Debrisoquine hydroxylase gene polymorphism and susceptibility to Parkinson's disease

doi:10.1016/0140-6736(92)91196-F

The Lancet

Volume 339, Issue 8806, 6 June 1992, Pages 1375-1377

https://doi.org/10.1016/0140-6736(92)91196-F Get rights and content

Abstract

The pathogenesis of Parkinson's disease may be influenced by genetic and environmental factors. Cytochrome P450 mono-oxygenases help to protect against toxic environmental compounds and individual variations in cytochrome P450 expression might, therefore, influence susceptibility to environmentally linked diseases. The frequency of mutant CYP2D6 alleles was studied in 229 patients with Parkinson's disease and 720 controls. Individuals with a metabolic defect in the cytochrome P450 CYP2D6-debrisoquine hydroxylase gene with the poor metaboliser phenotype had a 2·54-fold (95% Cl 1·51-4·28) increased risk of Parkinson's disease. Determination of CYP2D6 phenotype and genotype may help to identify those at greatest risk of Parkinson's disease and may also help to identify the environmental or metabolic agents involved in the pathogenesis of this disease.

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Cited by (436)

Association of cytochrome P2D6 gene polymorphism with the susceptibility of Egyptian patients to systemic sclerosis disease
2021, Meta Gene
Systemic Sclerosis (SSc) is a chronic disease of the connective tissue caused by an autoimmune inflammatory process. Genetic polymorphisms of cytochrome P2D6 (CYP2D6) enzymes have been implicated in the SSc disease etiopathogenesis.
Our work was designed to investigate the association between the CYP2D6 gene mutation and the risk of SSc development and its relation to different SSc clinical manifestations.
One hundred SSc patients were involved in the study and one hundred healthy individuals were included to serve as a contol group.
CYP2D6 *1, CYP2D6 *3, CYP2D6 *4 allelic frequencies were analyzed by the Polymerase Chain Reaction- Fragment Length Polymorphism (PCR-RFLP) method.
The heterozygous extensive metabolizers (CYP2D6 *1/*4) genotype showed a statistically significant risk for developing SSc, assessed by the odds ratio (OR = 2.4, P = 0.003). The homozygous extensive metabolizers (CYP2D6 *1/*1) which are the wild genotypes, were expressed less frequently in SSc patients with a significant difference (OR = 0.23) in comparison with the control group. As for the alleles frequency, a significant increase in the risk of SSc was associated with the mutant CYP2D6 *4 allele frequency (OR = 2.2), indicating that the presence of allele CYP2D6*4 is a risky genetic factor for SSc. Diffuse type systemic sclerosis, gastrointestinal (GIT), cardiac, pulmonary manifestations, positive anti-scleroderma 70, moderate restriction in pulmonary function tests, and abnormal Echocardiographic findings were significantly associated with the (CYP2D6 *1/*4) genotype.
Finding of the study revealed a higher prevalence of the heterozygotes extensive metabolizers (CYP2D6 *1/*4)genotypes and the mutant alleles (CYP2D6*4) in SSc patients, suggesting the high impact of the CYP2D6 gene mutation on the SSc development.
CYP2D6 (C2850T, G1846A, C100T) polymorphisms, haplotypes and MDR analysis in predicting coronary artery disease risk in north-west Indian population: A case-control study
2018, Gene
Citation Excerpt :
In the present study, the association of C2850T, G1846A and C100T polymorphisms of the CYP2D6 with CAD in North-West Indian population was investigated. In literature, numerous reports have documented the role of CYP2D6 polymorphisms in predisposing to several kinds of tumors (Sobti et al., 2005; Surekha et al., 2010; Levkovich et al., 2011; Shukla et al., 2012) and central nervous system disorders Parkinson's or Alzheimer's diseases (Smith et al., 1992; Lu et al., 2014) in different ethnic groups. A single report has come to attention on the role of CYP2D6 polymorphisms in cardiovascular diseases but not from the North-West Indian population.
The present study was aimed to evaluate the association of C2850T, G1846A and C100T polymorphisms of the CYP2D6 with coronary artery disease (CAD) in North-West Indian population.
In this case-control study, 200 patients with CAD and 200 age-, gender- and ethnicity-matched healthy controls were genotyped for C2850T, G1846A and C100T polymorphisms of CYP2D6 using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.
Genotype and allele distributions of C2850T and G1846A polymorphisms of the CYP2D6 were significantly different between cases and controls (p = 0.038, p = 0.021; p = 0.048, p = 0.012, respectively) whereas the distribution of genotype and allele for C100T polymorphism did not differ significantly (p = 0.098, p = 0.117, respectively). The 2850T and1846A variants were significantly associated with the increased risk of developing CAD, as observed from the odds ratios for the 2850 T/T and 1846 G/A genotypes (OR: 2.44, 95% CI: 1.99–4.99, p = 0.015 and OR: 1.62, 95% CI: 1.02–2.56, p = 0.041, respectively). Moreover, the recessive model in C2850T and the dominant model in G1846A are the best fit inheritance models to predict the susceptible gene effects (OR: 2. 07, 95% CI: 1.05–4.08, p = 0.031 and OR: 1.70, 95% CI: 1.10–2.62, p = 0.016, respectively). On gender stratification, these associations were observed only in females in addition to the C/T genotype of C2850T (OR: 2.52, 95% CI: 1.42–4.38, p = 0.001) and C100T (OR: 3.18, 95% CI: 1.52–6.67, p = 0.002). Furthermore, it is also observed that the CAT (OR: 2. 61, 95% CI: 1.07–6.34, p = 0.035) and TAC (OR: 15. 22, 95% CI: 1.97–117.58, p = 0.009) are high-risk haplotypes for CAD in the total group, whereas, the TGC (OR: 1. 64, 95% CI: 1.02–2.62, p = 0.042) and CAT (OR: 4. 21, 95% CI: 1.12–15.59, p = 0.035) haplotypes provide gender-specific risk in females.
