The CYP2C19 Intron 2 Branch Point SNP is the Ancestral Polymorphism Contributing to the Poor Metabolizer Phenotype in Livers with CYP2C19☆35 and CYP2C19☆2 Alleles

被引：26

作者：

Chaudhry, Amarjit S. ^{[1
]}

Prasad, Bhagwat ^{[2
]}

Shirasaka, Yoshiyuki ^{[2
]}

Fohner, Alison ^{[2
]}

Finkelstein, David ^{[3
]}

Fan, Yiping ^{[3
]}

Wang, Shuoguo ^{[3
]}

Wu, Gang ^{[3
]}

Aklillu, Eleni ^{[4
]}

Sim, Sarah C. ^{[5
]}

Thummel, Kenneth E. ^{[2
]}

Schuetz, Erin G. ^{[1
]}

机构：

[1] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA

[2] Univ Washington, Sch Pharm, Dept Pharmaceut, Seattle, WA 98195 USA

[3] St Jude Childrens Res Hosp, Dept Computat Biol, Memphis, TN 38105 USA

[4] Karolinska Inst, Dept Lab Med, Div Clin Pharmacol, Stockholm, Sweden

[5] Karolinska Inst, Dept Physiol & Pharmacol, Pharmacogenet Sect, Stockholm, Sweden

来源：

DRUG METABOLISM AND DISPOSITION | 2015年 / 43卷 / 08期

基金：

美国国家卫生研究院;

关键词：

MEPHENYTOIN HYDROXYLATION PHENOTYPE; PROTON PUMP INHIBITORS; PHARMACOGENETICS; IMPLEMENTATION; EXPRESSION; GENOTYPE; VARIANT; ANTIDEPRESSANTS; IDENTIFICATION; TRANSPORTERS;

D O I：

10.1124/dmd.115.064428

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

CYP2C19 rs12769205 alters an intron 2 branch point adenine leading to an alternative mRNA in human liver with complete inclusion of intron 2 (exon 2B). rs12769205 changes the mRNA reading frame, introduces 87 amino acids, and leads to a premature stop codon. The 1000 Genomes project (http://browser. 1000genomes. org/index.html) indicated rs12769205 is in linkage disequilibrium with rs4244285 on CYP2C19(star)2, but found alone on CYP2C19(star)35 in Blacks. Minigenes containing rs12769205 transfected into HepG2 cells demonstrated this single nucleotide polymorphism (SNP) alone leads to exon 2B and decreases CYP2C19 canonical mRNA. A residual amount of CYP2C19 protein was detectable by quantitative proteomics with tandem mass spectrometry in CYP2C19(star)2/(star)2 and (star)1/(star)35 liver microsomes with an exon 2 probe. However, an exon 4 probe, downstream from rs12769205, but upstream of rs4244285, failed to detect CYP2C19 protein in livers homozygous for rs12769205, demonstrating rs12769205 alone can lead to complete loss of CYP2C19 protein. CYP2C19 genotypes and mephenytoin phenotype were compared in 104 Ethiopians. Poor metabolism of mephenytoin was seen in persons homozygous for both rs12769205 and rs4244285 (CYP2C19(star)2/(star)2), but with little effect on mephenytoin disposition of CYP2C19(star)1/(star)2, CYP2C19(star)1/(star)3, or CYP2C19(star)1/(star)35 heterozygous alleles. Extended haplotype homozygosity tests of the HapMap Yorubans (YRI) showed both haplotypes carrying rs12769205 (CYP2C19(star)35 and CYP2C19(star)2) are under significant natural selection, with CYP2C19(star)35 having a higher relative extended haplotype homozygosity score. The phylogenetic tree of the YRI CYP2C19 haplotypes revealed rs12769205 arose first on CYP2C19(star)35 and that rs4244285 was added later, creating CYP2C19(star)2. In conclusion, rs12769205 is the ancestral polymorphism leading to aberrant splicing of CYP2C19(star)35 and CYP2C19(star)2 alleles in liver.

引用

页码：1226 / 1235

页数：10

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