Roles of CYP2C19 Gene Polymorphisms in Susceptibility to POAG and Individual Differences in Drug Treatment Response

Abstract

BackgroundThe aim of this study was to investigate the roles of cytochrome P450 2C19 (CYP2C19) polymorphisms in primary open-angle glaucoma (POAG) susceptibility and individual responses to drug treatment.Material/MethodsThis case-control study consisted of 93 cases with POAG and 125 controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to analyze CYP2C19 single-nucleotide polymorphisms (SNPs). After timolol treatment, patients were classified into side effect (SE) group and non-side effect (NSE) group. According to drug treatment responses, patients were divided into 3 groups: excellent group (Ex) (IOP ≥8 mm Hg); utility group (Ut) (5 <IOP ≤8 mm Hg), and ineffective group (In) (IOP ≤5 mm Hg). Data analysis was performed using SPSS software.ResultsWe found no statistical differences in the alleles and genotypes frequencies of CYP2C19 between the case group and the control group (both P>0.05). Frequencies of extensive metabolizer phenotype and poor metabolizer phenotype or poor metabolizer phenotype and intermediate metabolizer phenotype were significantly different between the SE group and NSE group (both P<0.05). The distribution of intermediate metabolizer phenotype and extensive metabolizer phenotype were significantly different among Ex group, Ut group, and In group (all P<0.05).ConclusionsWe found no evidence that CYP2C19 polymorphisms are associated with susceptibility to POAG. However, different CYP2C19 metabolizer phenotypes were identified and observed to have important effects on the individual differences in drug treatment response.

Effect of genotype on individual response to the pharmacological treatment of glaucoma: a systematic review and meta-analysis

“…N = 135 divided per each genotype PTGFR rs3766355 A > C was associated to higher pre-treatment IOP ( P < 0.05) Not reported HWE was tested by chi-square test and genotypes conformed to it rs11723068 G > A and rs757253 T > C of the Actin filament-associated protein (AFAP) gene; rs9503012 C > T and rs17134549 T > A of the GDP-mannose 4,6 dehydratase (GMDS) gene; rs3753380 C > T and rs3766355 A > C of the prostaglandin F2 receptor negative regulator (PTGFR) Latanoprost TT genotype of GMDS rs9503012 C > T as well as AA genotype of PTGFR rs3766355 A > C was correlated with a statistically significant better response to the therapy with latanoprost. On the contrary, age, CC + CT genotypes of GMDS rs9503012 C > T and CC + AC genotypes of PTGFR rs3766355 A > C were associated with worse response to latanoprost Gao et al [ 61 ] Prospective registered in the Chinese Clinical Trial Registry (registration number: ChiCTR-OCC- 11,001,326) POAG, N = 60 divided per each genotype No significant baseline differences, as reported in supplementary materials S1 ( P > 0.05) Chinese HWE was analyzed by using Pearson χ2 test of goodness-of-fit in the study sample proving respected Prostaglandin-endoperoxide synthase 1 (PTGS1) (rs3842787 and rs10306114); PTGFR (rs3753380 and rs3766355); multidrug resistance protein 4 (MRP4) (rs11568658 and rs11568668) Latanoprost No difference in frequency and type of side effects after treatment with latanoprost, but 3435C > T (CC and TT mainly) genotype frequency distribution was significantly higher in the group experiencing effectiveness ( P = 0.002 and P = 0.001, respectively) Liu et al [ 62 ] Case–control study The diagnosis of POAG was based on diagnostic criteria published by the Chinese Medical Association Glaucoma Branch in 2008. The criteria for diagnosis of POAG were as follows: (1) IOP ≥ 21 mmHg; (2) abnormal optic disc determined by optical coherence tomography; (3) glaucomatous visual field deletion (on the basis of mean deviation and corrected pattern standard deviation); (4) retinal nerve fiber layer defect; and (5) open anterior chamber angle N = 93 No baseline differences ( P > 0.05).…”

“…The pharmacological therapy included primarily topical beta-blockers that could be associated with miotics. The study by Liu et al [ 62 ] assessed the influence of cytochrome P450 2C19 (CYP2C19) polymorphisms on the response to treatment with timolol in terms of both efficacy and safety. Extensive, intermediate and poor metabolizers are not significantly associated to the susceptibility to POAG.…”

“…However, the criteria for POAG diagnosis are not reported. In the study by Liu et al [ 62 ], that is a case–control study, all patients with different allelic and genotypic frequencies were in HWE. The diagnosis of POAG was based on diagnostic criteria published by the Chinese Medical Association Glaucoma Branch in 2008.…”

“…latanoprost and timolol, divided per gene for which genetic variants were examined to assess the influence of genotype on responders and nonresponders to latanoprost. The studies analyzed in the subgroup of latanoprost include all the records investigating the gene PTGFR (Cui et al [ 60 ]; Gao et al [ 61 ]; Ussa et al [ 64 ]) and MRP4 (Gao et al [ 61 ], Liu et al [ 62 ]). The records subjected to subgroup analysis for timolol include the studies assessing genetic variants of CYP450 (Liu et al [ 63 ]; Yang et al [ 29 ]; Yuan et al [ 65 ]).…”