Epistatic interactions involving DRD2, DRD4, and COMT polymorphisms and risk of substance abuse in women with binge-purge eating disturbances

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Abstract

Substance abuse is common in individuals with bulimia-spectrum (binge-purge) eating disturbances, a co-occurrence that has been attributed to shared neurobiological substrates--notably alterations in dopaminergic activity. We examined the implications of variations of selected, dopamine-relevant polymorphisms (DRD2 Taq1A, DRD4 7R, and COMT) for risk of substance abuse in women with binge-purge eating syndromes. We genotyped 183 women (66.1% showing full-threshold BN and 33.9% showing sub-syndromic variants), and assessed lifetime presence of alcohol, cannabis, cocaine, and stimulant abuse or dependence using structured interviews. Tests for main and interaction effects of various allele combinations revealed that individuals who carried high function COMT and low-function DRD4 7R alleles (a combination expected to be associated with higher risk) did indeed show more lifetime substance abuse and, specifically, more cannabis abuse. Our findings suggest that a gene combination that, in theory, codes for low levels of dopaminergic neurotransmission coincides with sensitivity to substance abuse in a sample displaying binge-purge eating-disorder variants.

Section snippets

The present study

To date, no study has explored the association between dopaminergic gene variations and substance use in individuals with binge-purge eating syndromes. To fill this knowledge gap, we examined the bearing of variations within the DRD2 Taq1A, DRD4 7R, and COMT polymorphisms upon risk of misuse of alcohol, cannabis, cocaine and stimulants in women with bine-purge eating disorder variants. Although phenomenological differences exist, evidence has shown women with binge-purge or purge-only eating

Participants

All participants in this institutional ethics board approved study provided written informed consent and all received modest monetary compensation for time invested. Participants were recruited through a specialized eating disorders program using the criteria: Body Mass Index (BMI) above 17.5 and below 40, and meeting criteria for Bulimia Nervosa (BN) or Eating Disorder Not Otherwise Specified (EDNOS) with binge eating and/or purging according to the Diagnostic and Statistical Manual of Mental

Results

Table 1 shows genotype frequencies for DRD2, DRD4 and COMT variants. Hardy–Weinberg tests were conducted on observed genotypes and indicated genotype rates to be in equilibrium for DRD2 [χ2 (1) = 2.32, n.s.], COMT [χ2 (1) = 0.139, n.s.] and DRD4 [χ2 (1) = 5.89, n.s.]. For DRD4, we examined rates of carriers of alleles 7 or higher and of alleles 6 or lower--a dichotomization consistent with previous literature (Eisenberg et al., 2007). Table 2a, Table 2b displays percentages of use of substances

Discussion

We examined the extent to which variants of functional polymorphisms of genes acting upon dopamine function differentiated individuals with a binge-purge syndrome who did, or did not, show a lifetime history of substance abuse. Towards this end, we tested for main and interaction effects of three widely studied polymorphisms—DRD2 Taq1 rs1800497, DRD4 7R, and COMT rs4680—with outcomes being lifetime history of cannabis, alcohol, stimulant, cocaine, or “any substance” abuse. Our main findings

Contributors

Howard Steiger was Principal Investigator, responsible for the overall design and management of this project. Lea Thaler supervised data management and performed main data analyses. Ridha Joober supervised the processing of biological samples, DNA extraction and genotyping. Lise Gauvin was statistical and design consultant, and oversaw all aspects of the final data analysis. Mimi Israel contributed to the design of the study and supervised diagnostic interviews. Audrey Kucer was a student who

Role of the funding source

This research was supported by grants awarded to Dr. Steiger and colleagues (nos. MOP-79490 and MOP-57929) from the Canadian Institutes for Health Research. The funding agency had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report, or in the decision to submit the paper for publication.

Conflict of interest

The authors have no conflicts of interest to report.

Acknowledgment

This research was supported by grants awarded to Dr. Steiger and colleagues (nos. MOP-79490 and MOP-57929) from the Canadian Institutes for Health Research. The funding agencies had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report, or in the decision to submit the paper for publication.

The authors are grateful to Emeline Hetroy for assistance in manuscript preparation.

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