Important Variant Information for CYP3A5
Submitted by: Jatinder Lamba, Erin Schuetz (PAAR)
Reviewed by: Reviewed
Submitted date: February 16, 2006
There are Three Important Variants for CYP3A5.
| Gene HGNC Name: | CYP3A5 |
|---|---|
| Variant Summary: | Among Caucasians, the estimated allele frequency of CYP3A5*3 is 0.85. The allele frequency in other ethnic groups is as follows: African American, 0.55; Japanese, 0.85; Chinese, 0.65; Mexicans, 0.75; Southeast Asians (excluding Japanese and Chinese), 0.67; Pacific islanders, 0.65 and Southwest American Indians, 0.4. [PMID: 11279519 ]. Subjects who are homozygous for the CYP3A5*3 variant demonstrate significant reduction in the protein and activity. Liver microsomes from subjects homozygous for the nonfunctional CYP3A5*3 allele have about half the overall CYP3A catalytic activity toward midazolam [PMID: 11279519, 12065767] compared to subjects homozygous for CYP3A5*1. Persons with CYP3A5 expressor genotypes (CYP3A5*1/*1 and *1/*3) metabolize some CYP3A substrates more rapidly than CYP3A5 non-expressors. For example, they require larger tacrolimus dosing in organ transplant patients than CYP3A5 nonexpressors (CYP3A5*3/*3) [PMID: 15814280, 15729180, 15723604, 15808586 ]; conversely, the renal expression of CYP3A5 is associated with lower risk of nephrotoxicity from cyclosporine A and tacrolimus [PMID: 14583679]. CYP3A5 expressors had a higher rate of ifosfamide N-demethylation in liver and kidney [PMID: 15821045 ] and of cyclosporine A metabolism in kidney [PMID: 15450954 ]. CYP3A5 has been implicated as a genetic determinant of differences in lipid lowering response to statins [PMID: 15284534]. CYP3A5*3 is not associated with risk of t-AML in children treated for ALL [PMID: 12439220]. Among the African American population, CYP3A5*1/*3 subjects had 8 and 18 fold higher CYP3A5 content and CYP3A catalytic activity, respectively, compared to CYP3A5*3/*3 subjects [PMID: 12754175]. The CYP3A5*1 genotype (CYP3A5 expressors) has been associated with salt-sensitive hypertension, whereas subjects homozygous for CYP3A5*3 (CYP3A5 non-expressors) have a lower risk of hypertension [PMID: 15952872]. CYP3A5*3 is also significantly associated with systolic blood pressure, mean arterial pressure and creatinine clearance among the African American population [PMID: 12754175]. This was confirmed in a large trial-DEBATE study [PMID: 15952872]. The CYP3A5*3 allele frequency shows extreme variation across human populations and is significantly correlated with distance from the equator [PMID: 15492926]. CYP3A5 genotype has been associated with more rapid clearance of the antiretroviral drug saquinavir [PMID: 16338276] and with dose dependent effects on ABT-773 plasma levels [PMID: 15179406]. CYP3A5*3 genotype affects the extent of drug interactions. The magnitude of induction of CYP3A activity is greater in CYP3A5 nonexpressors [PMID: 14515058] and the extent of itraconazole inhibition of CYP3A-mediated midazolam hydroxylation is greater in CYP3A5 nonexpressors, likely due to the relatively CYP3A4-specific inhibition by itraconazole [PMID: 15289787]. Additional numbering information: 22893 G>A on AC005020 (6986G/A with respect to NG_000004.2 with translation start site as +1 on the CYP allele nomenclature website http://www.cypalleles.ki.se/cyp3a5.htm). The presence of a G at nt 22893 on AC005020 creates an alternate splice site and results in cryptic splicing whereas the presence of an A at nt 22893 is not associated with aberrant splicing. Creation of the alternate splice site by the G22893 allele results in insertion of a novel exon3B from intron 3 that changes the CYP3A5*3 reading frame and produces a premature stop codon after aa102. There is still no genomic CYP3A5 sequence available corresponding to the CYP3A5*1 allele initially described by Aoyama et al. 1989[PMID: 