Genome-wide Association Study Using Pooled DNA to Identify Candidate Markers Mediating Susceptibility to Postoperative Nausea and Vomiting Piotr K. Janicki, M.D., Ph.D.,* Ryan Vealey, B.S.,† Jiabin Liu, M.D., Ph.D.,‡ Jeremiah Escajeda, B.A.,§ Marek Postula, M.D., Ph.D., Kelli Welker, B.S.# ABSTRACT Background: A family history has been established as a risk factor for postoperative nausea and vomiting (PONV), but the identities of susceptibility genes remain unknown. The goal of this study was to identify the genetic loci that may contribute to PONV susceptibility in an adult population. Methods: The authors performed a genome-wide associa- tion study involving pooling of DNA obtained from 122 patients with severe PONV and 129 matched controls. Each pool was hybridized to a single nucleotide polymorphism (SNP) microarray, and probe intensity was used to predict allele frequency. Differences in allele frequency between SNP in the PONV and control groups were ranked after accounting for the pooling error. The highest ranking SNPs were selected for individual genotyping in the subjects from whom the DNA pool was comprised and in the new verifi- cation cohort consisting of 208 subjects (104 PONV pa- tients and 104 controls). Results: The authors identified 41 SNP targets showing substantial difference in allelic frequency between pools. These markers were first genotyped in the individual DNA samples from which the pools were comprised. The authors observed evidence for an association between PONV and 19 different loci in the genome. In the separate verification co- hort, the association with PONV was observed for four SNPs. This association remained significant after correcting for multiple testing (P  0.0023) for one SNP (rs2165870), which is located upstream of the promoter for the muscarinic acetylcholine receptor 3 subtype (CHRM3) gene. Conclusions: The authors performed the genome-wide as- sociation study for PONV using pooled DNA samples. Through individual genotyping, they confirmed association of at least one SNP that is predictive of PONV susceptibility. P OSTOPERATIVE nausea and vomiting (PONV) is the most common complication of anesthesia adminis- tration. Although, typically short-lived and nonfatal, PONV remains a common cause of postoperative morbidity. Well- established major PONV risk factors include female gender (postpuberty), use of volatile anesthetics, previous history of PONV or motion sickness, and the use of intra- or postop- erative opioids. 1 In recent studies, a family history of PONV also has been implicated as a risk factor. 2,3 It is believed that PONV resulting from the physiologic stress of surgery and/or the administration of anesthetic drugs might be mod- ulated by a variety of small genomic differences between individuals. Thus, a specific pattern of genetic variation seen in select patients may be associated with an increased suscep- tibility to PONV. It is this hereditary component to PONV that is the focus of this study. * Professor of Anesthesiology, Director, Perioperative Genomics Laboratory, Department of Anesthesiology, § Medical Student (MS- IV), # Clinical Research Coordinator, Department of Anesthesiology, Penn State College of Medicine, Hershey, Pennsylvania. † Visiting Medical Student (MS-IV), University of Vermont College of Medi- cine, Burlington, Vermont. ‡ Anesthesia Fellow (PGA-5), Depart- ment of Anesthesiology, Hospital for Special Surgery, New York, New York.  Visiting Fulbright Research Fellow, Department of Pharmacology, University Medical School, Warsaw, Poland. Received from the Perioperative Genomics Laboratory, Depart- ment of Anesthesiology, Penn State College of Medicine, Hershey, Pennsylvania. Submitted for publication February 20, 2010. Ac- cepted for publication February 1, 2011. Support was provided solely from institutional and/or departmental sources. Address correspondence to Dr. Janicki: Department of Anesthesi- ology, Penn State College of Medicine, Milton S. Hershey Medical Center, 500 University Drive, H 187, Hershey Pennsylvania 17033-0850. Pjanicki@hmc.psu.edu. This article may be accessed for personal use at no charge through the Journal Web site, www.anesthesiology.org. Copyright © 2011, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2011; 115:54 – 64 What We Already Know about This Topic • Genetic susceptibility to postoperative nausea and vomiting (PONV) has not been studied What This Article Tells Us That Is New • Using genome-wide association and an independent valida- tion cohort, one single nucleotide polymorphism (rs2165870) in the promoter region of the M3 muscarinic acetylcholine receptor (CHRM3) gene was found to be significantly associ- ated with PONV  This article is featured in “This Month in Anesthesiology.” Please see this issue of ANESTHESIOLOGY, page 9A.  Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org). Anesthesiology, V 115 • No 1 July 2011 54 Downloaded from anesthesiology.pubs.asahq.org by guest on 06/03/2020