<i>CYP1A2</i>
            Genetic Polymorphisms are Associated with Treatment Response to the Antidepressant Paroxetine

Lin, Keh‐Ming; Tsou, Hsiao-Hui; Tsai, I‐Ju; Hsiao, Mei‐Chun; Liu, Chia-Yih; Shen, Winston W.; Tang, Hwa-Sheng; Fang, Chun-Kai; Wu, Chi‐Shin; Lu, Shao‐Chun; Kuo, Hsin‐Wei; Liu, Shu Chih; Chan, Hsiu‐Wen; Hsu, Ya-Ting; Tian, Jia-Ni; Liu, Yuli

doi:10.2217/pgs.10.128

Cited by 35 publications

(16 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Evaluating the coverage of genotyping platforms to HapMap as the reference source, investigators found that approximately 80–90% of the SNPs in HapMap CEU population were covered in these platforms at an r 2 of 0.8. Similar results were obtained when using dbSNPs data as the references source (25–27). These studies showed that the Illumina Hap550 BeadChip showed consistently higher coverage than the Affymetrix 500K chip.…”

Section: Discussionsupporting

confidence: 82%

The limits of genome-wide methods for pharmacogenomic testing

Gamazon

Skol

Perera

2012

Pharmacogenetics and Genomics

View full text Add to dashboard Cite

Objective The goal of pharmacogenomics is the translation of genomic discoveries to individualized patient care. Recent advances in the means to survey human genetic variation are fundamentally transforming our understanding of the genetic basis of interindividual variation in therapeutic response. The goal of this study was to systematically evaluate high-throughput genotyping technologies for their ability to assay variation in pharmacogenetically important genes (pharmacogenes). These platforms are either being proposed for or are already widely used for clinical implementation; therefore, knowledge of coverage of pharmacogenes on these platforms would serve to better evaluate current or proposed pharmacogenetic association studies. Method Among the genes included in our study are drug metabolizing enzymes, transporters, receptors, and drug targets, of interest to the entire pharmacogenetic community. We considered absolute and LD-informed coverage, minor allele frequency spectrum and functional annotation for a Caucasian population. We also examined the effect of linkage disequilibrium, effect size and cohort size on power to detect SNP associations. Results In our analysis of 253 pharmacogenes, we found that no platform showed more than 85% coverage of these genes (after accounting for LD). Furthermore the lack of coverage showed a dramatic increase at minor allele frequencies of less than 20%. Even after accounting for LD, only 30% of missense polymorphisms (which are enriched for low frequency alleles) were covered by HapMap with still lower coverage on the other platforms. Conclusion We have conducted the first systematic evaluation of the Axiom Genomic Database, Omni 2.5M and the DMET chip. This study is the first to utilize the 1000 Genomes Project to present a comprehensive evaluative framework. Our results provide a much-needed assessment of microarray-based genotyping and next-generation sequencing technologies’ ability to survey fully the variation in genes of particular interest to the pharmacogenetics community. Our findings demonstrate the limitations of genome-wide methods and the challenges of implementing pharmacogenomic tests into the clinical context.

show abstract

Section: Discussionsupporting

confidence: 82%

The limits of genome-wide methods for pharmacogenomic testing

Gamazon

Skol

Perera

2012

Pharmacogenetics and Genomics

View full text Add to dashboard Cite

show abstract

“…The A allele was associated with an increased dose of paroxetine and also with increased likelihood of experiencing drug-related fatigue in Han Chinese patients with Major Depressive Disorder [44]. …”

Section: Important Variantsmentioning

confidence: 99%

PharmGKB summary

Thorn¹,

Aklillu

Klein³

et al. 2012

Pharmacogenetics and Genomics

View full text Add to dashboard Cite

“…The haplotype GTACAT is close to the clinically defined haplotypes CYP1A2 * 1 M and * 1Q [23]. It can be distinguished from other haplotypes because it carries derived mutations at rs762551 (-163C > A * ), rs2472304 (2159G > A * ), and rs2470890 (5347C > T * ), of which rs2472304 and rs2470890 are associated with rapid metabolism of caffeine and anti-depression drugs such as paroxetine [24,25]. Interestingly, these two SNPs are also in the list of highly differential mutations (Table 1), suggesting that they could be potential causal mutations in the CYP1A2 gene for local adaptation of Europeans, leading to specific genotypes and haplotypes in CEU.…”

Section: Resultsmentioning

confidence: 99%

Increased genetic diversity of ADME genes in African Americans compared with their putative ancestral source populations and implications for Pharmacogenomics

Lao

Zhang

et al. 2014

BMC Genet

View full text Add to dashboard Cite

BackgroundAfrican Americans have been treated as a representative population for African ancestry for many purposes, including pharmacogenomic studies. However, the contribution of European ancestry is expected to result in considerable differences in the genetic architecture of African American individuals compared with an African genome. In particular, the genetic admixture influences the genomic diversity of drug metabolism-related genes, and may cause high heterogeneity of drug responses in admixed populations such as African Americans.ResultsThe genomic ancestry information of African-American (ASW) samples was obtained from data of the 1000 Genomes Project, and local ancestral components were also extracted for 32 core genes and 252 extended genes, which are associated with drug absorption, distribution, metabolism, and excretion (ADME) genes. As expected, the global genetic diversity pattern in ASW was determined by the contributions of its putative ancestral source populations, and the whole profiles of ADME genes in ASW are much closer to those in YRI than in CEU. However, we observed much higher diversity in some functionally important ADME genes in ASW than either CEU or YRI, which could be a result of either genetic drift or natural selection, and we identified some signatures of the latter. We analyzed the clinically relevant polymorphic alleles and haplotypes, and found that 28 functional mutations (including 3 missense, 3 splice, and 22 regulator sites) exhibited significantly higher differentiation between the three populations.ConclusionsAnalysis of the genetic diversity of ADME genes showed differentiation between admixed population and its ancestral source populations. In particular, the different genetic diversity between ASW and YRI indicated that the ethnic differences in pharmacogenomic studies are broadly existed despite that African ancestry is dominant in Africans Americans. This study should advance our understanding of the genetic basis of the drug response heterogeneity between populations, especially in the case of population admixture, and have significant implications for evaluating potential inter-population heterogeneity in drug treatment effects.

show abstract

CYP1A2 Genetic Polymorphisms are Associated with Treatment Response to the Antidepressant Paroxetine

Abstract: Genetic variants in the CYP1A2 region may be indicators of treatment response in MDD patients to paroxetine.

Cited by 35 publications

References 41 publications

The limits of genome-wide methods for pharmacogenomic testing

The limits of genome-wide methods for pharmacogenomic testing

PharmGKB summary

Increased genetic diversity of ADME genes in African Americans compared with their putative ancestral source populations and implications for Pharmacogenomics

Contact Info

Product

Resources

About