COMT Val158Met Polymorphism, Executive Dysfunction, and Sexual Risk Behavior in the Context of HIV Infection and Methamphetamine Dependence.

Abstract

Catechol-O-methyltransferease (COMT) metabolizes prefrontal cortex dopamine (DA), a neurotransmitter involved in executive behavior; the Val158Met genotype has been linked to executive dysfunction, which might increase sexual risk behaviors favoring HIV transmission. Main and interaction effects of COMT genotype and executive functioning on sexual risk behavior were examined. 192 sexually active nonmonogamous men completed a sexual behavior questionnaire, executive functioning tests, and were genotyped using blood-derived DNA. Main effects for executive dysfunction but not COMT on number of sexual partners were observed. A COMT x executive dysfunction interaction was found for number of sexual partners and insertive anal sex, significant for carriers of the Met/Met and to a lesser extent Val/Met genotypes but not Val/Val carriers. In the context of HIV and methamphetamine dependence, dopaminergic overactivity in prefrontal cortex conferred by the Met/Met genotype appears to result in a liability for executive dysfunction and potentially associated risky sexual behavior.

Full text

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Hindawi Publishing Corporation
Interdisciplinary Perspectives on Infectious Diseases
Volume 2010, Article ID 678648, 9 pages
doi:10.1155/2010/678648
Research Article
COMT Val158Met Polymorphism,ExecutiveDysfunction,
andSexual RiskBehavior intheContext of HIVInfectionand
MethamphetamineDependence
C.A.Bousman,1,2M.Cherner,1J. H.Atkinson,1R.K.Heaton,1I.Grant,1
I.P.Everall,1and The HNRC Group3,4
1Department of Psychiatry, University of California San Diego, La Jolla, CA 92103, USA
2San Diego Joint Doctoral Program in Public Health (Health Behavior), San Diego State/University of California, CA 92182, USA
3The Naval Hospital, University of California, San Diego, CA 92055, USA
4The Veterans Affairs San Diego Healthcare System, CA 92161, USA
Correspondence should be addressed to C. A. Bousman, cbousman@ucsd.edu
Received 18 August 2009; Accepted 10 October 2009
Academic Editor: Marylou V. Solbrig
Copyright © 2010 C. A. Bousman et al.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Catechol-O-methyltransferease (COMT) metabolizes prefrontal cortex dopamine (DA), a neurotransmitter involved in executive
behavior; the Val158Met genotype has been linked to executive dysfunction, which might increase sexual risk behaviors favoring
HIV transmission. Main and interaction effects of COMT genotype and executive functioning on sexual risk behavior were
examined. 192 sexually active nonmonogamous men completed a sexual behavior questionnaire, executive functioning tests, and
were genotyped using blood-derived DNA. Main effects for executive dysfunction but not COMT on number of sexual partners
were observed. A COMT x executive dysfunction interaction was found for number of sexual partners and insertive anal sex,
significant for carriers of the Met/Met and to a lesser extent Val/Met genotypes but not Val/Val carriers. In the context of HIV
and methamphetamine dependence, dopaminergic overactivity in prefrontal cortex conferred by the Met/Met genotype appears
to result in a liability for executive dysfunction and potentially associated risky sexual behavior.
1.Introduction
HIV infection is a global pandemic and the population
is growing due to successful treatment with highly active
antiretroviral therapy (HAART) [1]. Although rates of HIV
have been reduced in the United States among most groups
as a result of successful public health efforts (e.g., condom
accessibility, education programs, media campaigns), sexual
risk behavior and subsequent acquisition and/or spread of
HIV and other sexually transmitted infections are still of
concern among men who have sex with men as well as
drug using populations [1]. Thus, it is evident that, despite
research and efforts to understand and curb sexual risk
behavior within these vulnerable populations, additional
work employing novel approaches are needed.
