Pharmacogenetic predictors of nausea and vomiting of pregnancy severity and response to antiemetic therapy: a pilot study

BMC Pregnancy and Childbirth

David M Haas²  Carrie Rouse²  Ariel R Topletz³  Catherine L McCormick²  Jamie L Renbarger¹  Amalia S Lehmann³ 

[1] Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA;Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, USA;Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA

关键词: Pharmacogenomics;    Antiemetics;    Nausea and vomiting of pregnancy;    Pregnancy;   

Others  :  1137989
DOI  :  10.1186/1471-2393-13-132

 received in 2012-12-04, accepted in 2013-06-17,  发布年份 2013

【 摘 要 】

Background

Nausea and vomiting of pregnancy (NVP) is a common condition. The objective of this study was to evaluate the association between response to antiemetics in the treatment of NVP and genetic polymorphisms in the serotonin receptor subunit genes HTR3A and HTR3B.

Methods

Pregnant women ≥18 years of age with NVP starting antiemetic therapy with promethazine, prochlorperazine, metoclopramide, or ondansetron at ≤ 16 weeks gestational age were eligible. The study recruited 29 women with complete data and sampling who returned for their one week follow-up and were genotyped for HTR3A and HTR3B polymorphisms. Severity of NVP was captured (using Pregnancy Unique Quantification of Emesis (PUQE) and Quality of Life (QOL) tools) upon enrollment and after one week of antiemetic therapy. These measures were correlated with pharmacogenetic variability.

Results

Subjects with genotype associated with high serotonin affinity of the 5-HT_3B receptor (rs1176744, CC) required more antiemetic medications (p < 0.001) than other subjects. Those with genotypes associated with increased expression of the 5-HT_3A receptor subunit (rs1062613, CT or TT) had worse final PUQE scores (p = 0.01) than other subjects while rs3782025 variants carriers had significantly better initial (p = 0.02) and final (p = 0.02) PUQE scores than other subjects.

Conclusions

HTR3B and HTR3A gene variants may contribute to variability in response to antiemetic therapy for NVP.

