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Get to know a gene: HTR2A

What is HTR2A?
The 5-HT2A receptor, encoded by the HTR2A gene, is responsible for post-synaptic serotonin signaling and is a target for many antipsychotics and antidepressants.1 Two single nucleotide polymorphisms (SNPs) in HTR2A, rs6311 (-1438G>A) and rs6313 (102C>T), have been studied for associations with response and side effects associated with various psychotropic medications. These two polymorphisms, which do not change the encoded protein, are in high linkage disequilibrium.1–4 Data for a third polymorphism, rs7997012, is also summarized here.5

What are the functional effects of HTR2A variants?
Six studies have investigated the effects of the -1438G>A and 102C>T polymorphisms on HTR2A RNA levels, with inconsistent results. Three ex vivo studies failed to find a consistent association between the SNPs and HTR2A RNA expression.6–8 A fourth ex vivo study found that healthy controls (n=35) with the -1438GG genotype had reduced mRNA levels compared with AA genotype subjects, with heterozygotes displaying intermediate levels.9

These results are contradicted by two recent studies that showed no differences in total HTR2A mRNA across genotypes, but did find that GG tissue samples had greater expression of an extended 5’UTR.1,10 This extended 5’UTR was shown to increase translational efficiency, implying increased protein production.1 However, receptor density studies have not supported this hypothesis; five studies failed to find association,3,6,11-13 while two studies found an opposite association wherein the -1438G allele was associated with lower receptor densities9,14. One study did find the AA genotype to be associated with higher receptor density in a healthy control group, but found no association in patients with mood disorders.15 Three additional studies that investigated the impact of -1438G>A on promoter activity failed to find a consistent association, providing no clarification of the functional effect of this polymorphism.2,8,16 The rs7997012 SNP is located in an intronic region; its function is unknown.17

What is the clinical significance of the HTR2A polymorphisms?
The -1438G>A and 102C>T variants have been extensively studied for associations with medication response, particularly with paroxetine. Three studies investigated the association between the -1438G>A and 102C>T polymorphisms and adverse events in paroxetine-treated patients. All three studies (total n = 237) found significantly increased incidence of adverse events in patients with the -1438GG (102CC) genotype.18–20 The effect size was large; a weighted average of these studies showed side effect rates increasing from 15% among -1438A (102T) carriers to 42% among -1438G (102C) homozygotes. Similar results have been found for other selective serotonin reuptake inhibitors (SSRIs), such as citalopram and fluvoxamine, but these results await replication in larger cohorts.21,22

Conversely, the effect of the HTR2A polymorphisms of efficacy is not well defined. No association was found between HTR2A genotype and paroxetine efficacy in two articles (total n = 115).23,24 Inconsistent results have been found for other antidepressants and antipsychotics.5,20,25

The rs7997012 was originally identified as a marker of citalopram response in the STAR*D study, but has so far failed to replicate. Three studies showed no impact of the polymorphism on antidepressant efficacy response,17,25,26 while two studies showed an association in the opposite direction.27,28 A meta-analysis by Niitsu et al. that included the aforementioned studies (including the STAR*D data) found no overall effect of the polymorphism.29 Limited evidence exists for the relationship between rs7997012 and side effects. Two studies (total n = 135) in subjects receiving SSRIs found that patients with the AA genotype suffered from significantly more side effects compared to G allele carriers.30,31 However, these results must be replicated in larger cohorts before a reliable association can be drawn.

Conclusions
The functional effects of HTR2A -1438A>G and 102T>C polymorphisms remain unclear and research on the impact of these polymorphisms (and rs7997012) on antidepressant efficacy is inconclusive. However, the 1438A>G and 102T>C polymorphisms appear to be reliable predictors of SSRI-induced adverse events (particularly with paroxetine), with side effect rates increasing from 15% among wild type carriers to 42% among homozygous variant individuals. HTR2A may be viewed as a clinically validated predictor of SSRI-induced side effects.

References
1. Smith RM, Papp AC, Webb A, et al. Multiple regulatory variants modulate expression of 5-hydroxytryptamine 2A receptors in human cortex. Biol Psychiatry. 2013;73(6):546-554. doi:10.1016/j.biopsych.2012.09.028.