Sexual risk behaviors can be viewed as a composite of
numerous behaviors that collectively make-up a complex
behavioral phenotype. As with most complex phenotypes,
sexual risk behavior is heterogeneous and several factors
contribute to the variance that can be observed from one
individual to another. To date, a majority of work examining
risk factors for sexual risk behavior phenotypes have primar-
ily focused on psychosocial factors (reviewed in [2]) and/or
other complex/heterogeneous behavioral phenotypes such
as substance use behaviors [3, 4] as indicators for current
or future sexual risk behavior. Ultimately these indicators,
upon sufficient replication, become candidates for public
health interventions that aim to prevent and reduce sexual
risk behaviors. However, the trouble with many of these
candidates is that they are too proximal to sexual risk behav-
iors and often cooccur, making it difficult to disentangle
temporal precedence and ultimately limit prevention efforts.
One relatively novel approach is to examine intermediate
phenotypes or endophenotypes [5] such as neurocognitive

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2Interdisciplinary Perspectives on Infectious Diseases
factors as well as biological (i.e., genetic) factors. These
factors are more distal to the onset of sexual risk behavior
and thus are potentially more advantageous candidates for
identifying vulnerable individuals and informing prevention
efforts for sexual risk behavior.
Studies in literature examining neurocognitive and bio-
logical factors as indicators for sexual risk behaviors are
limited. In fact, only two studies to date have examined
neurocognitive factors [6, 7] and none to our knowledge
have examined biological factors as potential indicators.
Although this paucity of research is surprising given
previous work linking both neurocognitive [8–10] and
genetic [11–13] indicators to other health related behaviors,
research has established the dopminergic system as a com-
mon link between neurocognitive functioning and sexual
behavior.
The dopminergic system has been shown to be involved
in sexual arousal, motivation and the subsequent rewarding
effect of sexual behavior (for detailed review see [14]).
Furthermore, DA in the human brain, specifically in the
prefrontal cortex (PFC), has been shown to be necessary
for proper cognitive functioning to occur and high or low
levels of DA in this brain region are known to contribute to
individual cognitive differences in humans [15, 16]. The PFC
is of particular importance when examining risk behavior in
that executive functions such as decision-making, planning,
self-monitoring as well as behavior initiation, organization,
and inhibition are largely dependent on PFC integrity
[17]. Impairment in executive functioning may result in
difficulties in assessing relationships between a person’s
current behavior and future outcomes; thereby resulting
in choices and/or responses on the premise of immediate
rewards (e.g., pleasure, social acceptance) versus long-
term consequences (e.g., viral infections) and an ultimate
potentialincreaseinthelikelihoodforparticipationinsexual
risk behaviors (e.g., unprotected sex, multiple partners)
[7, 18]. Thus, mechanisms responsible for maintaining a
dopaminebalancewithinthebrainandinparticularthePFC
would appear to be good biological candidates for further
exploration of an association between executive dysfunction
and sexual risk behavior.
One such candidate is catechol-O-methyltransferease
(COMT) which is a mammalian enzyme involved in the
metabolic degradation of released dopamine, particularly
in the PFC [19]. Of particular interest to this study is a
common polymorphism involving a Val to Met substitution
at codon 158. The Val allele of the COMT Val158Met
polymorphism is 40% more enzymatically active than the
Met allele [20]. Thus, carriers of the Met allele metabolize
dopamine at a less efficient rate, resulting in higher levels
of dopamine in the synapse and ultimately an escalation
in dopamine receptor activation. This differentiation of
dopamine receptor activity dependent on COMT genotype
has led to several investigations into the relationship between
COMT and executive dysfunction in which the Val allele
has been putatively linked to poor performance on executive
functioning tasks [21]. However, to our knowledge no work
has examined the relationship between COMT and sexual
risk behavior; albeit studies of similar behaviors such as
novelty seeking [22–24], reward dependence [22], as well
as affective arousal and regulation [25] have demonstrated
significant relationships.
Given the aforementioned paucity of research in the
current literature addressing the contribution of genetic
and neurocognitive factors on sexual risk behavior, the
primary aim of this study was to examine the main effects
of executive functioning as well as the main effects of the
COMT Val158Met polymorphism on sexual risk behavior
among a ethnically diverse population of men with and
without METH dependence and/or HIV infection. Within
this aim, we hypothesized that the highly active COMT
Val/Valgenotypeanditsputativelyassociateddeficitsinexec-
utive functioning would be independently associated with
sexual risk behaviors. In addition, as a result of previously
mentioned research that has demonstrated an association
between COMT genotype and executive functioning we also
explored the potential interaction effects of COMT and
executive dysfunction on sexual risk behavior.
