title: Genome-wide linkage of cotinine pharmacokinetics suggests candidate regions on chromosomes 9 and 11.
abstract: 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.
authors.affiliation: Center for Health Sciences, SRI International, Menlo Park, California 94025, USA. gary.swan@sri.com
authors.forename: Yungang
authors.initials: Y
authors.lastname: He
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Bergen
authors.forename: Hyman
authors.initials: H
authors.lastname: Hops
authors.forename: Judy A
authors.initials: JA
authors.lastname: Andrews
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tildesley
authors.forename: Christina N
authors.initials: CN
authors.lastname: Lessov-Schlaggar
authors.forename: Cris
authors.initials: C
authors.lastname: Webster
authors.forename: Neal
authors.initials: N
authors.lastname: Benowitz
authors.forename: Gary E
authors.initials: GE
authors.lastname: Swan
mesh_terms: 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*
chemical_list: D007202:Indicators and Reagents; D009538:Nicotine; D003903:Deuterium; D003367:Cotinine
references.citation: Clin Pharmacol Ther. 2006 Oct;80(4):319-30
references.pmid: 17015050
references.citation: Am J Hum Genet. 2006 Oct;79(4):745-51
references.pmid: 16960812
references.citation: Genet Epidemiol. 1997;14(3):223-9
references.pmid: 9181352
references.citation: Oncogene. 2002 Oct 21;21(48):7307-25
references.pmid: 12379875
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2006 Jun 5;141B(4):354-60
references.pmid: 16671072
references.citation: J Neurosci. 2007 Sep 26;27(39):10508-19
references.pmid: 17898222
references.citation: Hum Hered. 2002;54(2):99-110
references.pmid: 12566741
references.citation: Biol Mass Spectrom. 1991 May;20(5):247-52
references.pmid: 1883864
references.citation: J Biol Chem. 2005 Oct 7;280(40):34088-95
references.pmid: 16091357
references.citation: Cancer Epidemiol Biomarkers Prev. 2003 Oct;12(10):994-1005
references.pmid: 14578134
references.citation: Hum Genet. 2008 Mar;123(2):119-31
references.pmid: 18205015
references.citation: Am J Hum Genet. 1999 Feb;64(2):641-9
references.pmid: 9973303
references.citation: Clin Pharmacol Ther. 2006 Nov;80(5):522-30
references.pmid: 17112808
references.citation: Am J Hum Genet. 1997 Nov;61(5):1179-88
references.pmid: 9345087
references.citation: Curr Opin Genet Dev. 2004 Jun;14(3):233-40
references.pmid: 15172664
references.citation: Brain Res Mol Brain Res. 2004 Dec 20;132(2):181-91
references.pmid: 15582157
references.citation: Pharmacogenet Genomics. 2005 Feb;15(2):115-25
references.pmid: 15861035
references.citation: Am J Hum Genet. 2002 Aug;71(2):217-22
references.pmid: 12154779
references.citation: Ann Hum Genet. 1986 Jul;50(3):237-40
references.pmid: 3481957
references.citation: Genomics. 1992 Jul;13(3):908-9
references.pmid: 1639428
references.citation: Nat Genet. 2002 Jan;30(1):97-101
references.pmid: 11731797
references.citation: Genet Epidemiol. 1999;17 Suppl 1:S55-60
references.pmid: 10597412
references.citation: Am J Hum Genet. 2002 Aug;71(2):238-53
references.pmid: 12111667
references.citation: Nat Genet. 1995 Nov;11(3):241-7
references.pmid: 7581446
references.citation: J Natl Cancer Inst. 1999 Aug 18;91(16):1365-75
references.pmid: 10451441
references.citation: Nucleic Acids Res. 2007 Jan;35(Database issue):D26-31
references.pmid: 17148475
references.citation: Am J Hum Genet. 1998 Jul;63(1):259-66
references.pmid: 9634505
references.citation: Nucleic Acids Res. 2007 Jan;35(Database issue):D247-52
references.pmid: 17130144
references.citation: Genomics. 1996 Jun 15;34(3):426-9
references.pmid: 8786146
references.citation: Pharmacol Rev. 2005 Mar;57(1):79-115
references.pmid: 15734728
references.citation: Drug Alcohol Depend. 2000 Jul 1;60(1):13-8
references.pmid: 10821985
references.citation: Cytogenet Cell Genet. 1993;63(2):114-6
references.pmid: 8467709
references.citation: Drug Metab Dispos. 1996 Nov;24(11):1212-7
references.pmid: 8937855