Perioperative genomic profiles using structure-specific oligonucleotide probes.
OBJECTIVE
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, beta2AR, TPMT, F2, F5, F7, MTHFR, TNFalpha, TNFbeta, 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 one or more loci. Modes of two 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.
Hogan
Kirk J
KJ
Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, B6/319 Clinical Sciences Center, 600 Highland Avenue, Madison, WI 53792, USA. khogan@wiscmail.wisc.edu
Burmester
James K
JK
Caldwell
Michael D
MD
Hogan
Quinn H
QH
Coursin
Douglas B
DB
Green
Dawn N
DN
Selzer
Rebecca M R
RM
Broderick
Thomas P
TP
Rusy
Deborah A
DA
Poroli
Mark
M
Lutz
Anna L
AL
Sanders
Allison M
AM
Oldenburg
Mary C
MC
Koelbl
James A
JA
de Arruda-Indig
Monika
M
Halsey
Jennifer L
JL
Day
Stephen P
SP
Domanico
Michael J
MJ
D000483:Alleles; D000758:Anesthesia; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D023281:Genomics; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D008954:Models, Biological; D025202:Molecular Diagnostic Techniques; D009841:Oligonucleotides / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods*; D016133:Polymerase Chain Reaction; D057234:Preoperative Period
D009841:Oligonucleotides