2.Methods
2.1. Participants. Participants were volunteers evaluated at
the HIV Neurobehavioral Research Center (HNRC) at
the University of California in San Diego as part of a
cohort study focused on central nervous system effects
of HIV and methamphetamine. The current study com-
prised 192 sexually active non-monogamous men with
and without methamphetamine dependence (METH+/−)
and/or HIV infection (HIV+/−). Men were classified as non-
monogamous if they stated they had “no current partner”
at time of assessment. Monogamous men were excluded
because unsafe sexual behavior within a monogamous rela-
tionship is less risky than in non-monogamous relationships
[26].
All participants underwent a comprehensive characteri-
zation procedure that included collection of demographic,
neuromedical, psychiatric as well as neuropsychiatric infor-
mation. HIV serological status was determined by enzyme
linked immunosorbent assays (ELISA) plus a confirma-
tory test. Lifetime METH dependence was determined by
the Structured Clinical Interview for the Diagnostic and
Statistical Manual of Mental Disorders Version IV (SCID-
IV). However, participants were not actively using other
substances, with the exception of cannabis and alcohol.
Potential participants were excluded if they met lifetime
dependence criteria for other drugs, unless the dependence
wasjudgedtoberemote(morethan5yearsago)andepisodic
in nature by a doctoral level clinician. Alcohol dependence
within the last year was also an exclusion criterion. All
participants were seronegative for hepatitis C infection.
Additionalinformationforeachparticipantwascollected
as it relates to current depressed mood as well as lifetime
diagnosis of Major Depression Disorder (MDD) and/or
Bipolar Disorder I or II. Current depressed mood was
assessed utilizing the Beck Depression Inventory-I (BDI-I)
[27] and MDD and Bipolar Disorder were ascertained using
the SCID-IV. Information was also collected to determine
lifetime dependence on sedatives, cannabis, opioids, cocaine,

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Interdisciplinary Perspectives on Infectious Diseases3
hallucinogens, and alcohol, using the SCID-IV. For METH+
participants, additional information was collected regarding
age at first use, years of use, and days since last use of METH;
whereas for HIV+ participants, HIV RNA plasma copies
was ascertained as part of a larger neuromedical evaluation.
All participants gave written consent prior to enrollment
and all procedures were approved by the Human Research
Protection Program of the University of California, San
Diego and San Diego State University.
2.2. Executive Functioning. Executive functioning was deter-
mined as part of a larger comprehensive battery of tests
covering seven ability domains (Learning, Memory, Atten-
tion/Working Memory, Verbal Fluency, Processing Speed,
Abstraction/Problem Solving, and Motor Speed). The exec-
utive functioning domain deficit score, of particular focus
in this study, was made up of (1) perseverative responses
on the Wisconsin Card Sorting Test [28]; (2) errors on the
Halstead Category Test [29], which measures abstraction
and cognitive flexibility; and (3) time to complete the Trail
Making Test part B (Trails B) [30], reflecting ability to
switch and maintain attention between ongoing sequences.
Raw scores for each of these component tests were con-
verted to demographically-adjusted T-scores (M
SD=10), including adjustments for age, education, gender,
and ethnicity as available for each test. The demographically-
adjusted T-scores for each test were then converted into
deficit scores, which reflect degree of impairment by setting
performances within the normal range at zero with a range
from 0 (T-score > 39; no impairment) to 5 (T-score <
20; severe impairment). Finally, the individual deficit scores
were averaged to derive the domain deficit score, which
reflects the severity of executive functioning deficit. Previous
work has demonstrated that deficit scores achieve good
diagnostic agreement with classifications made by blind
clinical ratings [31, 32]. All neurocognitive testing and
scoring was performed by trained psychometrists blinded to
participants’ genotypes.
