From SNPedia
| Geno
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Mag
|
Summary
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| (A;A)
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3
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nonfunctional CYP3A5; drug metabolism effects
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| (A;G)
|
2
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carrier of 1 nonfunctional CYP3A5 allele; drug metabolism affects
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| (G;G)
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0
|
|
| ? | (A;A) (A;G) (G;G) | 28 |
|---|
 |
, also known as 6986G>A, is a SNP encoding the (nonfunctional) CYP3A5*3 allele of the
CYP3A5 gene.
CYP3A5*3 has been studied especially in connection with the metabolism of tacrolimus, an immunosuppressive drug used in organ transplantation. The optimal therapeutic dose is in a relatively narrow window, so blood concentration monitoring is recommended. CYP3A5*3 carriers tend to build up higher levels of tacrolimus than CYP3A5*1 carriers, unless their tacrolimus intake is reduced.
| PharmGKB | PA165110648 |
| Name | CYP3A5*3, intron 3 splicing defect, c.219-237A>G, rs776746 G alllele |
| Annotation | Risk or phenotype-associated allele: CYP3A5*3/*3 (rs776746 GG) genotype. Phenotype: Tacrolimus clearance was significantly lower in patients with the nonfunctional CYP3A5 enzyme encoded by the CYP3A5*3/*3 genotype (rs776746 GG) in comparison to carriers of the wild-type CYP3A5*1 ((rs776746 A) allele (p = 0.013).At 1 month after transplantation, creatinine clearance was higher in patients with the CYP3A5*1 allele than in those with CYP3A5*3/*3 (117.5 24.4 vs. 97.2 28.4 ml/min), but not to a statistically significant extent (p = 0.06). Tacrolimus clearance was significantly higher in patients with low (<33%) versus normal hematocrit levels (p = 0.007). The individualization of tacrolimus dosage should be based on weight, hematocrit level, and CYP3A5 polymorphism to maintain therapeutic range. However, interindividual and residual variability remained large even when genetic information was taken into account. In a simulated estimation, 20% of the patients received an overdose (C(0) > 20 ng/ml), and 19% received too low a dose (C(0) < 5 ng/ml), thereby reinforcing the need for monitoring. A standard dosage of 0.15 mg/kg twice daily was associated with underdosing in children with the CYP3A5*1 ((rs776746 A) allele, thus higher dosages (0.2-0.3 mg/kg twice daily) are recommended primarily in children with body weight <20 kg and low hematocrit levels. In contrast, for children with CYP3A5*3/*3 (rs776746 GG) genotype, the lower dosage of 0.1 mg/kg twice daily should be recommended, primarily in those with body weight >40 kg. Study size: 50. Study population/ethnicity: Pediatric kidney transplant patients (29 males) of 10 years mean age (2-18 y.o. range) recruited from nine French centers from 2005 to 2008. Significance metric(s): p = (0.007 - 0.013) Type of association: GN, PK. |
| Gene | CYP3A5, CYP3A |
| Featue | Intron, NA |
| Evidence | PubMed ID:19865079 |
| Drugs | tacrolimus |
| Diseases | Organ Transplantation, Transplantation |
| Curation Level | Curated |
[PMID 20617557] Functional polymorphisms in the CYP3A4, CYP3A5, and CYP21A2 genes in the risk for hypertension in pregnancy
[PMID 20685352] Functional polymorphisms in the CYP3A4, CYP3A5, and CYP21A2 genes in the risk for hypertension in pregnancy
| PharmGKB | PA165106756 |