2. Spurlock G, Heils A, Holmans P, et al. A family based association study of T102C polymorphism in 5HT2A and schizophrenia plus identification of new polymorphisms in the promoter. Mol Psychiatry. 1998;3(1):42-49. doi:10.1038/sj.mp.4000342.

3. Kouzmenko AP, Scaffidi A, Pereira AM, Hayes WL, Copolov DL. No Correlation between A(-1438)G Polymorphism in 5-HT2A Receptor Gene Promoter and the Density of Frotnal Cortical 5-HT2A Receptros in Schizophrenia. Hum Hered. 1999;49:103-105.

4. Kusumi I, Suzuki K, Sasaki Y, Kameda K, Sasaki T, Koyama T. Serotonin 5-HT2A receptor gene polymorphism, 5-HT2A receptor function and personality traits in healthy subjects: A negative study. J Affect Disord. 2002;68(2-3):235-241. doi:10.1016/S0165-0327(00)00324-4.

5. McMahon FJ, Buervenich S, Charney D, et al. Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet. 2006;78(5):804-814. doi:10.1086/503820.

6. Marinova Z, Monoranu C-M, Fetz S, Walitza S, Grünblatt E. Region-specific regulation of the serotonin 2A receptor expression in development and ageing in post mortem human brain. Neuropathol Appl Neurobiol. 2015;41(4):520-532. doi:10.1111/nan.12167.

7. Falkenberg VR, Gurbaxani BM, Unger ER, Rajeevan MS. Functional genomics of serotonin receptor 2A (HTR2A): Interaction of polymorphism, methylation, expression and disease association. NeuroMolecular Med. 2011;13(1):66-76. doi:10.1007/s12017-010-8138-2.

8. Myers RL, Airey DC, Manier DH, Shelton RC, Sanders-Bush E. Polymorphisms in the Regulatory Region of the Human Serotonin 5-HT2A Receptor Gene (HTR2A) Influence Gene Expression. Biol Psychiatry. 2007;61(2):167-173. doi:10.1016/j.biopsych.2005.12.018.

9. Polesskaya OO, Sokolov BP. Differential expression of the “C” and “T” alleles of the 5-HT2A receptor gene in the temporal cortex of normal individuals and schizophrenics. J Neurosci Res. 2002;67(6):812-822. doi:10.1002/jnr.10173.

10. Smith RM, Banks W, Hansen E, Sadee W, Herman GE. Family-Based clinical associations and functional characterization of the serotonin 2A receptor gene (HTR2A) in autism spectrum disorder. Autism Res. 2014;7(4):459-467. doi:10.1002/aur.1383.

11. Ono H, Shirakawa O, Kitamura N, et al. Tryptophan hydroxylase immunoreactivity is altered by the genetic variation in postmortem brain samples of both suicide victims and controls. Mol Psychiatry. 2002;7(10):1127-1132. doi:10.1038/sj.mp.4001150.

12. Hrdina PD, Du L, Turecki G, et al. Levels of serotonin receptor 2A higher in suicide victims? [6] (multiple letters). Am J Psychiatry. 2001;158(1):147-148. doi:10.1176/appi.ajp.158.1.147.

13. Du L, Faludi G, Palkovits M, et al. Frequency of long allele in serotonin transporter gene is increased in depressed suicide victims. Biol Psychiatry. 1999;46(2):196-201. doi:10.1016/S0006-3223(98)00376-X.

14. Turecki G, Briere R, Dewar K, Antonetti T. Prediction of level of serotonin 2A receptor binding by serotonin Receptor 2A Genetic Varaition in Postmortem Brain Samples From Subjects Who Did or Did Not Commit Suicide. Am J Psychiatry. 1999;156:1456-1458.

15. Khait VD, Huang Y, Zalsman G, et al. Association of serotonin 5-HT2A receptor binding and the T102C polymorphism in depressed and healthy Caucasian subjects. Neuropsychopharmacology. 2005;30(1):166-172. doi:10.1038/sj.npp.1300578.

16. Parsons MJ, D’Souza UM, Arranz M-J, Kerwin RW, Makoff AJ. The -1438A/G polymorphism in the 5-hydroxytryptamine type 2A receptor gene affects promoter activity. Biol Psychiatry. 2004;56(6):406-410. doi:10.1016/j.biopsych.2004.06.020.

