Specific polymorphic variation in the mitochondrial genome and increased in-hospital mortality after severe trauma.
OBJECTIVE
To determine whether specific genetic variations in the mtDNA that impact energy production and free-radical generation are potential new risk factors for in-hospital mortality after severe trauma.


BACKGROUND
Each of the 3 mitochondrial DNA polymorphisms selected for this study (at positions 4216, 10398, 4917) alter the amino acid sequence of different key subunits of Complex I in the electron transport chain. They have been previously implicated in phenotypes involving tissues with high-energy demand, such as the brain and retina.


METHODS
Seven hundred forty-five consecutive patients admitted to the trauma intensive care unit at Vanderbilt University Medical Center between April 11, 2005, and February 27, 2006, were potentially eligible for this study. Under an Institutional Review Board-approved protocol (which excluded patients <18 years of age and prisoners), 666 patients had DNA extracted from a blood sample. Detailed demographic and clinical covariates were also obtained (including age, gender, ethnicity, lactate measurements, and injury severity score). A flurogenic 5' nuclease allelic discrimination Taqman assay and the ABI 7900HT Sequence Detection System (v2.1) was used to genotype the T4216C, A10398G, and A4917G polymorphisms. The primary outcome was in-hospital mortality.


RESULTS
Multivariate logistic regression analysis revealed that the 4216T allele was a significant independent predictor of in-hospital mortality (OR = 2.63, 95% CI 1.14-6.07, P = 0.02) after adjustment for age, gender, injury severity score, highest lactate level, mechanism of injury, and the 10398 polymorphism.


CONCLUSIONS
Variation in the mtDNA, specifically the 4216T allele, appears to increase the risk of in-hospital mortality after severe injury.
Canter
Jeffrey A
JA
Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37212, USA. jeff.canter@vanderbilt.edu
Norris
Patrick R
PR
Moore
Jason H
JH
Jenkins
Judith M
JM
Morris
John A
JA
D000328:Adult; D000483:Alleles; D016009:Chi-Square Distribution; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D015894:Genome, Human; D005838:Genotype; D017052:Hospital Mortality; D006801:Humans; D015601:Injury Severity Score; D007773:Lactates / Q000097:blood; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D012307:Risk Factors; D018709:Statistics, Nonparametric; D014947:Wounds and Injuries / Q000401:mortality*
D004272:DNA, Mitochondrial; D007773:Lactates
Clin Chem Lab Med. 2003 Oct;41(10):1281-8
14580153
Neurosci Lett. 2004 Nov 23;371(2-3):158-62
15519748
Hum Genet. 2004 Jun;115(1):29-35
15108120
Neurosci Lett. 2004 Jul 15;365(1):28-32
15234467
Nature. 1981 Apr 9;290(5806):457-65
7219534
Proc Natl Acad Sci U S A. 1988 Sep;85(17):6465-7
3413108
Ann Neurol. 1992 Jul;32(1):113-4
1642467
Ann Surg. 1993 May;217(5):576-84; discussion 584-6
8489321
Genomics. 1993 Jul;17(1):171-84
8104867
Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8739-46
8090716
Gene. 1999 Sep 30;238(1):211-30
10570998
Am J Hum Genet. 2000 Sep;67(3):682-96
10936107
Exp Gerontol. 2001 Jul;36(7):1161-78
11404057
Eur J Hum Genet. 2005 Feb;13(2):166-70
15483642
AIDS. 2005 Sep 2;19(13):1341-9
16103764
Cancer Res. 2005 Sep 1;65(17):8028-33
16140977
Cancer Res. 2006 Feb 1;66(3):1880; author reply 1880-1
16452251
J Trauma. 2006 Jun;60(6):1165-73; discussion 1173-4
16766957
Ann Surg. 2006 Jun;243(6):804-12; discussion 812-4
16772784
Ann Surg. 2007 Apr;245(4):611-21
17414611
Biochem Biophys Res Commun. 2002 Jul 12;295(2):342-7
12150954
Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):171-6
12509511
Lancet. 2003 Feb 15;361(9357):567-71
12598142
Am J Hum Genet. 2003 Apr;72(4):804-11
12618962
Exp Gerontol. 2003 Apr;38(4):397-405
12670626
N Engl J Med. 2003 Jun 26;348(26):2656-68
12826641
J Physiol. 2003 Oct 15;552(Pt 2):335-44
14561818
Am J Hum Genet. 1995 Jul;57(1):133-49
7611282
Genetics. 1995 May;140(1):285-302
7635294
Biochim Biophys Acta. 1996 Sep 12;1276(2):87-105
8816944
Genetics. 1996 Dec;144(4):1835-50
8978068
Genomics. 1997 Jan 1;39(1):8-18
9027481
Am J Hum Genet. 1997 May;60(5):1107-21
9150158
Am J Hum Genet. 1997 Jun;60(6):1539-42
9199577
Sci Am. 1997 Aug;277(2):40-7
9245840
Lancet. 1998 Jan 17;351(9097):185-6
9449878
Biochim Biophys Acta. 1998 May 6;1364(2):271-86
9593934
Gerontology. 1998;44(6):349
9813436
Science. 1999 Mar 5;283(5407):1482-8
10066162
Am J Hum Genet. 1999 Jun;64(6):1505-10
10330338
J Med Genet. 2004 Apr;41(4):293-5
15060107