The sparteine/debrisoquine (CYP2D6) oxidation polymorphism and the risk of lung cancer: A meta- analysis

Christensen, P.; Gøtzsche, Peter C; Brøsen, Kim

doi:10.1007/s002280050219

Cited by 48 publications

(26 citation statements)

References 36 publications

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“…The CYP2D6 polymorphism has been studied as a risk factor for Parkinson's disease (PD), and a higher frequency of CYP2D6 poor metabolizers among PD patients has been reported [31], [32].…”

Section: Discussionmentioning

confidence: 99%

Polymorphism of CYP2D6, CYP2C19, CYP2C9 and CYP2C8 in the Faroese population

Halling

Petersen

Damkier

et al. 2005

Eur J Clin Pharmacol

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Objective: The purpose of the study was to study the distribution of poor and extensive metabolizers of CYP2C19 and CYP2D6 and to genotype for CYP2C8 and CYP2C9 among 312 randomly selected Faroese. Methods and Results:The participants were phenotyped for CYP2D6 with the use of sparteine. The distribution of the sparteine metabolic ratio (sparteine/didehydrosparteines) was bimodal, and 14.5% (n=44) (95% CI 10.7-18.9%) of the subjects were phenotyped as poor metabolizers. The frequency of poor metabolizers was higher (P=0.0002; χ 2 test) among the Faroese than in other European populations (7.4%). Genotype analysis for the CYP2D6*3, *4, *6 and *9 alleles were performed using real-time PCR (TaqMan®), and we found 14.6% (n=45) (95% CI 10.8-19.0%) with deficient CYP2D6 genes (*3/*4, *4/*4, *4/*6, *6/*6) in the Faroese population.The subjects were phenotyped for CYP2C19 with the use of mephenytoin and 10 subjects, i.e. 3.2% (95% CI 1.6-5.9%) were phenotyped as poor metabolizers. Genotype analysis for the CYP2C19*2 and *3 alleles was performed by PCR analysis and 2.9% (n=9) (95% CI 1.3-5.4%) of the Faroese were found to have a deficient CYP2C19 gene all explained by the CYP2C19*2/*2 genotype. The allele frequencies of the CYP2C9*2 and CYP2C9*3 alleles were 8.8% (95% CI 6.7-11.4%) and 5.3% (95% CI 3.7-7.4%), respectively, while the CYP2C8*3 allele frequency was 6.9% (95% CI 5.0-9.2%). Real-time PCR (TaqMan®) was used for both CYP2C9 and CYP2C8 genotype analyses. Conclusion:The frequency of CYP2D6 poor metabolizers is two fold higher among the Faroese population compared to other Caucasians, while the frequencies of Faroese subjects with decreased CYP2C19, CYP2C8 and CYP2C9 enzyme activity are the same as seen in other Caucasian populations. A possible consequence might be a higher incidence of side effects among Faroese patients taking pharmaceuticals that are CYP2D6 substrates.

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“…The CYP2D6 polymorphism has been studied as a risk factor for Parkinson's disease (PD), and a higher frequency of CYP2D6 poor metabolizers among PD patients has been reported [31], [32].…”

Section: Discussionmentioning

confidence: 99%

Polymorphism of CYP2D6, CYP2C19, CYP2C9 and CYP2C8 in the Faroese population

Halling

Petersen

Damkier

et al. 2005

Eur J Clin Pharmacol

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“…77,78 However, the findings were inconclusive. Although two meta-analyses 72,74 reported a significant association of the poormetabolizer genotype with PD, the other two did not reveal any significant association. 73,75 In research conducted since the publication of these meta-analyses, no association was found between CYP2D6 polymorphism and the risk of PD.…”

Section: Xenobiotic Metabolizing Enzymes Cytochrome P450 System Enzymesmentioning

confidence: 87%

“…70 Several reviews and meta-analysis were performed to determine whether there is an association between cytochrome P450 polymorphisms (CYP2D6, CYP1A1, CYP2C9, CYP2C19, CYP1A2, and CYP2E1) and the risk of PD. [71][72][73][74][75][76] The most studied is the CYP2D6 gene, which encodes for the enzyme debrisoquine 4-hydroxylase that metabolizes a wide range of drugs, including MPTP, and has a number of functional polymorphisms. 77,78 However, the findings were inconclusive.…”

