Identification and functional characterization of genetic variants of human organic cation transporters in a Korean population.
Genetic variants of three human organic cation transporter genes (hOCTs) were extensively explored in a Korean population. The functional changes of hOCT2 variants were evaluated in vitro, and those genetic polymorphisms of hOCTs were compared among different ethnic populations. From direct DNA sequencing, 7 of 13 coding variants were nonsynonymous single-nucleotide polymorphisms (SNPs), including four variants from hOCT1 (F160L, P283L, P341L, and M408V) and three from hOCT2 (T199I, T201M, and A270S), whereas 6 were synonymous SNPs. The linkage disequilibrium analysis presented for three independent LD blocks for each hOCT gene showed no significant linkage among all three hOCT genes. The transporter activities of MDCK cells that overexpress the hOCT2-T199I, -T201M, and -A270S variants showed significantly decreased uptake of [(3)H]methyl-4-phenylpyridinium acetate (MPP(+)) or [(14)C]tetraethylammonium compared with those cells that overexpress wild-type hOCT2, and the estimated kinetic parameters of these variants for [(3)H]MPP(+) uptake in oocytes showed a 2- to 5-fold increase in K(m) values and a 10- to 20-fold decrease in V(max) values. The allele frequencies of the five functional variants hOCT1-P283L, -P341L, and hOCT2-T199I, -T201M, and -A270S were 1.3, 17, 0.7, 0.7, and 11%, respectively, in a Korean population; the frequency distributions of these variants were not significantly different from those of Chinese and Vietnamese populations. These findings suggest that genetic variants of hOCTs are not linked among three genes in a Korean population, and several of the hOCT genetic variants cause decreased transport activity in vitro compared with the wild type, although the clinical relevance of these variants remains to be evaluated.
Kang
Ho-Jin
HJ
Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, 633-165 Gaegum 2-Dong, Jin-Gu, Busan 614-735, Korea.
Song
Im-Sook
IS
Shin
Ho Jung
HJ
Kim
Woo-Young
WY
Lee
Choong-Hee
CH
Shim
Joo-Cheol
JC
Zhou
Hong-Hao
HH
Lee
Sang Seop
SS
Shin
Jae-Gook
JG
D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D000818:Animals; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D002681:China; D004285:Dogs; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007700:Kinetics; D007723:Korea; D015810:Linkage Disequilibrium; D008845:Microinjections; D008969:Molecular Sequence Data; D009865:Oocytes / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D019789:Tetraethylammonium / Q000378:metabolism; D014162:Transfection; D014744:Vietnam; D014982:Xenopus laevis; D000099254:Organic Cation Transporter 3
D015655:1-Methyl-4-phenylpyridinium; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; D019789:Tetraethylammonium; D000099254:Organic Cation Transporter 3; C491013:SLC22A2 protein, human