= 50,
2.3. Sexual Risk Behavior. Sexual risk behavior was assessed
through an HNRC-developed self-report measure covering
the preceding year. Information was gathered with regard
to age at first intercourse as well as number of different
sex partners. Age at time of first intercourse was coded in
years for both male and female partners. However, when two
different ages were given for first intercourse, the younger of
the two ages was used. In addition, participants were asked
to indicate the percentage of time that they used a condom as
well as engaged in oral, vaginal, anal (receptive & insertive)
and/or intoxicated sex. Responses were recorded on a 6-
item, Likert-type scale with a value of 0=0%, 1=1%–5%,
2=6%–25%, 3=26%–50%, 4=51%–75% and 5=76%–
100%.
2.4. DNA Extraction and Genotyping. DNA was extracted
fromperipheralbloodmononuclearcellsstored(threetofive
years) at −70◦C using the QIAamp DNA Mini kit (Qiagen,
Valencia, CA; Catalog #51185). The COMT Val158Met
polymorphism (rs4680) was assayed along with eight other
SNPs as part of a concurrent genetic association project
at the HNRC. A multiplex PCR technique designed using
SequenomSpectroDESIGNERsoftware(version3.0.0.3) was
employed by inputting a sequence containing 100bp of
flanking sequence on either side of the COMT Val158Met
polymorphism. The SNP was then grouped into multiplexes
so that the extended product would not overlap in mass
with any other oligonucleotide present in the reaction mix,
and where no primer-primer, primer-product, or non-
specific interactions would occur. The PCR was carried
out in 384-well reaction plates in a volume of 5μl using
10ng genomic or whole-genome amplified (WGA) DNA. All
subsequent steps, up until the reaction, were spotted onto
the SpectroCHIP and carried out in the same reaction plate.
After PCR, any unincorporated dNTPs from the PCR were
removedfromthereactionbydigestionwithShrimpalkaline
phosphatase. dNTPs were removed so that they could not
play any role in the extension of the oligonucleotide at the
SNP site. The extension reaction was then carried out in the
presence of the extension oligonucleotide and a termination
mix containing mass-modified dideoxynucleotides which
extended the oligonucleotide over the SNP site with one
base. Before spotting onto the SpectroCHIP, the reaction
was cleaned by incubation with a cation-exchange resin
which removed any salts present. The extension product
was then spotted onto a 384-well spectroCHIP before
being flown in the MALDI-TOF mass spectrometer. Data
were collected, in real time, using SpectroTYPER Ana-
lyzer 3.3.0.15, SpectraAQUIRE 3.3.1.1 and SpectroCALLER
3.3.0.14 (Sequenom) algorithms. All genotyping was per-
formed by an accredited commercial laboratory (Harvard
Medical School-Partners Healthcare Center for Genetics and
Genomics, Cambridge, MA CLIA no. 22D1005307).
2.5. Statistical Analysis. All statistical tests and procedures
were conducted using SPSS 10.0 (SPSS, 2000). Univariate
comparisons across the three COMT genotypes (i.e., Val/Val,
Val/Met, Met/Met) were performed using one-way analysis
of variance (ANOVA) for continuous and chi-squared tests
for categorical variables. In cases, where data violated
normality assumptions medians were calculated and non-
parametrictests(i.e.,Kruskal-Wallis)performed.Toexamine
the main and explore the interaction effects of executive
functioning and COMT on sexual risk behaviors, hierarchi-
cal multiple linear regressions in accord with Barron and
Kenny’s approach [33] were conducted for each of the seven
sexual risk behaviors (see Section 2.3) under study. Prior
to running each analysis, the executive functioning variable
was centered and the COMT genotype contrast coded to
reduce problems resulting from multicollinearity (Kraemer
andBlasey,2004).Inaddition,interactiontermswerecreated
by multiplying COMT genotype by the centered executive
functioning variable. Next, multiple linear regressions were
used to examine potential confounders based on univariate
genotype comparisons described above. These confounders
included: ethnicity, METH status, HIV status and age at first
intercourse. We also included BDI scores based on inclusion
of this measure in recent work testing a similar hypothesis

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4Interdisciplinary Perspectives on Infectious Diseases
[7].ResultsshowedthatMETHstatus,HIVstatus,andageat
first intercourse accounted for a significant unique variance
for all sexual behaviors under investigation (R2range:
0.06–0.39, Ps < .02). Thus to control for these potential
confounding effects, the residuals derived from each of
the sexual behavior models were used as the dependent
variables for all subsequent regression models. The centered
executive functioning variable and COMT genotype as well
as the new interaction term were then entered as indepen-
dent variables into seven individual hierarchical multiple
regression models using the residuals described above as
the dependent variable. For models in which a significant
interaction was observed, a final round of regressions were
conducted stratified by COMT genotype to determine the
nature of the interaction between executive functioning and
COMT on the particular sexual risk behavior. Due to the
exploratory nature of the interaction analysiswe selected a
relaxed alpha threshold alpha < .10 to reduce Type II errors,
albeit the traditional alpha threshold of .05 was used for all
other analyses.