| Name | CYP3A5*3, CYP3A5:6986A>G |
| Annotation | A study in healthy Korean subjects indicates that CYP2C19 polymorphisms play an important role in the metabolism of cilostazol only in individuals with the CYP3A5*3/*3 genotype. |
| Gene | CYP3A5, CYP3A |
| Featue | Intron, NA |
| Evidence | PubMed ID:19516253 |
| Drugs | cilostazol |
| Diseases | |
| Curation Level | Curated |
| PharmGKB | PA165291997 |
| Name | rs776746 A>G, CYP3A5*3, Splicing defect |
| Annotation | Risk or phenotype-associated allele: A. Phenotype: This variant was associated with reduced risk for neurotoxicity with paclitaxel treatment. Study size: 132. Study population/ethnicity: Patients with Neoplasms receiving paclitaxel; Spain. Significance metric(s): HR = 0.55 (0.33-0.94); p = 0.027. Type of association: PK; TOX. |
| Gene | CYP3A5, CYP3A |
| Featue | Intron, NA |
| Evidence | PubMed ID:20212519 |
| Drugs | paclitaxel |
| Diseases | Drug Toxicity, Neurotoxicity Syndromes |
| Curation Level | Curated |
| PharmGKB | PA165363222 |
| Name | CYP3A5*3 |
| Annotation | Phenotype/associated allele: A meta-analysis of articles in PubMed in which dose-adjusted blood concentrations of Cyclosporine were measured in renal transplant patients implied that patients carrying the CYP3A5*3/*3 genotype will require a lower dose of Cyclosporine to reach target levels compared with CYP3A5*1/*1 or *1/*3 carriers. Study size: 15 studies ; 1742 subjects. Study population/ethnicity: France, the Netherlands, Belgium, United States, Germany, China, India ,Singapore and Malaysia. Type of association: PK. |
| Gene | CYP3A5, CYP3A |
| Featue | Intron, NA |
| Evidence | PubMed ID:20368718 |
| Drugs | cyclosporine |
| Diseases | Organ Transplantation, Transplantation |
| Curation Level | Curated |
| PharmGKB | PA165110780 |
| Name | CYP3A5*1, intron 3 splicing defect, c.219-237G>A, rs776746 A alllele |
| Annotation | Risk or phenotype-associated allele: CYP3A5*1, rs776746 AA genotype. Phenotype: Genotype frequencies were not in Hardy-Weinberg equilibrium for CYP3A5, where a greater than expected number of CYP3A5*1 (rs776746 AA) homozygotes was observed among cases (p = 0.006). CYP3A5*1 (rs776746 AA) homozygotes showed a non-significant increase in risk for lung cancer (OR = 5.24, p = 0.14). Study size: 1562 cancer cases, 432 controls. Study population/ethnicity: A case-control study was conducted in 801 Caucasian lung cancer patients that included 330 adenocarcinomas, 260 squamous cell carcinomas, 171 small cell lung cancers and 432 Caucasian hospital-based controls. Significance metric(s): Not significant, p = 0.14. Type of association: GN; PK |
| Gene | CYP3A5, CYP3A |
| Featue | Intron, NA |
| Evidence | PubMed ID:14515059 |
| Drugs | |
| Diseases | Adenocarcinoma, Carcinoma, Small Cell, Carcinoma, Squamous Cell |
| Curation Level | Curated |
| PharmGKB | PA165110654 |
| Name | CYP3A5*3, intron 3 splicing defect, c.219-237A>G, rs776746 G alllele |
| Annotation | Risk or phenotype-associated allele: CYP3A5*3/*3 (rs776746 GG) genotype. Phenotype: In kidney transplant patients, tacrolimus dose-adjusted trough levels were higher in patients carrying the CYP3A5*3/*3 (rs776746 GG) genotype (n = 45) than in carriers of the CYP3A5*1/*3 (rs776746 GA) plus CYP3A5*1/*1 (rs776746 AA) genotypes combined (n = 17), as follows: median and range, 94 (34-398) versus 61 (37-163) ng/mL per mg/kg (p < 0.0001). Thus, patients with the CYP3A5*3/*3 genotype require less tacrolimus to reach target predose concentrations compared with CYP3A5*1 (rs776746 A) allele carriers. Study size: 64. Study population/ethnicity: Renal transplant recipients from the outpatient clinic of the Erasmus Medical Center in Rotterdam in the Netherlands, who had received a renal graft at least 1 year before the start of the study and were administered tacrolimus. Significance metric(s): p < 0.0001 Type of association: GN; PK. |