Section: Xenobiotic Metabolizing Enzymes Cytochrome P450 System Enzymesmentioning

confidence: 99%

Polymorphism in candidate genes: implications for the risk and treatment of idiopathic Parkinson's disease

et al. 2004

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Idiopathic Parkinson's disease (IPD) is a progressive neurodegenerative disorder for which no restorative or neuroprotective therapy is available. Interest has recently been directed to association studies on polymorphisms of various genes, mainly those related to dopamine metabolism and transport, and their effect on response to PD, which includes primarily levodopa and dopaminomimetics. Approximately 15-20% of patients with PD do not respond to levodopa, and the majority of those who do respond develop adverse fluctuations in motor response, primarily levodopa-induced dyskinesias. This review summarizes the influence of polymorphisms in various genes on the relative risk of IPD and on levodopa efficacy. It focuses on the importance of well-designed polymorphism studies that include large samples of patients with IPD and tightly matched controls and use identical methodologies. Valid data on such polymorphisms might increase the efficacy of levodopa, decrease its side effects, and reduce the occurrence of levodopa-induced dyskinesias. They might also provide a novel diagnostic tool for PD.

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“…39 Polymorphisms in the methylenetetrahydrofolate reductase gene have been associated with a decreased risk of developing acute lymphocytic leukemia 40 and colorectal carcinoma 41,42 in determined population groups. Determined genotypes of some cytochrome P450 enzymes, such as CYP1A1 or CYP2D6, also have been correlated with a decreased risk of lung carcinoma, although meta-analyses have failed to confirm this observation 43,44 or have described only a small protective effect with a nonappreciable relation to individual susceptibility. 45 Two common polymorphisms of the p21WAF1/Cip1 gene have been associated with a potential protective role against ovarian carcinoma.…”

Section: Studies In Individuals Potentially Protected From Developingmentioning

confidence: 99%

The role of extreme phenotype selection studies in the identification of clinically relevant genotypes in cancer research

Perez-Gracia

Ruiz-Ilundáin

García-Ribas

et al. 2002

Cancer

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The investigation of genetic alterations that may be related to the prognosis of patients with malignant disease has become a frequently used strategy in recent years. Although some conclusions have been reached in certain studies, the complexity and the multifactorial nature of most neoplastic diseases makes it difficult to identify clinically relevant information, and the results of some studies have been of borderline significance or have been conflicting. In contrast, the identification and the study of patients or families with very characteristic phenotypes have yielded outstanding results in the identification of the genetic characteristics underlying such phenotypes. Although, in most cases, the individuals who are selected for these types of studies are characterized by a negative phenotype (i.e., individuals who are at increased risk for developing a specific disease), a few studies have been directed toward individuals with phenotypes that imply an unusually good prognosis (i.e., individuals who present with a decreased risk for developing specific diseases despite an important exposure to well-known risk factors). Therefore, it seems logical to develop this strategy further as a valid methodology for the study of other diseases, such as cancer. The study of individuals with phenotypes that imply an extremely good prognosis, such as long-term survivors of theoretically incurable malignancies or individuals who seem to be protected against a certain neoplastic disorder despite having a markedly increased risk for its development, may unveil genetic alterations that explain such characteristic phenotypes and may provide potentially useful therapeutic targets against these diseases. Cancer 2002;95:1605-10.

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The sparteine/debrisoquine (CYP2D6) oxidation polymorphism and the risk of lung cancer: A meta- analysis

Abstract: No association was found between the CYP2D6 oxidation polymorphism and lung cancer risk when sample size bias was taken into account.

Cited by 48 publications

References 36 publications

Polymorphism of CYP2D6, CYP2C19, CYP2C9 and CYP2C8 in the Faroese population

Polymorphism of CYP2D6, CYP2C19, CYP2C9 and CYP2C8 in the Faroese population

Polymorphism in candidate genes: implications for the risk and treatment of idiopathic Parkinson's disease

The role of extreme phenotype selection studies in the identification of clinically relevant genotypes in cancer research

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