2732228], on the cDNA level and encoding a functional CYP3A5 enzyme. The reference sequence for the CYP3A5*1 allele has been obtained by using the CYP3A5 sequence found in accession number NG_000004.2 (corresponding to the CYP3A5*3 allele) and replacing base 6986 G with an A (numbering based on translation start as +1). Likewise, the reference sequence for the CYP3A5*1 allele can be obtained by using the CYP3A5 sequence found in accession number AC005020 (corresponding to the CYP3A5*3 allele) by making the following base change, 22893 G>A (numbering based on translation start site as +1). |
| Key PubMed IDs: | 11279519, 12065767, 12324482, 15492926 |
| Genomic Variant & GenBank ID: | 260167 G>A on NG_000004.2 Note: CYP3A5*3 (G) > CYP3A5*1 (A) *See Variant Summary |
| mRNA Variant & GenBank ID: | Not applicable (intronic variant). Note: Alternatively spliced transcripts Genbank IDs: AF355804 (alternate exon3B), AF355802 (alternate exon5B), AF355801 (alternate exon4B); see splice variant information. |
| Protein Variant & GenBank ID: | no CYP3A5 protein produced |
| dbSNP rs#: | rs776746 |
| GoldenPath Position: | chr7:99108475 (PharmGKB and UCSC hg18) and 98881936(HAPMAP rel#19/phaseII) |
| Key Drugs/Substrates: | ( Adapted from http://medicine.iupui.edu/flockhart/table.htm ) Macrolide antibiotics: clarithromycin, telithromycin; Benzodiazepines: alprazolam, diazepam=>3OH, midazolam, triazolam; Immune Modulators: cyclosporine, tacrolimus (FK506); HIV Antivirals: indinavir, nelfinavir, ritonavir, saquinavir; Prokinetic: cisapride ; Antihistamines: astemizole, chlorpheniramine, terfenidine; Calcium Channel Blockers: amlodipine, diltiazem, felodipine, lercanidipine, nifedipine, nisoldipine, nitrendipine, verapamil; HMG CoA Reductase Inhibitors: atorvastatin, cerivastatin, lovastatin, simvastatin; Steroid 6beta-OH: estradiol, hydrocortisone, progesterone, testosterone; Miscellaneous drugs: alfentanil, aripiprazole, buspirone, cafergot, caffeine=>TMU, cilostazol, cocaine, codeine- N-demethylation, dapsone, dextromethorphan, docetaxel, domperidone, eplerenone, fentanyl, finasteride, gleevec, haloperidol, irinotecan, LAAM, lidocaine, methadone, nateglinide, ondansetron, pimozide, propranolol, quinine, salmeterol, sildenafil, sirolimus, tamoxifen, taxol, terfenadine, trazodone, vincristine, zaleplon, zolpidem |
| Key Phenotypes/Diseases: | CYP3A5 genotype is associated with risk of elevated blood pressure and hypertension [PMID: 12754175, 15952872, 15596575]. |
| DNA Source Containing Homozygous Reference Allele(Coriell Lines): |
(CYP3A5*1/1 [A/A]): NA18503 (PA130760116), NA18517 (PA130760126), NA18522 (PA130760130), NA15215 (PA126721210) |
| DNA Source Containing Heterozygous Reference Allele(Coriell Lines): |
(CYP3A5*1/3 [A/G]): NA07029 (PA126710371), NA07000 (PA126710358), NA10854 (PA126710313), NA15029 (PA126721208) |
| DNA Source Containing Homozygous Minor Allele(Coriell Lines): |
(CYP3A5*3/3 [G/G]): NA06985 (PA126721080), NA06991 (PA126721081), NA07019 (PA126710365), NA15236 (PA126721214) |
| Phenotype Data Sets: | Phenotype data sets PA130713012 [PMID: 11279519] and PA130713029 [PMID: 12065767] demonstrate association of CYP3A5 variants with CYP3A activity measured as MDZ hydroxylation and CYP3A5 expression measured as mRNA or protein in liver and intestine. Phenotype data sets PA130756033 [PMID: 12694072], PA132837944 [PMID: 14747421] and PA133888800 demonstrate that CYP3A5 expressor genotypes (CYP3A5*1/*1 and *1/*3) require higher tacrolimus doses than CYP3A5 nonexpressors (CYP3A5*3/*3) to achieve the same plasma concentration in pediatric heart transplant and adult lung transplant patients, respectively. Phenotype data set PA646601 [PMID: 12439220] demonstrates that CYP3A5*3 is not associated with risk of t-ML in children treated for acute lymphocytic leukemia. Phenotype data set PA130713028 [PMID: 