Investigation of the major cytochrome P450 1A2 genetic variant in a healthy Tibetan population in China

Ren,Yongchao; Liu,Fang; Shi,Xugang; Geng,Tingting; Yuan,Dongya; Wang,Li; Kang,Longli; Jin,Tianbo; Chen,Chao

doi:10.3892/mmr.2017.6645

Investigation of the major cytochrome P450 1A2 genetic variant in a healthy Tibetan population in China

Authors:
- Yongchao Ren
- Fang Liu
- Xugang Shi
- Tingting Geng
- Dongya Yuan
- Li Wang
- Longli Kang
- Tianbo Jin
- Chao Chen
View Affiliations

Affiliations: Qiannan Institute for Food and Drug Control, Duyun, Guizhou 558000, P.R. China, The Reproductive Centre, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi 710069, P.R. China, Key Laboratory of High Altitude Environment and Genes Related to Diseases of the Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, P.R. China, National Engineering Research Center for Miniaturized Detection Systems, Xi'an, Shaanxi 710069, P.R. China, School of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, P.R. China
Published online on: May 29, 2017 https://doi.org/10.3892/mmr.2017.6645
Pages: 573-580
Copyright: © Ren et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The cytochrome P450 (CYP) 1A2 gene is involved in the metabolism of several carcinogens and clinically important drugs, generating a high potential for pharmacokinetic interactions. Since no data are available for Tibetan aborigines, the present study aimed to investigate the distribution of variant CYP1A2 alleles in a population living in Tibetan region of China. Genotyping analyses of CYP1A2 were conducted in 96 unrelated, healthy volunteers of Tibetan ancestry using direct sequencing assays. A total of 14 different CYP1A2 polymorphisms, including two novel variants (1690G>A and 2896C>T) in the intron region and a novel non‑synonymous one (795G>C, Gln265His) were detected. CYP1A2*1A (6.77%), CYP1A2*1B (58.33%) and CYP1A2*1F (14.58%) were the most frequent defective alleles identified in the sample. The frequencies of the prevalent genotypes CYP1A2*1A/*1B, *1B/*1B, *1B/*1F were 13.54%, 16.67% and 29.17%, respectively. In addition, the novel non‑synonymous variant 795G>C (Gln265His) was predicted to be benign by PolyPhen‑2 and SIFT tools. The present study provides useful information on the pattern of CYP1A2 polymorphisms in Chinese Tibetan population. The current results may have potential benefits for the development of personalized medicine in the Tibetan population.

