SOFT 2004 Meeting Abstracts - Society of Forensic Toxicologists
SOFT 2004 Meeting Abstracts - Society of Forensic Toxicologists
SOFT 2004 Meeting Abstracts - Society of Forensic Toxicologists
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P61 <br />
A MULTI-CENTER STUDY OF PHARMACOGENOMICS AS AN ADJUNCT OF MOLECULAR<br />
AUTOPSY FOR METHADONE DEATH CERTIFICATION - PRELIMINARY FINDINGS OF<br />
DATA ACQUISITION AND MULTIPLEX GENOTYPING CYP 450 2D6, 2C9 AND 2C19 BY<br />
PYROSEQUENCING<br />
Steve Wong*, Susan Gock, and Jeffrey Jentzen, Milwaukee Medical Examiner Office, 933 Highland Ave.,<br />
Milwaukee, WI 53226 and the <strong>Forensic</strong> Pathologyrroxicology Pharmacogenomics Methadone Study<br />
Group (FPTPMSG<br />
Methadone is used in the treatment <strong>of</strong> heroin addiction and as an analgesic for pain management. Recently,<br />
there has been an increased incidence <strong>of</strong> methadone intoxication due to abuse and diversion. One <strong>of</strong> the<br />
contributing factors to drug therapy and toxicity is genetic variation. With the Human Genome Project near<br />
completion, genomic medicine based on genetic pr<strong>of</strong>iles has been proposed for personalized medicine for<br />
drug treatment and other therapeutic approaches. As an extension <strong>of</strong> genomics medicine in forensic<br />
science, a previous study examined the potential contribution <strong>of</strong> genetic variations in methadone death (J<br />
For Sci. 2003;48:1406-15). The allelic frequency <strong>of</strong> wild-type, defined for that study as non- CYP 2D6 *3,<br />
*4 and *5, was 71.4%, lower than that <strong>of</strong> living controls 82.7%. Due to the limited number <strong>of</strong> cases (n<br />
=21), the study was not adequately powered with sufficient cases to reach statistical significance. Studies<br />
for oxycodone and antidepressants also yielded a similar lower prevalence. Further, there is increasing<br />
understanding <strong>of</strong> methadone metabolism, readily characterized as mUlti-pathways with mUlti-enzymes<br />
(CYP 3A4, 2C9, 2C19, and 2D6). Some <strong>of</strong> the genes encoding these enzymes are polymorphic. Hence, a<br />
multi-center study was designed to enroll an adequate number <strong>of</strong> methadone cases to evaluate the potential<br />
contribution <strong>of</strong> genetic variation to methadone/related deaths Pharmacogenomics as an aspect <strong>of</strong><br />
Molecular Autopsy. The study was initiated with several planning sessions to consider all the key covariables<br />
and risk factors. In the fall <strong>of</strong> 2003, the following medical examiner/coroner <strong>of</strong>fices and personnel<br />
formed the <strong>Forensic</strong> Pathologyrroxicology Pharmacogenomics Methadone Study Group (FPTPMSG):<br />
Milwaukee - Wong, Jentzen, Gock, Jannetto, Schur, Sahin, Frolov, Rogalska. Cleveland/Cuyahoga<br />
Jenkins, Balraj, DetroitlWayne Hepler, Isenschmid, Schmidt, MiamilDade - Hearn, Uhlin-Hansen, New<br />
Hampshire - Wagner, Andrew, New Mexico - Kerrigan, North Carolina - Winecker, Ropera-MiIler, San<br />
Diego - McIntyre, San Francisco - Karch, Lemos, British Columbia/Canada- Langman, Washington, DC<br />
Couper, and Washington Logan, Gordon. In addition, drug-drug interaction interpretations will be<br />
performed by Moody (Univ. Utah) and secondary case reviews by Jortani (Univ. Louisville). The study<br />
period is 2002 and 2003, with some <strong>of</strong>fices providing samples before and after for trending studies. The<br />
Medical College <strong>of</strong> Wisconsin (MCW) approved an " Umbrella IRB", with subsequent endorsement by the<br />
participating <strong>of</strong>fices. Inclusion criteria are: cases certified with methadone toxicity, methadone related and<br />
methadone present. For the latter cases, each <strong>of</strong>fice would seek informed consent by decedent's family.<br />
Whole blood samples were mailed to the MeW Pharmacogenomics Lab for multiplex genotyping for CYP<br />
2D6 *3, *4, *5, *6, *7, *8., 2C9 *2 and *3., and 2C19*2,*3 and *4 by pyrosequencing (Clin Chern.<br />
2003;49:A] 2). By using a combination <strong>of</strong> Micros<strong>of</strong>t ACCESS and Excel database programs, case history<br />
and toxicology results were entered, followed by statistical analysis <strong>of</strong> transformed Excel data. At this<br />
preliminary stage, the study demonstrated the feasibility <strong>of</strong> coordinated planning and initial data entry and<br />
transfer to the MCW via Internet by 5 centers. The projected total caseload for FPTPMSG is more than<br />
1900. For a limited number <strong>of</strong> samples (n=22), the following variants were identified in 14 samples: 1<br />
homozygous for CYP 2D6*4, and the number for heterozygous variants 2 for 2D6*4 and 2C19*2., 1 for<br />
2D6*31*4., 2 for 2C9*2, 1 for 2C9*3, 4 for 2C19*2, Ifor 2D6*3, and 2 for 2D6*5. These preliminary<br />
results indicate that the multi-center study is proceeding on schedule, albeit with the expected degree <strong>of</strong><br />
logistic and technical difficulty.<br />
Key words: methadone, pharmacogenomics, death<br />
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