12202670] explains interindividual differences of docetaxel PK and PD in Asian populations are associated with CYP3A5 genotype. CYP3A5*3 allele frequency in various populations is significantly correlated with their distance from the equator [PMID: 15492926]. Persons with a CYP3A5*3 (non-expressors) genotype metabolize saquinavir less rapidly, achieve a higher Cmax and have slower clearance than CYP3A5*1 (expressor) carriers (PA142658557) [PMID: 16338276]. Other data sets of interest that demonstrate that CYP3A5 genotype is associated with drug metabolism and clearance: tacrolimus (PA133888947), etoposide (PA132837945), docetaxel and midazolam (PA129966512), midazolam (PA129411304), irinotecan (PA130150454, PA130713026 [PMID: 12960109], PA129966511, PA130150455). |
| Splice Variation : | Yes |
| Gene HGNC Name: | CYP3A5 |
|---|---|
| Variant Summary: | CYP3A5*6 (a G-to-A transition in exon 7 results in exon 7 skipping), causes alternative splicing of CYP3A5 and protein truncation, resulting in the absence of CYP3A5 protein [PMID: 11279519]. CYP3A5*6 alleles are relatively frequent in African American subjects (10-22%) but absent/very rare in White [PMID: 11279519, 15833928] and Asian populations [PMID: 12756511]; the frequency in the Dutch population is 0.01% [PMID: 12324482]. CYP3A5 variants are also associated with race and tumor characteristics but not with the disposition of Tamoxifen in Breast cancer patients [PMID:15596297]. Additional numbering information: 30597G>A on Genbank accession ID AC005020 (14690G/A with respect to NG_000004.2 with translation start site as +1 on the CYP allele nomenclature website (http://www.cypalleles.ki.se/cyp3a5.htm) |
| Key PubMed IDs: | 11279519, 12756511, 12324482, 15833928 |
| Genomic Variant & GenBank ID: | 267871 G>A on NG_000004.2 |
| mRNA Variant & GenBank ID: | 711G>A , NM_000777 (Genbank accession number for alternatively spliced form is AF355803) |
| Protein Variant & GenBank ID: | Lys208Lys on NP_000768 |
| dbSNP rs#: | rs10264272 |
| GoldenPath Position: | chr7:99100771 (hg18), Chr7: 98874232 (HapMap rel #19/phaseII) |
| DNA Source Containing Homozygous Reference Allele(Coriell Lines): |
NA15029 (PA126721208), NA15038 (PA126721221) |
| DNA Source Containing Heterozygous Reference Allele (Coriell Lines): |
NA15334 (PA126721239), NA15268 (PA126721228), NA15215 (PA126721210) |
| Phenotype Data Sets: | CYP3A5*6 is associated with a significant decrease in CYP3A5 protein and activity (PA130713012) [PMID: 11279519]. |
| Splice Variation: | Yes |
| Gene HGNC Name: | CYP3A5 |
|---|---|
| Variant Summary: | CYP3A5*7 (27131-2ins T) resides between codons 345/346 and results in a shift in reading frame. This shift introduces a premature termination codon at codon number 348 (D348). Therefore the variant alleles are null. CYP3A5*7 occurs with the frequency of 10-22% among the African population but is absent in White and Asian populations [PMID: 11740341, 15833928] and this may reflect evolutionary pressures generated by environmental factors in geographically distinct regions [PMID: 15833928]. However no genotype-phenotype association was observed between homozygous wildtype and heterozygous subjects with respect to disposition of midazolam [PMID: 14515058, 15114431]. Additional numbering information: 27131-27132insT (Genbank accession NG_000004.2 with translation start site as +1 on CYP allele nomenclature website http://www.cypalleles.ki.se/cyp3a5.htm); 43039 (Genbank AC005020); [PMID: 15833928] |
| Key PubMed IDs: | 11740341, 15833928, 15114431, 14515058, 16004554 |
| Genomic Variant & GenBank ID: | 280312 T>TT on NG_000004.2 |
| mRNA Variant & GenBank ID: | 1122 T>TT on NM_000777 |
| Protein Variant & GenBank ID: | Pro/Thr 345/6 Pro/Tyr, NP_000768 , but produces termination codon at codon number 348 (Asp348ter). |
| GoldenPath Position: | chr7:99088330 ;T/TT(hg18) |