Our results indicate significant association of C2850T, G1846A and C100T polymorphisms of CYP2D6 with CAD especially in females of North-West Indian population.
Hepatocyte nuclear factor (HNF) 4α transactivation of cytochrome P450 (Cyp) 2d40 promoter is enhanced during pregnancy in mice
2015, Biochemical Pharmacology
Citation Excerpt :
CYP2D6 mediates hepatic metabolism of approximately 25% of marketed drugs including antidepressants and antipsychotics [3,4]. Also, decreased CYP2D6 activity levels are associated with increased susceptibility to Parkinson's disease [5,6] or higher blood perfusion levels in brain regions linked to alertness in humans [7]. The detailed roles of CYP2D6 in altered biological functions in extrahepatic tissues (such as brain) remains unclear, in part due to a lack of animal models to study CYP2D6 function in vivo.
We have recently reported that transactivation of cytochrome P450 (CYP) 2D6 promoter by hepatocyte nuclear factor (HNF) 4α is enhanced during pregnancy, and this is triggered in part by altered expression of small heterodimer partner (SHP) and Krüppel-like factor 9 (KLF9). The objective of this study is to determine whether this is conserved for mouse endogenous Cyp2d gene(s). Among the eight Cyp2d homologs of mouse we examined, only Cyp2d40 expression was found induced (by 6-fold) at term pregnancy as compared to pre-pregnancy level. In mice where hepatic Hnf4α was knocked-down, the pregnancy-mediated increase in Cyp2d40 expression was abrogated. Results from transient transfection, promoter reporter assays, and electrophoretic mobility shift assays indicated that HNF4α transactivates Cyp2d40 promoter via direct binding to −117/−105 of the gene. Chromatin immunoprecipitation assay showed a 2.3-fold increase in HNF4α recruitment to Cyp2d40 promoter during pregnancy. Results from mice treated with an SHP inducer (i.e., GW4064) and HepG2 cells co-transfected with KLF9 suggest that neither SHP nor KLF9 is involved in the increased HNF4α transactivation of Cyp2d40 promoter during pregnancy. Together, our results indicate that while the underlying molecular mechanism is different from that for CYP2D6, Cyp2d40 is induced during pregnancy through enhanced transactivation by HNF4α.
Significance of the genetic polymorphism of CYP2D6 and NAT2 in patients with inflammatory bowel diseases
2014, Pharmacological Reports
The main types of inflammatory bowel diseases (IBD) are ulcerative colitis (UC) and Crohn's disease (CD). There is evidence that, in addition to immunological and environmental factors, genetic factors also play an important role in the pathogenesis of IBD. Determination of polymorphism of CYP2D6 and NAT2 genes encoding I and II phase enzymes of xenobiotic biotransformation may have clinical value as an indicator of individual predisposition to diseases, and also contribute to effective and safe pharmacotherapy. The aim of this study was to investigate the association between genetic polymorphism of CYP2D6 and NAT2 and the incidence of IBD, including UC and CD, among inhabitants of central Poland.
The study was performed in 258 individuals from central Poland (115 patients with IBD, including 65 patients with UC and 50 with CD; and in 143 healthy controls). The CYP2D6 genotypes of oxidation and NAT2 genotypes of acetylation were analyzed using the PCR-RFLP method.
There were no statistically significant differences in the frequency of the CYP2D6 genotypes and alleles in patients with IBD, UC and CD in comparison with the control group. The relative risk (OR) of IBD, UC and CD was higher in carriers of the allele NAT2*7 and was OR = 3.49 (p = 0.0019), OR = 3.86 (p = 0.0019), and OR = 3.02 (p = 0.0247), respectively.
Polymorphism of the gene encoding CYP2D6 does not affect the incidence of inflammatory bowel diseases. The carriers of the NAT2*7 allele which determines slow acetylation may be more predisposed to inflammatory bowel diseases, including ulcerative colitis and Crohn's disease.
The relationship between plasma concentration of metoprolol and CYP2D6 genotype in patients with ischemic heart disease
2014, Pharmacological Reports
Citation Excerpt :
Each subject agreed to sign a written informed consent. The blood samples were analyzed for two major defective alleles for the CYP2D6 gene – CYP2D6*4 and CYP2D6*3 – by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method according to the procedure proposed by Smith et al. [8]. DNA was arranged from leukocytes extracted from peripheral blood.
