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Serotonin Receptor 2A (HTR2A) Gene Polymorphisms Are Associated with Blood Pressure, Central Adiposity, and the Metabolic Syndrome.

ABSTRACT: Although the etiology of the metabolic syndrome remains unclear, recent evidence suggests that dysregulation of brain serotonergic activity may partly underlie the covariation of risk factors comprising the syndrome. In addition, prior studies have shown polymorphisms in the serotonin 2A receptor (HTR2A) gene to be associated with two syndrome components, hypertension and central adiposity. We conducted a study to confirm associations of HTR2A polymorphisms with elevated blood pressure and central adiposity and tested for association between these polymorphisms and the metabolic syndrome.The study sample included 934 unrelated individuals of European ancestry. We tested for association of two HTR2A polymorphisms, one in the promoter: (-1438[G/A]) and one in the first intron (2416 [C/T]), individually and as a diplotype, with elevated blood pressure, central adiposity, elevated fasting glucose, triglycerides, high density lipoprotein (HDL) cholesterol and presence of the metabolic syndrome, as defined by the American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI) Scientific Statement Executive Summary.Confirming previous reports, elevated blood pressure (>130/85 mm Hg) was associated with both the -1438 GG and 2416 TT genotypes and the GG/TT diplotype (ORs = 1.39-1.76); high waist circumference was associated with -1438 GG genotype only (OR = 1.57). In addition, both the -1438 GG and 2416 TT genotypes, and the GG/TT diplotype, predicted presence of the metabolic syndrome (ORs = 1.44-1.77). Fasting glucose, triglyceride and HDL cholesterol were not associated with either polymorphism.Elevated blood pressure, central adiposity, and the metabolic syndrome are associated with polymorphisms in HTR2A gene.

SUBMITTER: Halder I

PROVIDER: S-EPMC3237193 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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Serotonin Receptor 2A (HTR2A) Gene Polymorphisms Are Associated with Blood Pressure, Central Adiposity, and the Metabolic Syndrome.

Halder Indrani I Muldoon Matthew F MF Ferrell Robert E RE Manuck Stephen B SB

Metabolic syndrome and related disorders 20071201 4

<h4>Background</h4>Although the etiology of the metabolic syndrome remains unclear, recent evidence suggests that dysregulation of brain serotonergic activity may partly underlie the covariation of risk factors comprising the syndrome. In addition, prior studies have shown polymorphisms in the serotonin 2A receptor (HTR2A) gene to be associated with two syndrome components, hypertension and central adiposity. We conducted a study to confirm associations of HTR2A polymorphisms with elevated blood ...[more]

PMID: 18370802

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Project description:The serotonin 2A receptor is widely implicated in genetic association studies and remains an important drug target for psychiatric, neurological, and cardiovascular conditions. RNA sequencing redefined the architecture of the serotonin 2A receptor gene (HTR2A), revealing novel mRNA transcript isoforms utilizing unannotated untranslated regions of the gene. Expression of these untranslated regions is modulated by common single nucleotide polymorphisms (SNPs), namely rs6311. Previous studies did not fully capture the complexity of the sense- and antisense-encoded transcripts with respect to novel exons in the HTR2A gene locus. Here, we comprehensively catalogued exons and RNA isoforms for both HTR2A and HTR2A-AS1 using RNA-Seq from human prefrontal cortex and multiple mouse tissues. We subsequently tested associations between expression of newfound gene features and common SNPs in humans.We find that the human HTR2A gene spans ~66 kilobases and consists of 7, rather than 4 exons. Furthermore, the revised human HTR2A-AS1 gene spans ~474 kilobases and consists of 18, rather than 3 exons. Three HTR2A exons directly overlap with HTR2A-AS1 exons, suggesting potential for complementary nucleotide interactions. The repertoire of possible mouse Htr2a splice isoforms is remarkably similar to humans and we also find evidence for overlapping sense-antisense transcripts in the same relative positions as the human transcripts. rs6311 and SNPs in high linkage disequilibrium are associated with HTR2A-AS1 expression, in addition to previously described associations with expression of the extended 5' untranslated region of HTR2A.Our proposed HTR2A and HTR2A-AS1 gene structures dramatically differ from current annotations, now including overlapping exons on the sense and anti-sense strands. We also find orthologous transcript isoforms expressed in mice, providing opportunities to elucidate the biological roles of the human isoforms using a model system. Associations between rs6311 and expression of HTR2A and HTR2A-AS1 suggest this polymorphism is capable of modulating the expression of the sense or antisense transcripts. Still unclear is whether these SNPs act directly on the expression of the sense or antisense transcripts and whether overlapping exons are capable of interacting through complimentary base-pairing. Additional studies are necessary to determine the extent and nature of interactions between the SNPs and the transcripts prior to interpreting these findings in the context of phenotypes associated with HTR2A.

Dataset Information

Serotonin Receptor 2A (HTR2A) Gene Polymorphisms Are Associated with Blood Pressure, Central Adiposity, and the Metabolic Syndrome.

Publications

Serotonin Receptor 2A (HTR2A) Gene Polymorphisms Are Associated with Blood Pressure, Central Adiposity, and the Metabolic Syndrome.

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