3.Results
3.1. Participant Characteristics. Characteristics of the full
sample by each of the three COMT genotypes are summa-
rized in Table 1. All three genotype groups were comparable
in age, education, sexual behavior, executive functioning,
as well as psychiatric and substance dependence histories.
However, Val/Val carriers were significantly more likely to
identify as African-American (χ2= 17.67, P =.001), report
an earlier age of first intercourse (F(2,189) = 3.51, P =.032),
and be seropositive for HIV (χ2= 6.57, P =.038). Whereas,
Met-carriers (i.e., Met/Met or Val/Met) were significantly
more likely to identify as Caucasian (χ2= 14.32, P =.001).
Additionally, among METH+ participants Val/Val carriers
reported significantly greater total years of METH use
(F(2,87) =3.12, P = .050) compared to their Met-carrying
counterparts.
3.2. Main Effects of Executive Functioning and COMT.
Table 2 provides standardized multiple linear regression
coefficient estimates for main and interaction effects of
executive functioning and COMT genotype for each of
the seven sexual risk behaviors adjusting for METH status,
HIV status, and age at first intercourse. A significant
main effect for the executive functioning domain deficit
score was observed for number of partners (β
P =.005). Additionally, results from the individual executive
functioning tests showed a significant main effect for T-
scores on the Wisconsin Card Sort and Halstead Category
tests in adjusted models of oral sex (β =0.20, P =.009)
and condom use (β = −0.16, P =.030), respectively. Main
effects were not observed for COMT genotype in any of the
regression models.
=0.21,
3.3. Interaction Effects of Executive Functioning and COMT.
Applying an exploratory cut-off of P < .10, significant
interactions between the executive functioning domain
deficit score and COMT were observed for number of sexual
partners (β = 0.50, P = .038), insertive anal sex (β = 0.50,
P = .046), and receptive anal sex (β = 0.50, P = .081)
(Table 2). Subsequent stratified analysis by COMT genotype,
revealed that among carriers of the Met/Met (β = 0.52,
P = .001) and to a lesser extent Val/Met (β = 0.20, P = .048)
genotype, increases in the executive functioning domain
deficit score was significantly associated with increases in the
number of sexual partners in the past 12 months. Stratified
analysis for insertive and receptive anal sex revealed similar
results. Among Met/Met and Val/Met carriers, an increase
in executive deficit scores were associated with an increased
frequency of insertive (Met/Met: β = 0.18; Val/Met: β =
0.11) and receptive (Met/Met: β = 0.13; Val/Met: β =
0.11) anal sex in the past 12 months, albeit not statistically
significant.
Results of regression analyses to examine interactions
between each of the three individual executive functioning
tests and COMT genotype are also shown in Table 2. For
the Wisconsin Card Sort Test no interactions were observed.
However, for Trails B, significant interactions with COMT
were observed for insertive (β = −0.99, P = .015) and
receptive (β = −0.75, P = .066) anal sex, as well as oral
sex (β = −0.68, P = .096). Stratified regression analysis
showed that among carriers of the Met/Met genotype, poor
performance on Trails B (i.e., low T-scores) was significantly
associated with an increased frequency of insertive (β =
−0.38, P = .028) but not receptive (β = −0.22, P =
.225) anal sex. Interestingly, among carriers of the Val/Val
genotype, T-scores on Trails B had a significant positive
association with oral sex (β = 0.35, P = .013). Finally, for
the Halstead Category Test, a single interaction with COMT
was observed for condom use (β = −1.13, P = .006). Among
carriers of the Met/Met (β = −0.49, P = .004) and to
a lesser extent Val/Met (β = −0.19, P = .064) genotype,
Halstead Category Test T-scores were negatively associated
with condom use.
