Genetic variation in the proximal promoter of ABC and SLC superfamilies: liver and kidney specific expression and promoter activity predict variation.
Membrane transporters play crucial roles in the cellular uptake and efflux of an array of small molecules including nutrients, environmental toxins, and many clinically used drugs. We hypothesized that common genetic variation in the proximal promoter regions of transporter genes contribute to observed variation in drug response. A total of 579 polymorphisms were identified in the proximal promoters (-250 to +50 bp) and flanking 5' sequence of 107 transporters in the ATP Binding Cassette (ABC) and Solute Carrier (SLC) superfamilies in 272 DNA samples from ethnically diverse populations. Many transporter promoters contained multiple common polymorphisms. Using a sliding window analysis, we observed that, on average, nucleotide diversity (pi) was lowest at approximately 300 bp upstream of the transcription start site, suggesting that this region may harbor important functional elements. The proximal promoters of transporters that were highly expressed in the liver had greater nucleotide diversity than those that were highly expressed in the kidney consistent with greater negative selective pressure on the promoters of kidney transporters. Twenty-one promoters were evaluated for activity using reporter assays. Greater nucleotide diversity was observed in promoters with strong activity compared to promoters with weak activity, suggesting that weak promoters are under more negative selective pressure than promoters with high activity. Collectively, these results suggest that the proximal promoter region of membrane transporters is rich in variation and that variants in these regions may play a role in interindividual variation in drug disposition and response.
Hesselson
Stephanie E
SE
Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, United States of America.
Matsson
Pär
P
Shima
James E
JE
Fukushima
Hisayo
H
Yee
Sook Wah
SW
Kobayashi
Yuya
Y
Gow
Jason M
JM
Ha
Connie
C
Ma
Benjamin
B
Poon
Annie
A
Johns
Susan J
SJ
Stryke
Doug
D
Castro
Richard A
RA
Tahara
Harunobu
H
Choi
Ji Ha
JH
Chen
Ligong
L
Picard
Nicolas
N
Sjödin
Elin
E
Roelofs
Maarke J E
MJ
Ferrin
Thomas E
TE
Myers
Richard
R
Kroetz
Deanna L
DL
Kwok
Pui-Yan
PY
Giacomini
Kathleen M
KM
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D005810:Multigene Family; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic
D018528:ATP-Binding Cassette Transporters; D002352:Carrier Proteins