17. Noro M, Antonijevic I, Forray C, et al. 5HT1A and 5HT2A receptor genes in treatment response phenotypes in major depressive disorder. Int Clin Psychopharmacol. 2010;25(4):228-231. doi:10.1097/YIC.0b013e328338bcf4.

18. Kato M, Fukuda T, Wakeno M, et al. Effects of the serotonin type 2A, 3A and 3B receptor and the serotonin transporter genes on paroxetine and fluvoxamine efficacy and adverse drug reactions in depressed Japanese patients. Neuropsychobiology. 2006;53(4):186-195. doi:10.1159/000094727.

19. Murphy GM, Kremer C, Rodrigues HE, Schatzberg AF. Pharmacogenetics of antidepressant medication intolerance. Am J Psychiatry. 2003;160(10):1830-1835. https://www.ncbi.nlm.nih.gov/pubmed/14514498. Accessed June 12, 2014.

20. Wilkie MJ V, Smith G, Day RK, et al. Polymorphisms in the SLC6A4 and HTR2A genes influence treatment outcome following antidepressant therapy. Pharmacogenomics J. 2009;9(April 2006):61-70. doi:10.1038/sj.tpj.6500491.

21. Suzuki Y, Sawamura K, Someya T. Polymorphisms in the 5-hydroxytryptamine 2A receptor and CytochromeP4502D6 genes synergistically predict fluvoxamine-induced side effects in japanese depressed patients. Neuropsychopharmacology. 2006;31:825-831. doi:10.1097/00004850-200607000-00042.

22. Smith R, Papp A, Webb A, Ruble C. Multiple regulatory variants modulate expression of 5-hydroxytryptamine 2A receptors in human cortex. Biol Psychiatry. 2013;73(6):546-554. doi:10.1111/j.1600-6143.2008.02497.x.Plasma.

23. Kato M, Fukuda T, Wakeno M, et al. Effects of the serotonin type 2A, 3A and 3B receptor and the serotonin transporter genes on paroxetine and fluvoxamine efficacy and adverse drug reactions in depressed Japanese patients. Neuropsychobiology. 2006;53:186-195. doi:10.1159/000094727.

24. Wilkie MJ V, Smith G, Day RK, et al. Polymorphisms in the SLC6A4 and HTR2A genes influence treatment outcome following antidepressant therapy. Pharmacogenomics J. 2009;9(1):61-70. doi:10.1038/sj.tpj.6500491.

25. Illi A, Setälä-Soikkeli E, Viikki M, et al. 5-HTR1A, 5-HTR2A, 5-HTR6, TPH1 and TPH2 polymorphisms and major depression. Neuroreport. 2009;20(12):1125-1128. doi:10.1097/WNR.0b013e32832eb708.

26. Perlis RH, Fijal B, Adams DH, Sutton VK, Trivedi MH, Houston JP. Variation in catechol-O-methyltransferase is associated with duloxetine response in a clinical trial for major depressive disorder. Biol Psychiatry. 2009;65(9):785-791. doi:10.1016/j.biopsych.2008.10.002.

27. Horstmann S, Lucae S, Menke A, et al. Polymorphisms in GRIK4, HTR2A, and FKBP5 show interactive effects in predicting remission to antidepressant treatment. Neuropsychopharmacology. 2010;35(3):727-740. doi:10.1038/npp.2009.180.

28. Lucae S, Ising M, Horstmann S, et al. HTR2A gene variation is involved in antidepressant treatment response. Eur Neuropsychopharmacol. 2010;20(1):65-68. doi:10.1016/j.euroneuro.2009.08.006.

29.. Niitsu T, Fabbri C, Bentini F, Serretti A. Pharmacogenetics in major depression: A comprehensive meta-analysis. Prog Neuro-Psychopharmacology Biol Psychiatry. 2013;45:183-194. doi:10.1016/j.pnpbp.2013.05.011.

30. Staeker J, Leucht S, Laika B, Steimer W. Polymorphisms in serotonergic pathways influence the outcome of antidepressant therapy in psychiatric inpatients. Genet Test Mol Biomarkers. 2014;18(1):20-31. doi:10.1089/gtmb.2013.0217.

31. Laika B, Leucht S, Heres S, Schneider H, Steimer W. Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome. Pharmacogenomics J. 2010;10(1):20-29. doi:10.1038/tpj.2009.32.

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