View Figures

View References

1	Evans WE and Relling MV: Pharmacogenomics: Translating functional genomics into rational therapeutics. Science. 286:487–491. 1999. View Article : Google Scholar : PubMed/NCBI
2	Alexov E and Sternberg M: Understanding molecular effects of naturally occurring genetic differences. J Mol Biol. 425:3911–3913. 2013. View Article : Google Scholar : PubMed/NCBI
3	Klein K, Winter S, Turpeinen M, Schwab M and Zanger UM: Pathway-Targeted Pharmacogenomics of CYP1A2 in Human Liver. Front Pharmacol. 1:1292010. View Article : Google Scholar : PubMed/NCBI
4	Sachse C, Brockmöller J, Bauer S and Roots I: Functional significance of a C->A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Br J Clin Pharmacol. 47:445–449. 1999. View Article : Google Scholar : PubMed/NCBI
5	Chida M, Yokoi T, Fukui T, Kinoshita M, Yokota J and Kamataki T: Detection of three genetic polymorphisms in the 5′-flanking region and intron 1 of human CYP1A2 in the Japanese population. Jpn J Cancer Res. 90:899–902. 1999. View Article : Google Scholar : PubMed/NCBI
6	Sachse C, Bhambra U, Smith G, Lightfoot TJ, Barrett JH, Scollay J, Garner RC, Boobis AR, Wolf CR and Gooderham NJ: Colorectal Cancer Study Group: Polymorphisms in the cytochrome P450 CYP1A2 gene (CYP1A2) in colorectal cancer patients and controls: Allele frequencies, linkage disequilibrium and influence on caffeine metabolism. Br J Clin Pharmacol. 55:68–76. 2003. View Article : Google Scholar : PubMed/NCBI
7	Dobrinas M, Cornuz J, Pedrido L and Eap CB: Influence of cytochrome P450 oxidoreductase genetic polymorphisms on CYP1A2 activity and inducibility by smoking. Pharmacogenet Genomics. 22:143–151. 2012. View Article : Google Scholar : PubMed/NCBI
8	Perera V, Gross AS and McLachlan AJ: Influence of environmental and genetic factors on CYP1A2 activity in individuals of South Asian and European ancestry. Clin Pharmacol Ther. 92:511–519. 2012.PubMed/NCBI
9	Ng PC and Henikoff S: SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res. 31:3812–3814. 2003. View Article : Google Scholar : PubMed/NCBI
10	Liu X, Jian X and Boerwinkle E: dbNSFP: A lightweight database of human nonsynonymous SNPs and their functional predictions. Hum Mutat. 32:894–899. 2011. View Article : Google Scholar : PubMed/NCBI
11	Pavanello S, Fedeli U, Mastrangelo G, Rota F, Overvad K, Raaschou-Nielsen O, Tjønneland A and Vogel U: Role of CYP1A2 polymorphisms on lung cancer risk in a prospective study. Cancer Genet. 205:278–284. 2012. View Article : Google Scholar : PubMed/NCBI
12	Chida M, Yokoi T, Fukui T, Kinoshita M, Yokota J and Kamataki T: Detection of three genetic polymorphisms in the 5′-flanking region and intron 1 of human CYP1A2 in the Japanese population. Jpn J Cancer Res. 90:899–902. 1999. View Article : Google Scholar : PubMed/NCBI
13	Han XM, Ou-Yang DS, Lu PX, Jiang CH, Shu Y, Chen XP, Tan ZR and Zhou HH: Plasma caffeine metabolite ratio (17X/137X) in vivo associated with G-2964A and C734A polymorphisms of human CYP1A2. Pharmacogenetics. 11:429–435. 2001. View Article : Google Scholar : PubMed/NCBI
14	Gunes A and Dahl ML: Variation in CYP1A2 activity and its clinical implications: Influence of environmental factors and genetic polymorphisms. Pharmacogenomics. 9:625–637. 2008. View Article : Google Scholar : PubMed/NCBI
15	Browning SL, Tarekegn A, Bekele E, Bradman N and Thomas MG: CYP1A2 is more variable than previously thought: A genomic biography of the gene behind the human drug-metabolizing enzyme. Pharmacogenet Genomics. 20:647–664. 2010. View Article : Google Scholar : PubMed/NCBI
16	B'Chir F, Pavanello S, Knani J, Boughattas S, Arnaud MJ and Saguem S: CYP1A2 genetic polymorphisms and adenocarcinoma lung cancer risk in the Tunisian population. Life Sci. 84:779–784. 2009. View Article : Google Scholar : PubMed/NCBI
17	Hamdy SI, Hiratsuka M, Narahara K, Endo N, El-Enany M, Moursi N, Ahmed MS and Mizugaki M: Genotyping of four genetic polymorphisms in the CYP1A2 gene in the Egyptian population. Br J Clin Pharmacol. 55:321–324. 2003. View Article : Google Scholar : PubMed/NCBI
18	Aklillu E, Carrillo JA, Makonnen E, Hellman K, Pitarque M, Bertilsson L and Ingelman-Sundberg M: Genetic polymorphism of CYP1A2 in Ethiopians affecting induction and expression: Characterization of novel haplotypes with single-nucleotide polymorphisms in intron 1. Mol Pharmacol. 64:659–669. 2003. View Article : Google Scholar : PubMed/NCBI
19	Djordjevic N, Ghotbi R, Jankovic S and Aklillu E: Induction of CYP1A2 by heavy coffee consumption is associated with the CYP1A2 −163C>A polymorphism. Eur J Clin Pharmacol. 66:697–703. 2010. View Article : Google Scholar : PubMed/NCBI
20	Ghotbi R, Christensen M, Roh HK, Ingelman-Sundberg M, Aklillu E and Bertilsson L: Comparisons of CYP1A2 genetic polymorphisms, enzyme activity and the genotype-phenotype relationship in Swedes and Koreans. Eur J Clin Pharmacol. 63:537–546. 2007. View Article : Google Scholar : PubMed/NCBI
21	Soyama A, Saito Y, Hanioka N, Maekawa K, Komamura K, Kamakura S, Kitakaze M, Tomoike H, Ueno K, Goto Y, et al: Single nucleotide polymorphisms and haplotypes of CYP1A2 in a Japanese population. Drug Metab Pharmacokinet. 20:24–33. 2005. View Article : Google Scholar : PubMed/NCBI
22	Chen X, Wang L, Zhi L, Zhou G, Wang H, Zhang X, Hao B, Zhu Y, Cheng Z and He F: The G-113A polymorphism in CYP1A2 affects the caffeine metabolic ratio in a Chinese population. Clin Pharmacol Ther. 78:249–259. 2005. View Article : Google Scholar : PubMed/NCBI
23	Myrand SP, Sekiguchi K, Man MZ, Lin X, Tzeng RY, Teng CH, Hee B, Garrett M, Kikkawa H, Lin CY, et al: Pharmacokinetics/genotype associations for major cytochrome P450 enzymes in native and first- and third-generation Japanese populations: Comparison with Korean, Chinese, and Caucasian populations. Clin Pharmacol Ther. 84:347–361. 2008. View Article : Google Scholar : PubMed/NCBI
24	Dandara C, Lombard Z, Du Plooy I, McLellan T, Norris SA and Ramsay M: Genetic variants in CYP (−1A2, −2C9, −2C19, −3A4 and −3A5), VKORC1 and ABCB1 genes in a black South African population: A window into diversity. Pharmacogenomics. 12:1663–1670. 2011. View Article : Google Scholar : PubMed/NCBI