1. Search for the molecular basis of ultra-rapid CYP2C9-catalysed metabolism: relationship between SNP IVS8-109A>T and the losartan metabolism phenotype in Swedes.
- Author
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Hatta, Fazleen, Teh, Lay, Helldén, Anders, Hellgren, Karin, Roh, Hyung-Keun, Salleh, Mohd, Aklillu, Eleni, and Bertilsson, Leif
- Subjects
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CHI-squared test , *CONFIDENCE intervals , *FISHER exact test , *GENES , *GENETIC polymorphisms , *GENETIC mutation , *OXIDOREDUCTASES , *POLYMERASE chain reaction , *RACE , *RESEARCH funding , *STATISTICS , *U-statistics , *PHENOTYPES , *LOSARTAN , *DATA analysis software , *DESCRIPTIVE statistics - Abstract
Aim: To search for a relationship between ultra-rapid metabolism catalysed by cytochrome P450 2C9 (CYP2C9) and its genotypes. Methods: DNA from a Swedish ultra-rapid metaboliser patient [losartan metabolic ratio (MR) <0.13] and three healthy Swedes with normal CYP2C9 activity and a MR of about 1 were assessed for variation in the CYP2C9 gene. Direct DNA sequencing was performed for all exons and exon-intron junctions and also for −2100 bp of the 5′-flanking regions of the CYP2C9 gene. This analysis revealed four intronic mutations [single nucleotide polymorphisms (SNPs) 1-4] in the three samples with normal MR while no variation was observed in the ultra-rapid metaboliser. PCR/restriction fragment length polymorphism and allele-specific PCR methods were subsequently developed to screen 85 Swedes and 128 Koreans without CYP2C9*2 or *3. Results: We found a significant relationship between SNP 4 (IVS8-109A>T) and CYP2C9 activity (χ-test, p = 0.011) in the Swedes. Twenty Swedes with the lowest MR were compared with 20 Swedes with the highest MR, revealing a strong association ( p = 0.001) between SNP4 and higher MR. For homozygous SNP 1 (IVS1+83T>C), SNP 2 (IVS2+73T>C), and SNP 3 (IVS6+95A>G), no phenotype and genotype relationships were found, but the MR was generally higher among the Swedes compared to the Koreans (Mann-Whitney test, p < 0.05). Conclusions: We found that the SNP 4 IVS8-109T allele is associated with a higher CYP2C9 MR in healthy Swedish subjects, but further investigations need to be carried out to establish a molecular explanation for ultra-rapid CYP2C9-catalysed metabolism. Haplotype based on SNPs 1-4 did not seem to contribute to variation in the MR of the Korean subjects nor play a role in determining the MR of the Swedish ones. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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