Metoprolol is the one of the most commonly used β-blockers in the treatment of ischemic heart disease and it is extensively metabolized in the liver undergoing oxidation by CYP2D6 isoenzyme of cytochrome P450. Gene encoding the CYP2D6 enzyme is characterized by genetic polymorphism. The CYP2D6 oxidation polymorphism has a major impact on the effectiveness and safety of the treatment. The aim of the study was to evaluate the relationship between plasma concentration of metoprolol and the CYP2D6 genotype in patients with ischemic heart disease.
Fifty patients were interviewed and subsequently enrolled into the study. The patients received metoprolol twice daily at a dose of 50 mg. The blood samples were analyzed for two major defective alleles for CYP2D6 – CYP2D6*4 and CYP2D6*3 – by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Metoprolol concentration in plasma was determined by using the new and unique high-performance liquid chromatography (HPLC) method in the author's own modification with Corona CAD detector (Charged Aerosol Detection).
In the test group, genotypes conditioning poor oxidation (PM) occurred in 3 patients (6%), while 47 patients (94%) had genotypes coding for extensive metabolism (EM). Patients with PM genotypes had significantly higher plasma concentrations of metoprolol than the patients with EM genotype (mean 92.25 ± SD 36.78 ng/ml vs. mean 168.22 ± SD 5.61 ng/ml, respectively). Established relationships were statistically significant (NIR test, p = 0.0009).
This study demonstrated that the CYP2D6 genotype remains a major determinant of the metoprolol plasma concentrations. The pharmacogenetic effect is likely to have consequences on both, the clinical benefit of metoprolol treatment and adverse drug reactions. The use of Corona CAD detector seems to be a very good alternative method for the determination of metoprolol concentration in plasma.
CYP2D6 phenotypes and Parkinson's disease risk: A meta-analysis
2014, Journal of the Neurological Sciences
Citation Excerpt :
Meta-regression analysis showed that the source of the controls was the major factor contributing to heterogeneity (regression coefficient = − 0.263; 95%CI: − 472–0.053; P = 0.015). When the sensitivity analysis was conducted, our results indicated that the study by Smith [7] apparently influenced the overall results. After excluding that study from the analysis, the pooled ORs (95%CI) of the remaining studies were still insignificant (OR: 1.03, 95%CI: 0.95–1.12; P = 0.515), and there was still significant heterogeneity (I2 = 32.0%, P = 0.002).
CYP2D6 polymorphisms have been reported to be associated with Parkinson's disease (PD) susceptibility, but the results of these previous studies were inconsistent.
To explore whether PD patients with CYP2D6 gene variation have different risk to PD to those with normal function of CYP2D6.
Systematic review with meta-analysis of case-controlled studies on the association between CYP2D6 and PD risk was conducted. Studies published up to August 1, 2013 were identified by searching electronic databases PubMed and Embase. Odds ratios (ORs) together with their corresponding 95% confidence intervals (CIs) were used to estimated the association between CYP2D6 polymorphisms and PD risk in different phenotype models. Meta-regression, subgroup analysis, sensitivity analysis and publication bias were also performed.
A total of 3521 PD Patients and 4476 controls from 29 case–control studies were identified. Overall, a borderline significant influence of the CYP2D6 polymorphisms on PD risk was observed (OR: 1.07, 95%CI: 0.99–1.16, p = 0.106). Significant association was found when comparisons were performed in different phenotypes in PM versus EM (OR = 1.33, 95% CI = 1.01–1.74, p = 0.044) and PM versus IM + EM (OR = 1.32, 95% CI = 1.11–1.56, p = 0.002). In subgroup analysis stratified by country, significant association was demonstrated in British but not in other white subjects. No significant association was detected in subgroup analysis according to the age of onset and the source of patients.
The present meta-analysis demonstrated that the poor metabolizer phenotype of CYP2D6 confers a significant genetic susceptibility to PD in Caucasians, especially in British white subjects.

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ORIGINAL ARTICLESDebrisoquine hydroxylase gene polymorphism and susceptibility to Parkinson's disease

Abstract

J Biol Chem

Lancet

Lancet

Methods Enzymol

Lancet

Lancet

Life Sci

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Pharmacol Ther

Metabolic factors in cancer susceptibility

Cancer Surv

The genetics of Parkinson's disease

Neurology

Genetic susceptibility to Parkinson's disease

Neurology

A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population

J Med Genet

Identification of the primary gene defect at the cytochrome P450 CYP2D6 locus

Nature

The human CYP2D6 locus associated with a common genetic defect in drug oxidation: a G1943 to A base change in intron 3 of a mutant CYP2D6 allele results in an aberrrant 3' splice recognition site.

Am J Hum Genet

Deletion of the entire CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism

Am J Hum Genet

ORIGINAL ARTICLES
Debrisoquine hydroxylase gene polymorphism and susceptibility to Parkinson's disease