Serotonin (5-HT) receptor 5A sequence variants affect human plasma triglyceride levels

Y. Zhang, E. M. Smith, T. M. Baye, J. V. Eckert, L. J. Abraham, E. K. Moses, A. H. Kissebah, L. J. Martin, M. Olivier

    Research output: Contribution to journalArticle

    17 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)168-176
    Number of pages9
    JournalPhysiological Genomics
    Volume42
    Issue number2
    DOIs
    StatePublished - Jul 2010

    Keywords

    • Electrophoretic mobility shift assay
    • Family study
    • Single nucleotide polymorphism association

    ASJC Scopus subject areas

    • Physiology
    • Genetics

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