Endothelial nitric oxide synthase gene variation associated with chronic kidney disease after liver transplant.
OBJECTIVE
To identify single nucleotide polymorphisms (SNPs) associated with risk of developing chronic kidney disease (CKD), a prevalent comorbidity, after liver transplant (LT).


METHODS
This study consists of a cohort of adult (> or =18 years) primary-LT recipients who had normal renal function before LT and who survived 1 year or more after LT at a high-volume US LT program between January 1, 1990, and December 31, 2000. Patients with adequate renal function (estimated glomerular filtration rate, > or =40 mL/min per 1.73 m(2) during follow-up; n=308) and patients with incident CKD (estimated glomerular filtration rate, <40 mL/min per 1.73 m(2) after LT; n=92) were identified. To investigate the association of 6 candidate genes with post-LT CKD, we selected SNPs that have been associated with renal function in the literature. Hazard ratios were estimated using Cox regression, adjusted for potential confounding variables.


RESULTS
The variant allele (298Asp) of the Glu298Asp SNP in the endothelial nitric oxide synthase gene (NOS3) was significantly associated with CKD after LT (P=.05; adjusted for multiple comparisons). The 5-year incidence of CKD was 70% among patients homozygous for the NOS3 variant allele (298Asp) compared with 42% among those not homozygous for the NOS3 variant allele. Specifically, homozygosity for the NOS3 variant allele conferred a 2.5-fold increased risk of developing CKD after LT (P=.005, adjusted for confounding variables).


CONCLUSIONS
Homozygosity for the variant allele of NOS3 (298Asp) is associated with CKD after LT and may be useful for identifying recipients at higher risk of post-LT CKD.
Bambha
Kiran
K
Division of Gastroenterology and Hepatology, University of Colorado Health Sciences Center, Denver, USA.
Kim
W Ray
WR
Rosen
Charles B
CB
Pedersen
Rachel A
RA
Rys
Cynthia
C
Kolbert
Christopher P
CP
Cunningham
Julie M
JM
Therneau
Terry M
TM
D000483:Alleles; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D005919:Glomerular Filtration Rate; D006720:Homozygote; D006801:Humans; D053208:Kaplan-Meier Estimate; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000235:genetics*; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016016:Proportional Hazards Models
C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III
Nephrol Dial Transplant. 2000 Nov;15(11):1794-800
11071967
Clin Nephrol. 2001 Jun;55(6):453-9
11434356
Am J Med Sci. 2005 Jan;329(1):13-7
15654174
Nephrol Dial Transplant. 2000 May;15(5):586-8
10809796
Kidney Int Suppl. 1995 Dec;52:S70-4
8587288
Clin Nephrol. 1999 Jul;52(1):37-43
10442494
Toxicology. 2005 Feb 28;207(3):463-74
15664273
N Engl J Med. 2003 Sep 4;349(10):931-40
12954741
J Am Soc Nephrol. 1998 Apr;9(4):598-604
9555662
Mol Cell Biochem. 2003 Feb;244(1-2):113-8
12701818
Am J Kidney Dis. 2002 Feb;39(2 Suppl 1):S1-266
11904577
Clin Chem. 2000 Nov;46(11):1858-60
11067831
Am J Physiol. 1998 Apr;274(4):F791-8
9575905
Hypertension. 2002 Oct;40(4):535-40
12364359
FASEB J. 2007 Sep;21(11):2655-63
17449720
Clin Auton Res. 2001 Apr;11(2):67-78
11570606
J Hypertens. 1999 Dec;17(12 Pt 1):1707-13
10658936
Circulation. 1999 Jun 22;99(24):3096-8
10377070
Brief Bioinform. 2002 Jun;3(2):146-53
12139434
Kidney Int. 1994 Sep;46(3):773-9
7996799
Mol Genet Metab. 2000 Aug;70(4):241-51
10993711
Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2832-5
10717002
Surgery. 2002 Oct;132(4):775-80; discussion 780
12407365
J Heart Lung Transplant. 2000 Sep;19(9):866-72
11008076
Kidney Int. 1995 Jun;47(6):1507-14
7543959
J Pharmacol Exp Ther. 2003 Jun;305(3):840-5
12626650
Am J Surg. 2002 May;183(5):595-9
12034401
Eur J Pharmacol. 2000 Nov 24;408(3):323-6
11090650
Transplant Proc. 2001 Feb-Mar;33(1-2):1567-9
11267423
Clin Genet. 2000 Oct;58(4):250-64
11076050
J Biol Chem. 2001 Jul 13;276(28):26674-9
11331296
J Am Soc Nephrol. 1992 Jul;3(1):42-50
1391707
Kidney Int. 1998 Jun;53(6):1455-60
9607174
J Am Soc Nephrol. 1993 Nov;4(5):1159-71
8305642
Kidney Int. 2000 Mar;57(3):1100-6
10720962
Hypertension. 2002 Feb;39(2):209-13
11847185
J Physiol Pharmacol. 2001 Mar;52(1):21-38
11321510
Transplantation. 2001 Dec 27;72(12):1934-9
11773892
Hypertension. 1999 May;33(5):1169-74
10334806
Pharmacol Rev. 1991 Jun;43(2):109-42
1852778
Transplantation. 1991 Feb;51(2):428-30
1994538
Hypertension. 1994 Jun;23(6 Pt 2):957-61
8206635
J Hum Genet. 2007;52(2):143-151
17143591
Kidney Int. 2000 Sep;58(3):1174-85
10972680
Kidney Int. 2003 Feb;63(2):522-33
12631117
J Am Soc Nephrol. 2003 Oct;14(10):2596-602
14514737
Kidney Int. 2001 Jul;60(1):46-54
11422735
Ann Surg. 2005 Jun;241(6):905-16; discussion 916-8
15912040
Int Urol Nephrol. 2005;37(3):587-94
16307347