Functional consequences of genetic variations in the human organic anion transporting polypeptide 1B3 (OATP1B3) in the Korean population

The objectives of this study were to investigate the allele frequencies and linkage disequilibrium (LD) in the organic anion transporting polypeptide 1B3 (OATP1B3) in the Korean population and to examine the functional consequences. Using samples from 48 Koreans, direct sequencing was carried out to determine the allele frequencies and LD of OATP1B3 in a representative Korean population. Thirty-six genetic variations in the transporter were found in Koreans; among them, five undocumented variations (i.e.,−6436G>C in the 5′-upstream region, 26A>C and 586A>G in the protein coding region, and IVS6-72A>T and IVS12-80A>T in intron regions) were identified. In the upstream region, −5035G>A was found to have lowered gene expression, as determined by a reporter gene assay, suggesting that this variation reduces the expression of OATP1B3 in humans. The functional relevance of the genetic variations in the protein coding region was determined by an uptake study involving representative substrates in human embryonic kidney 293 cells expressing wild type or variant forms. Variations involving 699G>A showed a reduced uptake activity for testosterone, but not for estradiol 17β- d -glucuronide or methotrexate, indicating that the functional impact of the variations is substrate specific. Considering the kinetic relevance of OATP1B3, the functionally affected variations may be therapeutically important.