Bulimia Nervosa (BN), a severe eating disorder characterized by recurrent binge-eating and compensations (through such means as vomiting, fasting or laxative abuse), affects from 1% to 3% of adolescent to young-adult females (American Psychiatric Association, 2000). Most contemporary etiological theories attribute BN to the activation, by environmental pressures, of hereditary susceptibilities (e.g., Bulik, 2005, Steiger and Bruce, 2007 and Treasure et al., 2010). One such causal path appears to implicate appetitive dysregulation, following the effects of prolonged dieting, in genetically susceptible individuals. Consistent with this notion, several studies report that individuals with certain genetic liabilities (e.g., hereditary risk of ED development, or propensity toward reduced serotonin reuptake), when they also report high levels of antecedent dieting, evince increased bulimic behavior (Akkermann et al., 2011 and Racine et al., 2011). Explorations into a second causal path of interest have been guided by the assumption that BN depends upon the amplification, by environmental pressures, of hereditary psychopathological traits (e.g., poor response inhibition, sensation seeking, negative emotionality) that convey risk: In non-eating-disordered contexts, the expression of such traits as depression (Caspi et al., 2003, Caspi et al., 2010 and Kaufman et al., 2004), behavioral disinhibition (Paaver et al., 2008) and impulsivity (Wagner et al., 2009) has been shown to sometimes involve stress-induced activation of genetic susceptibilities. In parallel, our group has shown that bulimic women carrying low-function alleles of the serotonin transporter promoter polymorphism, 5HTTLPR, when they report exposure to childhood sexual or physical abuse, also evince more pronounced manifestations of such traits as sensation seeking, affective instability (Steiger et al., 2007) and dissocial behavior (Steiger et al., 2008). A related gene-environment interaction effect has been shown to increase risk for AN, in carriers of low-function 5HTTLPR alleles reporting a history of problematic family interactions (Karwautz et al, 2011). Importantly, the studies cited report gene × stress interactions associated with elevations on a targeted symptom (e.g., sensation seeking) or syndrome (e.g., Anorexia Nervosa), but not main genetic effects. In other words, observed expressions of genetic effects appear to occur when there has been an environmental trigger.
Following upon the preceding line of thinking, we recently turned our attention to effects associated with a polymorphism that, in theory, might be quite a direct mediator of stress-induced effects—the BcII restriction fragment length polymorphism. Interest in this polymorphism is motivated, in part, by a body of evidence associating BN with altered hypothalamic-pituitary-adrenal (HPA) axis (stress-system) function ( Brambilla and Monteleone, 2003, Fichter et al., 1990, Neudek et al., 2001 and Steiger et al., 2001). The most widely studied of polymorphisms associated with glucocorticoid receptor (GR) expression, the BcII restriction fragment length polymorphism is a C/G single nucleotide polymorphism in intron B, 646 nucleotides downstream of exon 2. BcII is believed to mediate inhibitory feedback within the HPA axis and, in this fashion, to contribute to variability in stress reactivity ( Wüst et al., 2004, Kumsta et al., 2007 and van Rossum et al., 2003). Consistent with an established role of HPA axis function in depression ( Belmaker and Agam, 2008), BcII has been observed to influence risk of major depression ( Spijker and van Rossum, 2009 and Zobel et al., 2008). More importantly, in interaction with adverse childhood experiences, BcII has been reported to predict increased expressions of biomarkers for, and actual vulnerability to, adult depression ( Bet et al, 2009). Such findings led us to predict a BN-linked influence of traumatic experiences in individuals whose genetic propensities (linked to BcII) code for lesser modulatory feedback within the HPA axis. Consistent with our hypothesis, compared to 98 comparison women, we found a sample of 129 bulimic women to be significantly more likely to be carriers of BcII low-function (C) alleles, to report a history of childhood abuse and, more importantly, to be positive for both factors ( Steiger et al., 2011a).
The effect just-described suggests that traumatic stress can be etiological for BN in individuals disposed to lower GR modulation. However, it does not establish the extent to which a BcII × abuse interaction might have a BN-specific effect, or a nonspecific effect associated with increased expressions of such bulimia-related traits as behavioral disinhibition, sensation seeking, affective instability, or depression. To address this question, we aimed to evaluate, in an expanded pool of bulimic and normal eaters, the extent to which any BcII × Abuse interaction effect obtained might be attributable to such psychopathological trait expressions as behavioral impulsivity, affective instability, novelty seeking or depression--that could indirectly, but nonspecifically, contribute to risk of BN. To achieve these ends, we had bulimic and non-eating-disordered comparison women provide blood samples for assays of the BcII polymorphism, and complete structured interviews and self-report questionnaires assessing eating symptoms, psychiatric symptoms, and childhood abuse. Should the gene by environment interaction effect of interest here be BN-specific, the effect should reliably predict membership in bulimic or normal-eater groups despite controls for potentially mediating effects of the psychopathological traits. In contrast, if the gene × environment effect were generalized, or enacted through increased expressions of the psychopathological traits in question, prediction of the bulimic/nonbulimic distinction should be attenuated by inclusion of trait variables in predictive models.
