Association Study of 27 Annotated Genes for Clozapine Pharmacogenetics

Lee, Seung Tae; Ryu, Seunghyong; Kim, Suk-Ran; Kim, Minji; Kim, Seonwoo; Kim, Jong-Won; Lee, Soo-Youn; Hong, Kyung Sue

doi:10.1097/jcp.0b013e31825ac35c

Cited by 63 publications

(41 citation statements)

References 62 publications

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“…CYP1A2*1F polymorphisms were associated with a super-refractory schizophrenia group of patients, compared to controls, thus replicating previous work, and identifying this polymorphism as a moderator of clozapine response 50. However, as is the case in clozapine pharmacodynamic pharmacogenetic research, other studies have not replicated these findings in relation to CYP1A2 polymorphism and clozapine response 51,52. Ethnic variation between the study populations has been suggested as a cause of this, with there being a higher frequency of the CYP1A2*1F allele in those of European ancestry 27…”

Section: Pharmacogenomics and Clozapine Responsesupporting

confidence: 72%

Treatment-resistant schizophrenia: current insights on the pharmacogenomics of antipsychotics

Lally¹,

Gaughran²,

Timms³

et al. 2016

PGPM

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Up to 30% of people with schizophrenia do not respond to two (or more) trials of dopaminergic antipsychotics. They are said to have treatment-resistant schizophrenia (TRS). Clozapine is still the only effective treatment for TRS, although it is underused in clinical practice. Initial use is delayed, it can be hard for patients to tolerate, and clinicians can be uncertain as to when to use it. What if, at the start of treatment, we could identify those patients likely to respond to clozapine – and those likely to suffer adverse effects? It is likely that clinicians would feel less inhibited about using it, allowing clozapine to be used earlier and more appropriately. Genetic testing holds out the tantalizing possibility of being able to do just this, and hence the vital importance of pharmacogenomic studies. These can potentially identify genetic markers for both tolerance of and vulnerability to clozapine. We aim to summarize progress so far, possible clinical applications, limitations to the evidence, and problems in applying these findings to the management of TRS. Pharmacogenomic studies of clozapine response and tolerability have produced conflicting results. These are due, at least in part, to significant differences in the patient groups studied. The use of clinical pharmacogenomic testing – to personalize clozapine treatment and identify patients at high risk of treatment failure or of adverse events – has moved closer over the last 20 years. However, to develop such testing that could be used clinically will require larger, multicenter, prospective studies.

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Section: Pharmacogenomics and Clozapine Responsesupporting

confidence: 72%

Treatment-resistant schizophrenia: current insights on the pharmacogenomics of antipsychotics

Lally¹,

Gaughran²,

Timms³

et al. 2016

PGPM

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“…Despite the important function of rs2069522, its association with breast cancer risk has not been clearly demonstrated. Genetic studies have only shown that it had the potential to affect colorectal cancer risk and the treatment response to clozapine in schizophrenic patients among British Caucasians and Koreans, respectively [41,42]. However, those results were not significant after correction for multiple testing.…”

Section: Discussionmentioning

confidence: 99%

Genetic Polymorphisms in Estrogen-Related Genes and the Risk of Breast Cancer among Han Chinese Women

Sun

Zhu

et al. 2015

IJMS

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Exposure to high levels of estrogen is considered an important risk factor for susceptibility to breast cancer. Common polymorphisms in genes that affect estrogen levels may be associated with breast cancer risk, but no comprehensive study has been performed among Han Chinese women. In the present study, 32 single-nucleotide polymorphisms (SNPs) in estrogen-related genes were genotyped using the MassARRAY IPLEX platform in 1076 Han Chinese women. Genotypic and allelic frequencies were compared between case and control groups. Unconditional logistic regression was used to assess the effects of SNPs on breast cancer risk. Associations were also evaluated for breast cancer subtypes stratified by estrogen receptor (ER) and progesterone receptor (PR) status. Case-control analysis showed a significant relation between heterozygous genotypes of rs700519 and rs2069522 and breast cancer risk (OR = 0.723, 95% CI = 0.541–0.965, p = 0.028 and OR = 1.500, 95% CI = 1.078–2.087, p = 0.016, respectively). Subgroup comparisons revealed that rs2446405 and rs17268974 were related to ER status, and rs130021 was associated with PR status. Our findings suggest that rs700519 and rs2069522 are associated with susceptibility to breast cancer among the Han Chinese population and have a cumulative effect with three other identified SNPs. Further genetic and functional studies are needed to identify additional SNPs, and to elucidate the underlying molecular mechanisms.

