Abstract
Objectives: Many complications in the perioperative interval are associated with genetic susceptibilities that may be unknown in advance of surgery and anesthesia, including drug toxicity and inefficacy, thrombosis, prolonged neuromuscular blockade, organ failure and sepsis. The aims of this study were to design and validate the first genetic testing platform and panel designed for use in perioperative care, to establish allele frequencies in a target population, and to determine the number of mutant alleles per patient undergoing surgery.
Design/Setting/Participants and Methods: One hundred fifty patients at Marshfield Clinic, Marshfield, Wisconsin, 100 patients at the Medical College of Wisconsin Zablocki Veteran’s Administration Medical Center, Milwaukee, Wisconsin, and 200 patients at the University of Wisconsin Hospitals and Clinics, Madison, Wisconsin undergoing surgery and anesthesia were tested for 48 polymorphisms in 22 genes including ABC, BChE, ACE, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, β2AR, TPMT, F2, F5, F7, MTHFR, TNFα, TNFβ, CCR5, ApoE, HBB, MYH7, ABO and Gender (PRKY, PFKFB1). Using structure-specific cleavage of oligonucleotide probes (Invader®, Third Wave Technologies, Inc., Madison, WI), 96-well plates were configured so that each well contained reagents for detection of both the wild type and mutant alleles at each locus.
Results: There were 21,600 genotypes confirmed in duplicate. After withdrawal of polymorphisms in non-pathogenic genes (i.e., the ABO blood group and gender-specific alleles), 376 of 450 patients were found to be homozygous for mutant alleles at 1 or more loci. Modes of 2 mutant homozygous loci and 10 mutant alleles in aggregate (i.e., the sum of homozygous and heterozygous mutant polymorphisms) were observed per patient.
Conclusions: Significant genetic heterogeneity that may not be accounted for by taking a family medical history, or by obtaining routine laboratory test results, is present in most patients presenting for surgery and may be detected using a newly developed genotyping platform.
- Genetic polymorphisms
- Genetic predisposition testing
- Genetic susceptibility
- Genetic variation
- Molecular diagnostic techniques
- Oligonucleotide probes
- Perioperative care
- Perioperative complications
- Pharmacogenetics
Footnotes
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↵1 Present address: Roche NimbleGen, Inc. Madison, Wisconsin 53701
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↵2 Present address: Aurora West Allis Medical Center West Allis, Wisconsin 53227
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↵3 Present address: Blood Center of Wisconsin, Milwaukee, Wisconsin 53201
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Presented in part at the American Society of Anesthesiologists Annual Meeting, Chicago, Illinois, October 14–18, 2006, and in part at the 9th International Meeting on Human Genome Variation and Complex Genome Analysis, Sitges, Spain, September 6–8, 2007.
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Grant Support: Grant No. IR43GM64317-01 from the National Institutes of Health, Bethesda, Maryland. Dr. K. Hogan, Dr. Caldwell and Dr. Q. Hogan received research support and consulting fees from the NIH grant. Dr. Domanico, Dr. de Arruda-Indig, Dr. Day, Ms. Lutz, Ms. Sanders, Ms. Oldenburg, and Mr. Koelbl were employed by Third Wave Technologies, Inc., a wholly owned subsidiary of Holologic, Inc.
- Received December 29, 2008.
- Revision received March 5, 2009.
- Accepted March 11, 2009.
