feb;15(2):269-75
15687290
Am J Hum Genet. 2000 Apr;66(4):1237-45
10729112
Neuropharmacology. 1999 Aug;38(8):1083-152
10462127
Nat Genet. 2009 Jan;41(1):25-34
19079261
Nat Genet. 2009 Feb;41(2):157-9
19151714
Brain Res. 2008 Oct 21;1236:140-4
18755168
Obes Res. 1995 Nov;3 Suppl 4:471S-476S
8697045
Hum Biol. 2005 Oct;77(5):541-59
16596940
Genomics. 2006 Oct;88(4):407-14
16713172
Nat Genet. 2008 Feb;40(2):189-97
18193044
Nat Genet. 2005 Nov;37(11):1234-41
16227999
Nat Biotechnol. 2003 Jun;21(6):673-8
12730666
Cell Mol Neurobiol. 2009 Mar;29(2):157-68
18773289
Nat Genet. 2008 Feb;40(2):161-9
18193043
Am J Epidemiol. 1987 Feb;125(2):308-18
3812436
Diabetologia. 2000 Mar;43(3):373-6
10768099
Nat Genet. 2009 Jan;41(1):18-24
19079260
J Lipid Res. 2010 Apr;51(4):701-8
19965593
Neuropsychopharmacology. 1999 Aug;21(2 Suppl):91S-98S
10432494