Clinical Annotations
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Variant Annotations
PharmGKB variant annotations provide information about variant-drug pairs based on individual PubMed publications. Each annotation represents information from a single paper and the goal is to report the information that the author states, not an interpretation of the paper. The PMID for supporting PubMed publications is found in the "Evidence" field.
Information presented, including study size, allele frequencies and statistics is taken directly from the publication. However, if the author does not correct p-values in cases of multiple hypotheses, curators may apply a Bonferroni correction. Curators attempt to report study size based on the actual number of participants used for the calculation of the association statistics, so the number may vary slightly from what is reported in the abstract of the paper. OMB Race Category information is derived from the paper and mapped to standardized categories. Category definitions may be found by clicking on the "OMB Race Category" link.
There are 46 annotations for this variant. Register or sign in to see them.
There are 7 disease-related annotations for this variant. Register or sign in to see them.
VIP Variant in CYP3A5
Note: The CYP3A5 gene is found on the minus chromosomal strand. Please note that for standardization, the PharmGKB presents all allele base pairs on the positive chromosomal strand; therefore the alleles within our variant annotations will differ (in a complementary manner) from those in this VIP summary that are given on the minus strand as reported in the literature.
The most common nonfunctional variant of CYP3A5 is designated as CYP3A5*3 [Article:11279519] and is represented by Genbank sequence AC005020, which has a G at position 22,893. CYP3A5*3 is assigned dbSNP # rs776746. On the CYP allele nomenclature website, it is designated as 6986A>G. CYP3A5*1 has an A at this position. Change from 'A' to 'G' at this position creates a cryptic splice site in intron 3, resulting in altered mRNA splicing. The alternatively spliced isoform has an insertion from intron 3, which changes the reading frame and results in a premature termination codon and hence a non-functional protein [Article:11279519]. Subjects with CYP3A5*3/*3 genotype are considered to be CYP3A5 non-expressors.
CYP3A5*3 is the most frequent and well-studied variant allele of CYP3A5. Its frequency varies widely across human populations. In White populations, the estimated allele frequency of CYP3A5*3 is 0.82-0.95 [Articles:11279519, 12439220, 12893984, 15492926, 22123129]. The allele frequency in other ethnic groups is as follows: African American, 0.33 [Article:11279519]; 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. [Article:11279519]. In one study which used the HGDP-CEPH panel, the frequency ranged from 0.06 in Yorubans (Nigerians) to 0.96 in Basques and was significantly correlated with population distance from the equator [Article:15492926].
Variant-Drug associations:
People with CYP3A5 expressor genotypes (CYP3A5*1/*1 and *1/*3) metabolize some CYP3A substrates more rapidly than do CYP3A5 non-expressors (for example, *3/*3). One such substrate is tacrolimus, which is used to prevent post-transplantation organ rejection. CYP3A5*1 carriers have a higher rate of tacrolimus clearance than do people with the other genotypes, with *1/*1 having higher clearance than *1/*3 individuals, which have higher clearance than *3/*3 [Article:21671989]. In ideal situations, target tacrolimus concentration must be high enough to prevent transplant rejection [Articles:19494792, 19681975] but low enough to minimize toxicity [Article:8878381]. Tacrolimus trough concentrations are routinely monitored after transplantation, and dose is appropriately adjusted. Despite the well-established association of CYP3A5 genotype with clearance rate and trough levels [Articles:12694072, 15147425, 15729180, 15723604, 16146556, 15808586, 17192769, 19067682, 20170205], it has not been consistently shown to be associated with the risk of acute organ rejection. It has also not been shown yet that genotype-guided dosing leads to improved clinical outcome. A recent study comparing genotype-guided dosing to the standard regimen demonstrated more rapid attainment of target concentration but did not demonstrate improved clinical outcome [Article:20393454]. A tacrolimus dosing equation which includes CYP3A5 genotype along with days post-transplant, age, transplant at a steroid sparing center or not, and calcium channel blocker (CCB) use was recently published [Article:21671989] for use in adult kidney transplant recipients, and the results await validation and prospective testing. This equation for calculating tacrolimus clearance is: 38.4 x [(0.86, if days 6-10) or (0.71, if days 11-180)] x [(1.69, if CYP3A5*1/*3 genotype) or (2.00, if CYP3A5*1/*1 genotype)] or (0.70, if receiving a transplant at a steroid sparing center) x ([age in years/50]-0.4) x (0.94, if CCB is present). Then this clearance rate estimate is used to determine the tacrolimus dose to achieve the desired trough.