4.Discussion
To our knowledge this study is the first to examine main
effects as well as explore the interaction effects of COMT
genotype and executive functioning on sexual risk behavior.
Our main findings suggest significant executive dysfunction
main effects for number of sexual partners as well as
frequency of oral sex and condom use. In addition, results
of our exploratory interaction analyses provide evidence
that COMT genotype and executive dysfunction interact in
models of number of sexual partners, condom use, insertive
and receptive anal sex, as well as oral sex. Stratified analyses
further suggest that the strength of these associations is
dependent on the number of Met alleles the individual was
carrying, with the exception of oral sex in which Val/Val was
the informative genotype.
Our significant executive dysfunction main effects for
sexual risk behaviors are discordant with the only other
study, to our knowledge, that has examined the association
between executive dysfunction and sexual risk behavior [7].
In that study, no association was found between executive

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Interdisciplinary Perspectives on Infectious Diseases5
Table 1: Characteristics of full sample by COMT genotype.
COMT genotype
Val/Met
(n =103)
38 (9)
13 (2)
100 (12)
Full sample
(n =192)
37 (9)
13 (2)
100 (12)
Val/Val
(n =54)
35 (9)
13 (2)
99 (11)
Met/Met
(n =35)
39 (11)
14 (2)
104 (11)
Age (years) M (sd)
Education (years) M (sd)
WRAT4 M (sd)
Ethnicity (row %)
Caucasian
African-American
Hispanic
71
15
14
52
32
17
78
7
16
83
11
6
v/v < v/m, m/m∗∗
v/v > v/m, m/m∗∗
Executive Functioning Battery
Wisconsin card sort test T (sd)
Trials part B T (sd)
Halstead category Test T (sd)
Domain deficit score M (sd)
Executive impairment (%)
45 (14)
49 (11)
46 (10)
.55 (.69)
45
47 (16)
51 (12)
47 (10)
.56 (.68)
46
44 (13)
47 (10)
44 (10)
.62 (.74)
50
46 (13)
52 (11)
47 (9)
.35 (.47)
31
Sexual Characteristics/Behavior
Age at first intercourse M (sd)
Sexual preference (% heterosexual)
Number partners in past 12mo Median (IQR)
Condom use (>0% in past 12mo)
Insertive anal (>0% in past 12mo)
Receptive anal (>0% in past 12mo)
Oral sex (>0% in past 12mo)
Intoxicated sex (>0% in past 12mo)
Vaginal sex (>0% in past 12mo)
15 (4)
33
3 (1,10)
72
62
58
93
64
37
14 (4)
35
4 (1, 11)
74
60
60
94
63
35
16 (4)
31
3 (1, 10)
71
67
62
93
66
35
17 (4)
38
2 (1, 5)
70
52
46
94
61
44
v/v < m/m∗
DSM-IV Psychiatric Disorder (% lifetime)
Major depression
Bipolar I or II
Beck depression inventory M (sd)
36
4
36
8
35
3
40
3
12 (9) 11 (8)13 (10)10 (9)
DSM-IV Substance Dependence (% lifetime)
Sedative
Cannabis
Opioid
Cocaine
Hallucinogen
Alcohol
0
9
0
7
0
17
0
9
0
7
0
15
00
6
0
14
0
14
11
0
5
0
20
Methamphetamine Parameters
Methamphetamine dependent (%)
Age at first METH use, yrs M (sd)
Total METH use, yrs M (sd)
Last use of METH, days Median (IQR)
47 375249
24 (9)
11 (6)
91 (36, 274)
23 (9)
13 (7)
25 (8)
11 (6)
91 (32, 236)
27 (10)
8 (4)
91 (30, 244)
v/v > m/m∗
122 (45, 731)
HIV Parameters
HIV seropositive (%)
HIV RNA, plasma (log copies/mL) M (sd)
56705149v/v > v/m, m/m∗
2.1 (1.9) 2.4 (1.7)2.0 (2.0)1.7 (1.9)