DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

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SECTION I
GENERAL PRINCIPLES
Ethnic Diversity
Polymorphisms differ in their frequencies within human
populations (Burchard et al., 2003; Rosenberg et al., 2002,
2003). Frequencies of polymorphisms in ethnically or
racially diverse human populations have been examined in
whole genome scanning studies (Cargill et al., 1999;
Stephens et al., 2001). In these studies, polymorphisms
have been classified as either cosmopolitan or population
(or race and ethnic) specific. Cosmopolitan polymorphisms
are those polymorphisms present in all ethnic groups,
although frequencies may differ among ethnic groups.
Cosmopolitan polymorphisms are usually found at higher
allele frequencies in comparison to population-specific
polymorphisms. Likely to have arisen before migrations of
humans from Africa, cosmopolitan polymorphisms are
generally older than population-specific polymorphisms.
The presence of ethnic and race-specific polymorphisms
is consistent with geographical isolation
of human populations (Xie et al., 2001). These polymorphisms
probably arose in isolated populations and
then reached a certain frequency because they are
advantageous (positive selection) or more likely,
neutral, conferring no advantage or disadvantage to a
population. Large-scale sequence studies in ethnically
diverse populations in the U.S. demonstrate that
African Americans have the highest number of population-specific
polymorphisms in comparison to
European Americans, Mexican Americans, and Asian
Americans (Leabman et al., 2003; Stephens et al.,
2001). Africans are believed to be the oldest population
and therefore have both recently derived, population-specific
polymorphisms, and a large number of
older polymorphisms that occurred before migrations
out of Africa.
Consider the coding region variants of two membrane transporters
identified in 247 ethnically diverse DNA samples (Figure 7–6).
DAT Dopamine Transporter
Extracellular
Cytoplasm
MRP2 Multidrug Resistance Protein 2
Extracellular
Non-synonymous
Synonymous
Cytosolic
Figure 7–6. Coding region polymorphisms in two membrane transporters. Shown are the dopamine transporter, DAT (encoded by
SLC6A3) and multidrug resistance associated protein, MRP2 (encoded by ABCC2). Coding region variants were identified in 247
ethnically diverse DNA samples (100 African Americans, 100 European Americans, 30 Asians, 10 Mexicans, and 7 Pacific islanders).
Shown in blue circles are synonymous variants, and in red circles, non-synonymous variants.