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Novel single nucleotide polymorphisms (SNPs) of CYP2W1 gene in Chinese Uygur and Han populations

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Abstract

Cytochrome P450 2W1 (CYP2W1) is expressed specially in certain cancers and could metabolize some substances into cytotoxic antitumor drugs in Caucasian ethnic population. To investigate the genetic polymorphism of CYP2W1 in Chinese, all the nine exons and exon–intron junctions were sequenced by dideoxy chain termination method among 385 Chinese subjects (including 223 Han and 162 Uygur). The present results showed that 40 single nucleotide polymorphisms (SNPs) were detected (14 in the exons and 26 in the introns), 10 were novel variants of which in Chinese. There were 7 novel SNPs in the exons and other 3 novel SNPs in the introns. Four of the 6 novel non-synonymous variations in exons, 131T > C (Leu44Pro), 1289C > A (Ala88Glu), 2027G > A (Arg187Gln) and 5070C > T (Thr383Met) were computationally predicted to affect CYP2W1 protein function, in spite of these variants were heterozygotes. Moreover, the allele frequencies in 6 known SNPs including CYP2W1*2 (2008G > A) and CYP2W1*3 (173A > C) were analyzed, which were significantly lower in Chinese Han (2.9% and 0.0%, respectively) and Uygur (5.2% and 0.0%, respectively) individuals, than those reported previously in Caucasians (9.1% and 33.1%, respectively, P < 0.05). These data provide useful information on the pharmacogenetic studies of CYP2W1 among Chinese and other ethnic populations.

Introduction

Cytochrome P450 2W1 (CYP2W1) was demonstrated to be expressed in fetal tissues, predominantly the colon, but silenced after birth and could not be detected in adult tissues [1]. However, CYP2W1 was re-expressed in some transformed tissues, like colorectal, hepatic and adrenal tumors [2], [3]. Initially, CYP2W1 was considered to be an orphan enzyme, whereas, some potential substrates of it had been found recently, such as aromatic amines [4], lysophospholipids [5] and duocarmycin analogs [6]. Promisingly CYP2W1 might be an anticancer drug target because it could metabolize some duocarmycin analogs into cytotoxic substances and subsequently inhibit the growth of cancer cells.

CYP2W1 locates on chromosome 7p22.3, spanning over 5.5 kb with nine exons. The open-reading frame is 1473-nucleotide long and encodes a 490-amino acid long polypeptide. Until now there are seven alleles of CYP2W1 (CYP2W1*1A, *1B, *2*6) in the CYP allele nomenclature webpage (http://www.cypalleles.ki.se/cyp2w1.htm), including five non-synonymous single nucleotide polymorphisms (SNPs): 173A > C (Glu58Ala), 2008G > A (Ala181Thr), 5432G > A (Val432Ile), 5584G > C (Gln482His), and 5601C > T (Pro488Leu), and one synonymous SNP: 166C > T [7]. Association of CYP2W1 variants with colorectal cancer risk had been investigated in Caucasians [8], [9]. However, genetic polymorphisms of CYP2W1 in Chinese had not been reported yet.

Until recently the systematic investigation of genetic variants of CYP2W1 had only been performed in one Japanese population. Besides a Han majority group, Chinese Uygur is a larger minority group with the population of approximately 10.07 million people (2010 census), who reside in the Silk Road of northwestern China with genetic admixture between Orientals and Caucasians and our previous studies showed that intermediate allele frequencies of MDR1, CYP3A5, CYP2C19 and CYP2E1 were observed in Chinese Uygur between Han and Caucasians populations [10], [11]. To investigate the genetic polymorphism of CYP2W1 among Chinese, all the nine exons and exon–intron junctions were sequenced in 385 healthy Chinese subjects (including 223 Han and 162 Uygur).

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Materials and methods

Three hundred and eighty-five unrelated mainland Chinese healthy volunteers, including 223 Chinese Han and 162 Chinese Uygur, were recruited for the present study. Each subject had the same ethnic origin for at least three generations, i.e., on both mothers' and fathers' sides, also the status of the grandparents. The present study protocol was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Beijing University, Beijing, China. Written informed

Results and discussion

Ten novel SNPs were found as follows:

  • 1)

    SNP: 150901Zhang/Qi001; GENE NAME: CYP2W1; ACCESSION NUMBER: NC_000007.14; LENGTH: 25 bases; 5′-TCGTCGGGAACCT/CGCACTTGCTGCG-3′.

  • 2)

    SNP: 150901Zhang/Qi002; GENE NAME: CYP2W1; ACCESSION NUMBER: NC_000007.14; LENGTH: 25 bases; 5′-CTGGGCCTGTCGG/TCTGCCTGCTCAG-3′.

  • 3)

    SNP: 150901Zhang/Qi003; GENE NAME: CYP2W1; ACCESSION NUMBER: NC_000007.14; LENGTH: 25 bases; 5′-CCCCCCTCGGCCC/GTCAGGTGTTCAA-3′.

  • 4)

    SNP: 150901Zhang/Qi004; GENE NAME: CYP2W1; ACCESSION NUMBER: NC_000007.14;

Conflict of interest

No conflict of interests have been declared.

Acknowledgments

We are grateful to Mr. An-ping Zhu, Ms. Zhen Wang and Ms. Ping Zhang (The Central University for Nationalities, P. R. China) for their assistance in subject recruitment. This study was supported by National Natural Science Foundation of China (Grants No.30973585 91029747 and 81473276), and the Beijing University Center for Human Disease Genomics (Grant No 2000A-1).

References (14)

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On September 1, 2015, the variation was not found on the CYP allele nomenclature webpage (http://www.cypalleles.ki.se/cyp2w1.htm), the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/SNP/), or the PharmGKB (http://www.pharmgkb.org/) database.

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