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“…A good example of inconsistent replication result of genetic associations is the atypical antipsychotic clozapine with its complex pharmacological effects via the dopaminergic, serotonergic, adrenergic, and histaminergic receptors within the central nervous system. Over the years, conflicting study results exist in the literature for association between clozapine response with either SNPs of each known pharmacological receptor subtype [10–13], combinations of polymorphisms [14], and metabolizing enzymes and transporters [15]. It is also of note that the original association regarding combination of polymorphisms was not replicated in a subsequent study [16].…”

Section: Scientific Challenges and Complexitymentioning

confidence: 99%

“…It is also of note that the original association regarding combination of polymorphisms was not replicated in a subsequent study [16]. The recent identification of yet another new candidate gene for clozapine treatment response [15] illustrates the limitation of candidate gene approach in that there is always the possibility of involvement of other yet-to-be-identified genes, including those that have not been known to be linked to the pharmacology of the drug, that could account for additional variability in patient's therapeutic response. More importantly, the effect size of most genetic variants is small to modest.…”

Section: Scientific Challenges and Complexitymentioning

confidence: 99%

“…With an annual cost that is at least ten times higher, the atypical antipsychotic agents are more expensive yet no more efficacious and, hence, likely to be less cost-effective, than the typical antipsychotic agents [89, 90]. Rather than focusing on using biomarkers to predict efficacy of the more expensive atypical antipsychotic agents [10–15], genotyping for the Glycine9 allele of the Ser9Gly polymorphism in the dopamine 3 receptor gene [91, 92] might be used to identify patients susceptible to tardive dyskinesia, a highly prevalent adverse drug reaction associated with the use of the less expensive typical antipsychotic agents. The genetic testing might enable appropriate dose reduction for the typical antipsychotic agents and lessen the incidence of adverse drug reaction.…”

Section: Scientific Challenges and Complexitymentioning

confidence: 99%

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Scientific Challenges and Implementation Barriers to Translation of Pharmacogenomics in Clinical Practice

Lam

2013

ISRN Pharmacology

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The mapping of the human genome and subsequent advancements in genetic technology had provided clinicians and scientists an understanding of the genetic basis of altered drug pharmacokinetics and pharmacodynamics, as well as some examples of applying genomic data in clinical practice. This has raised the public expectation that predicting patients' responses to drug therapy is now possible in every therapeutic area, and personalized drug therapy would come sooner than later. However, debate continues among most stakeholders involved in drug development and clinical decision-making on whether pharmacogenomic biomarkers should be used in patient assessment, as well as when and in whom to use the biomarker-based diagnostic tests. Currently, most would agree that achieving the goal of personalized therapy remains years, if not decades, away. Realistic application of genomic findings and technologies in clinical practice and drug development require addressing multiple logistics and challenges that go beyond discovery of gene variants and/or completion of prospective controlled clinical trials. The goal of personalized medicine can only be achieved when all stakeholders in the field work together, with willingness to accept occasional paradigm change in their current approach.

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Association Study of 27 Annotated Genes for Clozapine Pharmacogenetics

Cited by 63 publications

References 62 publications

Treatment-resistant schizophrenia: current insights on the pharmacogenomics of antipsychotics

Treatment-resistant schizophrenia: current insights on the pharmacogenomics of antipsychotics

Genetic Polymorphisms in Estrogen-Related Genes and the Risk of Breast Cancer among Han Chinese Women

Scientific Challenges and Implementation Barriers to Translation of Pharmacogenomics in Clinical Practice

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