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 30 annotations for this variant. Register or sign in to see them.
There are 5 disease-related annotations for this variant. Register or sign in to see them.
VIP Variant in SLCO1B1
In cellular studies, OATP1B1-Ala174 and associated haplotypes, particularly SLCO1B1*15, have demonstrated reduced transport activity in comparison to OATP1B1-Val174 [Articles:18499754, 11477075, 12130747, 15970799, 15564882, 15608127]. This may be a result of intracellular protein sequestration and reduced surface expression [Article:11477075].
As mentioned previously, OATP1B1-dependent transport is an important step in mediating hepatic clearance of statins. The minor allele of SLCO1B1 T521C (present in *5, *15, *16, *17 haplotypes) has been consistently associated with elevated circulating concentrations of statins, as measured by plasma area under the curve (AUC) values or Cmax [Articles:12811365, 15226675, 17622941, 17177112, 15116054, 17473846], implying reduced hepatic access. Because statins act primarily through hepatic mechanisms, reduced hepatic statin availability associated with SLCO1B1 T521C may also influence statin efficacy. However, studies describing a relationship of this variant with either statin-mediated LDL-cholesterol lowering or CVD risk reduction are conflicting and the evidence remains weak [Articles:16103896, 16917677, 16678544, 15548849, 18563955, 17439540]. Collectively, these data suggest that any effect of SLCO1B1 T521C on statin efficacy is minor. In contrast, reduced transporter function may promote adverse drug responses through prolonged systemic statin exposure. This theory is supported by a recent genome-wide association study that identified this same SLCO1B1 variant (rs4149056) as the genotype most predictive of simvastatin-induced myotoxicity [Article:18650507].
Associations have also been observed between SLCO1B1 T521C and pharmacokinetic handling and drug efficacy for other classes of drugs. Repaglinide is an antidiabetic agent and OATP1B1 substrate. Repaglinide plasma AUC was increased in SLCO1B1:T521C carriers in several studies across a range of dosages [Articles:19238654, 18187595, 18823304]. Furthermore, increased repaglinide efficacy, as measured by plasma glucose AUC reductions, was also observed in these studies [Articles:19238654, 18187595].
SLCO1B1 T521C, as observed in the *5 and *15 haplotypes, has also been associated with increased irinotecan plasma AUC, an anticancer agent, and, in two studies, was predictive of irinotecan-induced neutropenia [Articles:19349540, 18221820, 18998132, 16906022]. This variant has also been associated with altered steady state concentrations of the antihypertensive agent, torasemide [Article:18399713].
SLCO1B1:T521C has also been associated with increased serum bilirubin levels. Bilirubin is an endogenous heme metabolite; low plasma bilirubin concentrations have been associated with elevated CVD risk [Article:8620339]. SLCO1B1:T521C carriers exhibited increased serum bilirubin (as well as estrone sulfate) concentrations in two Caucasian populations [Articles:18499754, 17973861] These results are further supported by the results of a recent genome wide association study meta analysis that identified rs4149056 as the major genetic predictor of serum bilirubin levels in a combined population of ~9,500 Caucasians [Article:19414484].
Population Frequencies: The genotypic frequencies for the SNPs and variants identified appear to be dependent on ethnicity. Summary given in Table 3 below.
Table 3. Population frequencies SLCO1B1 variants
| Common name | rsID | Protein change | Haplotype | African-American [Articles:11477075, 18185926] | Japanese [Article:12130747] | Asian (includes Japanese) [Articles:12811365, 19122343]] | Caucasian [Articles:11477075, 18781850, 18185926, 16758257] |
| T521C | rs4149056 | Val174Ala | *5 | 1%-4% | 0.7% | 6%-19% | 12% \-20% |
| G388A | rs2306283 | Asn130Asp | *1b | 74%-78% | 54% | 56%-81% | 37%-46% |
| T521C + G388A | Val174Ala + Asn130Asp | *15 | 10% |
| Key Publications: | |
|---|---|
| Drugs / Other Molecules |
Drug (19)
|
Appendix
2. SLC01B1:V174A commonly known as T521C
| Genomic Variant & GenBank ID: | 14,090,523 T>C on NT_009714 |
|---|---|
| mRNA Variant & GenBank ID: | 625T>C on NM_006446.4 |
| Protein Variant & GenBank ID: | 174 V>A on NP_006437.3 |
| GoldenPath Position: | Chr12:21,222,816 (hg18) |
| Key Drugs/Substrates: | Same as wild type |
Connected Drugs
Connected Drug Classes
| Evidence | Drug Class |
|---|---|
| VIP Annotation | Arsenic compounds |
| Variant Annotation | hmg coa reductase inhibitors |
Publications related to rs4149056 at chr12:21331549: 30
Cross-References
- UCSC Golden Path:
- chr12:21331549
- dbSNP:
- rs4149056
- HapMap:
- rs4149056
- JSNP:
- ssj0003182
Platform Availability
- Affymetrix
- Illumina