| Gene | CYP3A5, CYP3A |
| Featue | Intron, NA |
| Evidence | PubMed ID:12966368 |
| Drugs | tacrolimus |
| Diseases | Organ Transplantation, Transplantation |
| Curation Level | Curated |
| PharmGKB | PA165111316 |
| Name | CYP3A5*1, intron 3 splicing defect, c.219-237G>A, rs776746 A alllele |
| Annotation | Risk or phenotype-associated allele: CYP3A5*1, rs776746 AA genotype. Phenotype: Genotype frequencies were not in Hardy-Weinberg equilibrium for CYP3A5, where a greater than expected number of CYP3A5*1 (rs776746 AA) homozygotes was observed among cases (p = 0.006). CYP3A5*1 (rs776746 AA) homozygotes showed a non-significant increase in risk for lung cancer (OR = 5.24, p = 0.14). Study size: 1562 cancer cases, 432 controls. Study population/ethnicity: A case-control study was conducted in 801 Caucasian lung cancer patients that included 330 adenocarcinomas, 260 squamous cell carcinomas, 171 small cell lung cancers, and 432 Caucasian hospital-based controls. Significance metric(s): Not significant, p = 0.14. Type of association: GN; PK; CO |
| Gene | CYP3A5, CYP3A |
| Featue | Intron, NA |
| Evidence | PubMed ID:14515059 |
| Drugs | |
| Diseases | Adenocarcinoma, Carcinoma, Small Cell, Carcinoma, Squamous Cell |
| Curation Level | Curated |
| PharmGKB | PA165111319 |
| Name | CYP3A5*3C, g.6986A>G, rs776746 G allele, splice variant |
| Annotation | Risk or phenotype-associated allele: CYP3A5*3C, g.6986A>G, rs776746 G allele, splice variant. Phenotype: There was no significant association between systemic exposure of tipifarnib (AUC levels) and CYP3A5*3C genotype. Study size: 28 (16 male). Study population/ethnicity: Caucasian cancer patients, aged 34-75. Significance metric(s): Not significant, p = 0.52. Type of association: GN; PK |
| Gene | CYP3A5, CYP3A |
| Featue | Intron, NA |
| Evidence | PubMed ID:15122075 |
| Drugs | Tipifarnib |
| Diseases | |
| Curation Level | Curated |
| PharmGKB | PA165111625 |
| Name | g.6986A>G |
| Annotation | Risk or phenotype-associated allele: G. Phenotype: This variant is statistically correlated with the mean of maximum transaminase values (ALT) in patients from Mozambique, with higher ALT mean value for G genotype carriers. Study size: 156. Study population/ethnicity: HIV infected patients from Mozambique. Significance metric(s): p= 0.019. Type of association: GN; CO |
| Gene | CYP3A5, CYP3A |
| Featue | Intron, NA |
| Evidence | PubMed ID:20017669 |
| Drugs | nevirapine |
| Diseases | Drug Toxicity, HIV Infections |
| Curation Level | Curated |
[PMID 21206424] Novel Polymorphisms Associated With Tacrolimus Trough Concentrations: Results From a Multicenter Kidney Transplant Consortium
[PMID 22015057] Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study
[PMID 22120734] Identification of pharmacogenetic predictors of lipid-lowering response to atorvastatin in Chilean subjects with hypercholesterolemia
[PMID 21806386] Pharmacogenetics of calcineurin inhibitors in Brazilian renal transplant patients
[PMID 22108237] The use of a DNA biobank linked to electronic medical records to characterize pharmacogenomic predictors of tacrolimus dose requirement in kidney transplant recipients.
