Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene.
OBJECTIVE
There is increasing evidence that polymorphism of the ABCB1 (MDR1) gene contributes to interindividual variability in bioavailability and tissue distribution of P-glycoprotein substrates. The aim of the present study was to (1) identify and describe novel variants in the ABCB1 gene, (2) understand the extent of variation in ABCB1 at the population level, (3) analyze how variation in ABCB1 is structured in haplotypes, and (4) functionally characterize the effect of the most common amino acid change in P-glycoprotein.


RESULTS
Forty-eight variant sites, including 30 novel variants and 13 coding for amino acid changes, were identified in a collection of 247 ethnically diverse DNA samples. These variants comprised 64 statistically inferred haplotypes, 33 of which accounted for 92% of chromosomes analyzed. The two most common haplotypes, ABCB1*1 and ABCB1*13, differed at six sites (three intronic, two synonymous, and one non-synonymous) and were present in 36% of all chromosomes. Significant population substructure was detected at both the nucleotide and haplotype level. Linkage disequilibrium was significant across the entire ABCB1 gene, especially between the variant sites found in ABCB1*13, and recombination was inferred. The Ala893Ser change found in the common ABCB1*13 haplotype did not affect P-glycoprotein function.


CONCLUSIONS
This study represents a comprehensive analysis of ABCB1 nucleotide diversity and haplotype structure in different populations and illustrates the importance of haplotype considerations in characterizing the functional consequences of ABCB1 polymorphisms.
Kroetz
Deanna L
DL
Department of Biopharmaceutical Sciences, University of California-San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0446, USA. deanna@itsa.ucsf.edu
Pauli-Magnus
Christiane
C
Hodges
Laura M
LM
Huang
Conrad C
CC
Kawamoto
Michiko
M
Johns
Susan J
SJ
Stryke
Doug
D
Ferrin
Thomas E
TE
DeYoung
Joseph
J
Taylor
Travis
T
Carlson
Elaine J
EJ
Herskowitz
Ira
I
Giacomini
Kathleen M
KM
Clark
Andrew G
AG
D001483:Base Sequence; D002461:Cell Line, Transformed; D017931:DNA Primers; D005006:Ethnicity / Q000235:genetics; D019450:Genes, MDR; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D011995:Recombination, Genetic
D017931:DNA Primers