title: Haplotypes in the 5'-untranslated region of the CYP1A2 gene are inversely associated with lung cancer risk but do not correlate with caffeine metabolism.
abstract: In this study, we analyzed the influence of CYP1A2 genetic variation and enzyme activity on lung cancer risk in a high-incidence area. A total of 95 lung cancer patients and 196 controls were genotyped for the -3860G/A, -3113A/G, -2467T/delT, -739T/G, and -163C/A polymorphisms in the 5'-untranslated region of the gene. In addition, a subset of 70 patients and 115 controls were phenotyped by high-performance liquid chromatography determination of the caffeine metabolic ratio (CMR). The -2467T/delT polymorphism and the CYP1A2*1V haplotype (-163C>A, -2467T>delT) were inversely associated with lung cancer risk (odds ratio [OR] = 0.47 [0.2-0.9]; P = 0.02 and OR = 0.13 [0.02-1.0]; P = 0.04; respectively). In addition, the CYP*1A/*1V and *1F (-163C>A)/*1D (-163C>A, -2467T>delT) diplotypes were absent in the patients group, whereas accounting for 7.1% (P = 0.017) and 5.6% (P = 0.037) of controls, respectively. Mean CMR was significantly higher in patients than in controls (10.50 ± 17.31 vs. 6.52 ± 6.26, P = 0.01) but regression analyses did not yield significant ORs for the association with lung cancer risk. Similarly, no significant correlations were found between any genetic variant and enzyme activity. Several CYP1A2 haplotypes and diplotypes containing the -2467delT variant were associated with lower lung cancer risk; however, they did not correlate with significant changes in CYP1A2 metabolic activity toward caffeine.
authors.affiliation: Department of Medical & Surgical Therapeutics, Division of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain. ggervasi@unex.es
authors.forename: Guillermo
authors.initials: G
authors.lastname: Gervasini
authors.forename: Roza
authors.initials: R
authors.lastname: Ghotbi
authors.forename: Eleni
authors.initials: E
authors.lastname: Aklillu
authors.forename: Carmen
authors.initials: C
authors.lastname: San Jose
authors.forename: Agustin
authors.initials: A
authors.lastname: Cabanillas
authors.forename: Junko
authors.initials: J
authors.lastname: Kishikawa
authors.forename: Julio
authors.initials: J
authors.lastname: Benitez
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Carrillo
mesh_terms: D020121:5' Untranslated Regions; D000368:Aged; D002110:Caffeine / Q000097:blood / Q000378:metabolism* / Q000652:urine; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006239:Haplotypes; D006801:Humans; D015994:Incidence; D008175:Lung Neoplasms / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D012306:Risk; D012907:Smoking / Q000009:adverse effects; D013030:Spain / Q000453:epidemiology; D011795:Surveys and Questionnaires
chemical_list: D020121:5' Untranslated Regions; D002110:Caffeine; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2