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than infants with the L/S or L/L genotypes. 89 The
5-HTT LPR was also strongly associated with childhood
aggression. 90 Homozygosity for the short variant
of the 5-HTT LPR polymorphism was shown to be significantly
more frequent in bipolar patients than in
controls. 73 Courtet and associates 74 reported a significant
association between the 5-HTT LPR S/S genotype
and further suicide attempts among patients who had
previously attempted suicide. The S allele was also
more likely to have higher symptom counts for aggressivity,
attention deficit, and conduct disorders in males.
However, among females, the short variant (S/S, L/S)
was associated with lower levels of such behavior. 91
The S variant has been shown in vitro to be less transcriptionally
active than the L allele, resulting in decreased
5-HTT expression and uptake, 92 and a poorer response
to SSRI therapy in Caucasian subjects with mood
disorders. 93,94
The 5-HTT VNTR-2 polymorphism comprises 9,
10, or 12 copies of a 17 base pair repeat element in
intron 2. 95 This polymorphism has been suggested to
regulate transcriptional activity of the 5-HTT gene, and
the 12-repeat allele has been associated with increased
5-HTT expression, compared with the 9- and 10-repeat
variants. 95,96 Using an ethnically homogeneous sample
of highly aggressive Caucasian children and their
matched controls, Beitchman and colleagues 97 reported
an association of this polymorphism with aggression. It
has also been suggested that 5-HTT VNTR-2 influences
age of onset in patients with bipolar affective disorder. 72
Moreover, a recent meta-analysis of 12 populationbased
association studies consisting of 2177 cases and
2369 control subjects showed a highly significant association
between the 5-HTT VNTR-2 polymorphism
and schizophrenia. 98 The 3�UTR G/T is an SNP located
in a putative polyadenylation site of the 3'untranslated
region of the 5-HTT gene. 99 This polymorphism has
been linked with bipolar and attention deficit hyperactivity
disorders. 100,101
To date, studies of these three 5-HTT polymorphisms
in PMDD have found no significant differences
in genotype distribution between healthy controls and
PMDD subjects in any of the markers. 102,103
Monoamine oxidase A
MAOA is a mitochondrial enzyme that catalyzes the
oxidative deamination of neurotransmitters such as
dopamine, norepinephrine, and serotonin. Increased
MAOA activity might feasibly be expected to contribute
to the pathogenesis of conditions associated with reduced
serotonergic neurotransmission, such as PMDD. Several
different polymorphisms in the MAOA gene have been
identified: of these, the VNTR-1 and the Fnu 4H1
GENETICS 165
RFLP are of particular interest. Transcriptional activity
of the human MAOA gene is modulated by the VNTR-
1 polymorphism. Based on functional characterization,
alleles with 3.5 or 4 copies of the repeat sequence are
transcribed 2–10 times more efficiently than those with
3 or 5 copies of the repeat. 104,105 The presence of an
Fnu 4H1 restriction site in exon 8 (the G allele) has
been associated with a high MAOA activity in healthy
individuals. 106 MAOA gene polymorphisms have been
linked to the pathogenesis of major depression, associated
with insomnia in depressed individuals, attention
deficit hyperactivity disorder, alcoholism and binge
drinking. 106–109
Our collaborative group has recently studied the
association between the VNTR-1 and Fnu 4H1 polymorphisms
and PMDD. 103 We found no significant distribution
pattern associated with the high-activity
alleles 3.5 and 4, or the lower-activity alleles 4 and 5 in
the VNTR-1 in our cases and controls. Although the
G/T genotype in the Fnu 4H1 RFLP was more common
in the PMDD group than in the controls, this difference
was not statistically significant, and the overall frequency
of the G and T alleles was similar in both
cohorts. 103
Serotonin receptors
Over the past decade, more than 14 different serotonin
receptors have been cloned through molecular biological
techniques. There are seven classes of serotonin
receptors. Some of these are divided into several
subclasses based on structural and operational characteristics
(e.g. 5HT 1A , 5HT 1B , 5HT 1D , 5HT 1E , 5HT 1F ,
5HT 2A , 5HT 2B , and 5HT 2C ).
The proposed mechanisms by which gonadal hormones
influence neurotransmitters, in general, and
serotonin, in particular, are not only achieved by affecting
their rate of production and catabolism but also by
modulating their individual receptor’s function and
responsivity. For example, it has been shown that estrogen
increases serotonin (5-HT) postsynaptic responsivity,
up-regulates 5-HT 1 receptors, and down-regulates
5-HT 2 receptors. 110,111 Research investigating vulnerability
to anxiety and irritability indicated that agonists
of 5-HT 1A receptor and antagonists of the activating
5-HT 2 receptor decrease anxiety. 112–114 Moreover, the
5-HT 1A receptor is expressed as a postsynaptic receptor,
in addition to being the major presynaptic autoreceptor
on serotonergic raphe neurons. 114 The electrophysiological
activity of serotonergic neurons is regulated,
at least in part, through a negative feedback mechanism
triggered by the stimulation of presynaptic
5-HT 1A autoreceptors. This receptor activity has also
been linked to responsiveness to SSRI therapy in some