Liver microsomes from subjects homozygous for the nonfunctional CYP3A5*3 allele had less than half the overall CYP3A catalytic activity toward midazolam (which is a substrate for CYP3A5 and CYP3A4) compared to individuals with at least one wild-type CYP3A5*1 allele [Articles:11279519, 12065767]. In African Americans, CYP3A5*1/*3 subjects had eight- and 18- fold higher mean kidney microsomal CYP3A5 content and CYP3A catalytic activity, respectively, compared to CYP3A5*3/*3 subjects [Article:12754175]. In vivo, in a study group of 23 Whites plus 34 African-Americans, oral clearance of midazolam after rifampicin induction showed a relationship with CYPA5*3 genotype (the magnitude of induction by rifampin of CYP3A activity was greater in CYP3A5 non-expressors than in expressors [Article:14515058] but it did not reach significance (this result could be due to the linked CYP3A4*1B)). No association was observed with induced systemic midazolam clearance or with magnitude of clearance in this group [Article:14515058]. No significant relationship between CYP3A5 genotype and midazolam pharmacokinetics was found in another study group which consisted of 19 Whites plus two Africans [Article:15114431]. CYP3A5*3 genotype affects the extent of drug interactions, and the extent of itraconazole inhibition of CYP3A-mediated midazolam hydroxylation is greater in CYP3A5 non-expressors than in expressors, likely due to the relatively CYP3A4-specific inhibition by itraconazole [Article:15289787].
CYP3A5 *1/*3 genotype has been associated with more rapid clearance of the antiretroviral drug saquinavir compared to *3/*3 [Articles:15373940, 16338276] . CYP3A5 genotype may also have dose-dependent effects on ABT-773 plasma levels [Article:15179406]. CYP3A5 expressors have a higher rate of ifosfamide N-demethylation in liver and kidney [Article:15821045] and of cyclosporine A metabolism in kidney [Article:15450954].
In pediatric precursor B cell acute lymphoblastic leukemia patients treated with vincristine, CYP3A5 expressors had less treatment-related neurotoxicity [Article:21225912]. In a recent study of advanced renal-cell carcinoma patients treated with sunitinib, CYP3A5*1 was associated with increased risk of dose reductions due to toxicity [Article:22015057].
CYP3A5 has been implicated as a genetic determinant of differences in lipid lowering response to statin drugs, but results have been inconsistent [Article:19530969] . In one study, lovastatin, simvastatin and atorvastatin were significantly less effective in subjects carrying *1 than in *3/*3 subjects [Article:15284534] . In contrast, another study found that *3 carriers had a reduced response to atorvastatin [Article:18727922]. The CYP3A5 genotype also has been associated with severity of side effects from statin treatment [Article:15900215] (*3/*3 patients taking atorvastatin who developed myalgia were more likely to sustain greater muscle damage) .
Variant-Disease Associations:
There have also been inconsistent results from studies of CYP3A5 genotype association with blood pressure/hypertension (see review [Article:19290795]). Studies showing an association of the *1 allele with higher blood pressure or with hypertension have all been done in subjects of African descent or in older Caucasian subjects [Article:19290795]. In a recent meta-analysis (for hypertension: 10 studies including more than 9500 subjects, and for blood pressure: 12 studies including more than 9000 subjects) no association was found overall with CYP3A5 genotype, and, in Whites, a modest association between *1 and lower systolic blood pressure was noted [Article:21814220].
One study, performed in a White(Nordic) population, showed that risk of developing childhood ALL is higher for CYP3A5 expressors than for non-expressors; in a study of 616 childhood ALL patients and 203 controls, the OR for subjects with at least one expressor allele was 1.64 (95% CI: 1.009-2.657) (p = 0.044) [Article:21418106]. For T-ALL, Event Free Survival was better in expressors(EFS = 94.1%) than in non-expressor patients(EFS = 61.5%)(p = 0.015) [Article:21418106]. In Asian Indians, the CYP3A5 *3 allele has recently been shown to be associated with risk of developing CML(44.2% *3/*3 in CML patients vs. 19.1 % in controls (p<0.0001) [Article:21039054].
Japanese women who are CYP3A5 expressors were shown to have a higher risk for breast cancer than those who are non-expressors (OR 1.49(95% CI:1.10-2.04);study size: 403 case-control pairs.) [Article:19229255]. In one small study(48 African American and 50 Caucasian women), association between tamoxifen level/side effects during treatment for breast cancer and *1 vs.*3 vs.*6 was examined, and no association was found . The authors state that the study was sufficiently powered. However, there was a significant association(p < 0.02) noted between larger tumor size and having at least one copy of *6 [Article:15596297].
Appendix
| Genomic Variant & GenBank ID: | 260167 G>A on NG_000004.2 Note: CYP3A5*3 (G) > CYP3A5*1 (A) |
|---|---|
| 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 |
| 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) |
Connected Drugs
Connected Diseases
Publications related to rs776746 at chr7:99270539: 72
Cross-References
- UCSC Golden Path:
- chr7:99270539
- dbSNP:
- rs776746
- ALFRED:
- SI582180Y
- HapMap:
- rs776746
- JSNP:
- ssj0007960
Platform Availability
- Affymetrix
- Illumina