Genome-wide linkage of cotinine pharmacokinetics suggests candidate regions on chromosomes 9 and 11.
Characterizing cotinine pharmacokinetics is a useful way to study nicotine metabolism because the same liver enzyme is primarily responsible for the metabolism of both, and the clearances of nicotine and cotinine are highly correlated. We conducted a whole-genome linkage analysis to search for candidate regions influencing quantitative variation in cotinine pharmacokinetics in a large-scale pharmacokinetic study with 61 families containing 224 healthy adult participants. The strongest linkage signal was identified at 135 cM of chromosome 9 with LOD = 2.81 and P = 0.0002; two other suggestive linkage peaks appear at 31.4 and 73.5 cM of chromosome 11 with LOD = 1.96 (P = 0.0013) and 1.94 (P = 0.0014). The confidence level of the linkage between the three genome regions and cotinine pharmacokinetics is statistically significant with a genome-wide empirical probability of P = 0.029.
He
Yungang
Y
Center for Health Sciences, SRI International, Menlo Park, California 94025, USA. gary.swan@sri.com
Bergen
Andrew W
AW
Hops
Hyman
H
Andrews
Judy A
JA
Tildesley
Elizabeth
E
Lessov-Schlaggar
Christina N
CN
Webster
Cris
C
Benowitz
Neal
N
Swan
Gary E
GE
D000293:Adolescent; D002648:Child; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D003367:Cotinine / Q000493:pharmacokinetics*; D003903:Deuterium / Q000032:analysis; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007202:Indicators and Reagents / Q000493:pharmacokinetics*; D008297:Male; D009538:Nicotine / Q000378:metabolism*
D007202:Indicators and Reagents; D009538:Nicotine; D003903:Deuterium; D003367:Cotinine
Clin Pharmacol Ther. 2006 Oct;80(4):319-30
17015050
Am J Hum Genet. 2006 Oct;79(4):745-51
16960812
Genet Epidemiol. 1997;14(3):223-9
9181352
Oncogene. 2002 Oct 21;21(48):7307-25
12379875
Am J Med Genet B Neuropsychiatr Genet. 2006 Jun 5;141B(4):354-60
16671072
J Neurosci. 2007 Sep 26;27(39):10508-19
17898222
Hum Hered. 2002;54(2):99-110
12566741
Biol Mass Spectrom. 1991 May;20(5):247-52
1883864
J Biol Chem. 2005 Oct 7;280(40):34088-95
16091357
Cancer Epidemiol Biomarkers Prev. 2003 Oct;12(10):994-1005
14578134
Hum Genet. 2008 Mar;123(2):119-31
18205015
Am J Hum Genet. 1999 Feb;64(2):641-9
9973303
Clin Pharmacol Ther. 2006 Nov;80(5):522-30
17112808
Am J Hum Genet. 1997 Nov;61(5):1179-88
9345087
Curr Opin Genet Dev. 2004 Jun;14(3):233-40
15172664
Brain Res Mol Brain Res. 2004 Dec 20;132(2):181-91
15582157
Pharmacogenet Genomics. 2005 Feb;15(2):115-25
15861035
Am J Hum Genet. 2002 Aug;71(2):217-22
12154779
Ann Hum Genet. 1986 Jul;50(3):237-40
3481957
Genomics. 1992 Jul;13(3):908-9
1639428
Nat Genet. 2002 Jan;30(1):97-101
11731797
Genet Epidemiol. 1999;17 Suppl 1:S55-60
10597412
Am J Hum Genet. 2002 Aug;71(2):238-53
12111667
Nat Genet. 1995 Nov;11(3):241-7
7581446
J Natl Cancer Inst. 1999 Aug 18;91(16):1365-75
10451441
Nucleic Acids Res. 2007 Jan;35(Database issue):D26-31
17148475
Am J Hum Genet. 1998 Jul;63(1):259-66
9634505
Nucleic Acids Res. 2007 Jan;35(Database issue):D247-52
17130144
Genomics. 1996 Jun 15;34(3):426-9
8786146
Pharmacol Rev. 2005 Mar;57(1):79-115
15734728
Drug Alcohol Depend. 2000 Jul 1;60(1):13-8
10821985
Cytogenet Cell Genet. 1993;63(2):114-6
8467709
Drug Metab Dispos. 1996 Nov;24(11):1212-7
8937855