Biomedical Engineering Reference
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also failed to reproduce the correlation between
ABCB1
3435 genotype and refrac-
tory epilepsy,
131
,
151
although another study demonstrated an association between the
ABCB1
1236C/2677G/3435C haplotype and increased pharmacoresistance in patients
with temporal lobe epilepsy.
152
The conflicting data in the field speak to the lack of
knowledge about the causal mechanism of refractory epilepsy, although it is likely
that transporters play a role.
ABCB1
genetic variability has also recently been considered in Parkinson's dis-
ease, another debilitating neurological disorder. Because it has been shown that Pgp
located on the blood-brain barrier limits the brain's exposure to xenobiotics in both
mice
153
,
154
and humans,
155
it was hypothesized that the level of Pgp expression and/or
function at the blood-brain barrier modulates the amount of neurotoxic agents that
enters the brain and therefore susceptibility to neurological disorders. A small pilot
study examined the effect of the
ABCB1
2677G
T haplotype on patient
age at the onset of Parkinson's disease. Although there was no statistically significant
association between
ABCB1
genotype and Parkinson's disease, the frequency of the
2677T/3435T haplotype was highest in the patient group with early-onset Parkin-
son's disease (36%), second highest in the group with late-onset Parkinson's disease
(23%), and lowest in the control group (19%).
156
This haplotype has previously
been linked with decreased Pgp expression,
8
,
148
,
149
providing a plausible hypothe-
sis for the association with earlier development of Parkinson's disease: lower Pgp
expression at the blood-brain barrier leads to higher brain exposure to neurotoxic
xenobiotics, thus increasing susceptibility to Parkinson's. The trends in this study
have been reproduced,
157
suggesting that
ABCB1
genotype may be a risk factor for
the development of Parkinson's disease.
The connection between Pgp function and Parkinson's disease is still being es-
tablished, but
ABCB1
is a logical candidate gene for this disease, given that the
passage of neurotoxic xenobiotics across the blood-brain barrier is likely controlled
to some degree by membrane transporters. At times, however, xenobiotic membrane
transporters are not obvious candidate genes, and the association between transporter
pharmacogenetics and clinical phenotype is somewhat surprising. For example, ul-
cerative colitis is a disorder attributed to an abnormal immune response to bacteria in
the digestive tract.
158
mdr1a
knockout mice were reported to be susceptible to a form
of colitis similar to ulcerative colitis,
159
>
T/3435C
>
prompting an investigation into the effect
of the
ABCB1
3435C
T polymorphism on predisposition to ulcerative colitis. Be-
cause the 3435T allele has been associated with lower Pgp expression,
8
,
148
,
149
it was
hypothesized that
ABCB1
3435T carriers were predisposed to ulcerative colitis. In a
study with 149 patients with ulcerative colitis and 998 controls, the 3435TT genotype
was associated significantly with ulcerative colitis, suggesting a previously uncharac-
terized antibacterial role for Pgp.
160
This association was replicated in a recent study
in which the 3435T allele was correlated with susceptibility to late-onset ulcerative
colitis.
161
However, this genotype-phenotype relationship was not replicated in two
other studies;
162
,
163
subsequently, questions were raised about how the composition
of patient and control populations can affect the reproducibility of clinical findings.
Through SNP discovery efforts, polymorphisms in other ABC transporter genes
have been identified, and several have been singled out as causing altered transport
>
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