Rs4149056

rs4149056, also known as 37041T>C or V174A, is a SNP in the SLCO1B1 gene, which encodes the 'organic anion transporting polypeptide 1B1' (OATP1B1) protein. This protein, found primarily in the liver, regulates the uptake of numerous drugs and natural compounds. The rs4149056(C) SNP defines the SLCO1B1*5 allele.

The rs4149056(C) allele gives rise to an amino acid change (from valine to alanine at residue 174) which has reduced uptake/transport activity. Therefore, drugs metabolized by OATP1B1 tend to build up to higher circulating concentrations than they would otherwise.[PMID 16758257].

The drugs known (or in some cases, thought) to be transported less well by the variant OATP1B1 protein encoded by the rs4149056(C) allele include:

• Several cholesterol lowering statins, generally leading to reduced inhibitory effects on liver cholesterol synthesis and possibly worse side effects, by such drugs as:
  • simvastatin
  • pravastatin
  • rosuvastatin
  • pitavastatin
• fexofenadine
• repaglinide
• methotrexate
• the SN-38 active metabolite of irinotecan
• rifampicin
• caspofungin
• lopinavir

[PMID 18650507] rs4363657 in nearly complete linkage disequilibrium with rs4149056 SNP (r²=0.97), which has been linked to statin metabolism. rs4149056(C) odds ratio for myopathy among 20,000 individuals taking either 40 or 80mg of simvastatin daily was 4.5 (CI: 2.6-7.7) per copy of the C allele, and 16.9 (CI: 4.7-61.1) in (C;C) as compared with (T;T) homozygotes.

The Gene Sherpa points out a 16x odds ratio for myopathy when taking statins and suggests fenofibrates might be a good alterative.

[PMID 19833260] A study of ~500 individuals taking statins concluded that rs4149056(C), i.e. SLCO1B1*5, was associated with statin-induced side-effects, most likely somewhat correlated to the number of such alleles being carried.

[PMID 21178985] A study of >4000 individuals with type 2 diabetes using routine prescribing data from the Electronic Medical Record in Tayside Scotland suggests high proportion rs4149056(C) homozygotes discontinue or reduce their doses of statins

spittoon discussion of this SNP

[PMID 19414484] Genome-wide association meta-analysis for total serum bilirubin levels

[PMID 19642078] Prevalence of risk factors for statin-induced myopathy in rheumatoid arthritis patients

[PMID 19901119] Germline Genetic Variation in an Organic Anion Transporter Polypeptide Associated With Methotrexate Pharmacokinetics and Clinical Effects

[PMID 20837016] Loci from a genome-wide analysis of bilirubin levels are associated with gallstone risk and composition

[PMID 21243006] Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin

[PMID 21245207] Organic Anion Transporting Polypeptide 1B1: a Genetically Polymorphic Transporter of Major Importance for Hepatic Drug Uptake

[PMID 21630030] Frequency of the SLCO1B1 388A>G and the 521T>C polymorphism in Tanzania genotyped by a new LightCycler®-based method

[PMID 21851379] The effects of a SNP in SLCO1B1 on the pharmacodynamics of pravastatin

[PMID 21992719] SLCO1B1 rs4149056 polymorphism associated with statin-induced myopathy is differently distributed according to ethnicity in the Brazilian general population: Amerindians as a high risk ethnic group

[PMID 22189199] Genetic variation at the SLCO1B1 gene locus and low density lipoprotein cholesterol lowering response to pravastatin in the elderly

[PMID 22477766] Estimation of the effect of SLCO1B1 polymorphisms on lopinavir plasma concentration in HIV-infected adults