【 授权许可】

   
2013 Lehmann et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Emelianova S, Mazzotta P, Einarson A, Koren G: Prevalence and severity of nausea and vomiting of pregnancy and effect of vitamin supplementation. Clin Invest Med 1999, 22(3):106-110.
• [2]Gadsby R, Barnie-Adshead A, Jagger C: A prospective study of nausea and vomiting during pregnancy. Br J Gen Pract 1993, 43:245-248.
• [3]Mazzotta P, Maltepe C, Navioz Y, Magee L, Koren G: Attitudes, management, and consequences of nausea and vomiting of pregnancy in the United States and Canada. Int J Gynaecol Obstetrics 2000, 70:359-365.
• [4]Miller F: Nausea and vomiting of pregnancy: the problem of perception–is it really a disease? Am J Obstet Gynecol 2002, 186:S182-S183.
• [5]Mazzotta P, Stewart D, Atanakovic G, Koren G, Magee L: Psychosocial morbidity among women with nausea and vomiting of pregnancy: prevalence and association with antiemetic therapy. J Psychosom Obstet Gynecol 2000, 21:129-136.
• [6]Mazzotta P, Magee L, Koren G: Therapeutic abortions due to severe morning sickness. Unacceptable combination. Can Fam Physician 1997, 43:1055-1057.
• [7]Magee LA, Mazzotta P, Koren G: Evidence-based view of safety and effectiveness of pharmacologic therapy for nausea and vomiting of pregnancy (NVP). Am J Obstet Gynecol 2002, 186(5 Suppl Understanding):S256-S261.
• [8]Berkovitch M, Mazzota P, Greenberg R, Elbirt D, Addis A, Schuler-Faccini L, Merlob P, Arnon J, Stahl B, Magee L, et al.: Metoclopramide for nausea and vomiting of pregnancy: a prospective multicenter international study. Am J Perinatol 2002, 19(6):311-316.
• [9]Einarson A, Koren G, Bergman U: Nausea and vomiting in pregnancy: a comparative European study. Eur J Obstet Gynecol Reprod Biol 1998, 76(1):1-3.
• [10]Einarson A, Maltepe C, Navioz Y, Kennedy D, Tan MP, Koren G: The safety of ondansetron for nausea and vomiting of pregnancy: a prospective comparative study. BJOG 2004, 111(9):940-943.
• [11]Fitzgerald JP: The effect of promethazine in nausea and vomiting of pregnancy. N Z Med J 1955, 54(300):215-218.
• [12]Lask S: Treatment of nausea and vomiting of pregnancy with antihistamines. Br Med J 1953, 1(4811):652-653.
• [13]Sullivan CA, Johnson CA, Roach H, Martin RW, Stewart DK, Morrison JC: A pilot study of intravenous ondansetron for hyperemesis gravidarum. Am J Obstet Gynecol 1996, 174(5):1565-1568.
• [14]Tremblay PB, Kaiser R, Sezer O, Rosler N, Schelenz C, Possinger K, Roots I, Brockmoller J: Variations in the 5-hydroxytryptamine type 3B receptor gene as predictors of the efficacy of antiemetic treatment in cancer patients. J Clin Oncol 2003, 21(11):2147-2155.
• [15]Sugai T, Suzuki Y, Sawamura K, Fukui N, Inoue Y, Someya T: The effect of 5-hydroxytryptamine 3A and 3B receptor genes on nausea induced by paroxetine. Pharmacogenomics J 2006, 6(5):351-356.
• [16]Goecke TW, Ekici AB, Niesler B, Loehberg CR, Hammer C, Rappold G, Schanze D, Straub V, Altmann HH, Strissel P, et al.: Two naturally occurring variants of the serotonin receptor gene HTR3C are associated with nausea in pregnancy. Acta Obstet Gynecol Scand 2010, 89(1):7-14.
• [17]Koren G, Boskovic R, Hard M, Maltepe C, Navioz Y, Einarson A: Motherisk-PUQE (pregnancy-unique quantification of emesis and nausea) scoring system for nausea and vomiting of pregnancy. Am J Obstet Gynecol 2002, 186(5 Suppl Understanding):S228-S231.
• [18]Koren G, Piwko C, Ahn E, Boskovic R, Maltepe C, Einarson A, Navioz Y, Ungar WJ: Validation studies of the Pregnancy Unique-Quantification of Emesis (PUQE) scores. J Obstet Gynaecol 2005, 25(3):241-244.
• [19]Andrews PL, Bhandari P: The 5-hydroxytryptamine receptor antagonists as antiemetics: preclinical evaluation and mechanism of action. Eur J Cancer 1993, 29A(Suppl 1):S11-S16.
• [20]Cubeddu LX, Hoffmann IS, Fuenmayor NT, Finn AL: Efficacy of ondansetron (GR 38032F) and the role of serotonin in cisplatin-induced nausea and vomiting. N Engl J Med 1990, 322(12):810-816.
• [21]Tyers MB, Bunce KT, Humphrey PP: Pharmacological and anti-emetic properties of ondansetron. Eur J Cancer Clin Oncol 1989, 25(Suppl 1):S15-S19.
• [22]Niesler B, Walstab J, Combrink S, Möller D, Kapeller J, Rietdorf J, Bönisch H, Göthert M, Rappold G, Brüss M: Characterization of the Novel Human Serotonin Receptor Subunits 5-HT3C,5-HT3D, and 5-HT3E. Mol Pharmacol 2007, 72(1):8-17.
• [23]Davies PA, Pistis M, Hanna MC, Peters JA, Lambert JJ, Hales TG, Kirkness EF: The 5-HT3B subunit is a major determinant of serotonin-receptor function. Nature 1999, 397(6717):359-363.
• [24]Krzywkowski K, Davies PA, Feinberg-Zadek PL, Bräuner-Osborne H, Jensen AA: High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT3AB receptor. Proc Natl Acad Sci 2008, 105(2):722-727.
• [25]Niesler B, Flohr T, Nöthen MM, Fischer C, Rietschel M, Franzek E, Albus M, Propping P, Rappold GA: Association between the 5’ UTR variant C178T of the serotonin receptor gene HTR3A and bipolar affective disorder. Pharmacogenet Genomics 2001, 11(6):471-475.
• [26]Kaiser R, Tremblay P-B, Sezer O, Possinger K, Roots I, Brockmöller J: Investigation of the association between 5-HT3A receptor gene polymorphisms and efficiency of antiemetic treatment with 5-HT3 receptor antagonists. Pharmacogenet Genomics 2004, 14(5):271-278.
• [27]Frank B, Niesler B, Nöthen MM, Neidt H, Propping P, Bondy B, Rietschel M, Maier W, Albus M, Rappold G: Investigation of the human serotonin receptor gene HTR3B in bipolar affective and schizophrenic patients. Am J Med Genet B Neuropsychiatr Genet 2004, 131B(1):1-5.
• [28]Meineke C, Tzvetkov MV, Bokelmann K, Oetjen E, Hirsch-Ernst K, Kaiser R, Brockmöller J: Functional characterization of a −100_-102delAAG deletion-insertion polymorphism in the promoter region of the HTR3B gene. Pharmacogenet Genomics 2008, 18(3):219-230. 210.1097/FPC.1090b1013e3282f51092
• [29]Ducci F, Enoch MA, Yuan Q, Shen PH, White KV, Hodgkinson C, Albaugh B, Virkkunen M, Goldman D: HTR3B is associated with alcoholism with antisocial behavior and alpha EEG power–an intermediate phenotype for alcoholism and co-morbid behaviors. Alcohol 2009, 43(1):73-84.