Glucocorticoid Receptor Gene and Coronary Artery Disease: Right Idea, Wrong Gene Variant?

Artery Disease: Right Idea, Wrong Gene Variant? To the Editor: Recent data reported by Lin et al1 suggest that coronary artery disease (CAD) is associated with an Asn363Ser variant in exon 2 of the glucocorticoid receptor gene (GRL). The study is based on the notion that a dysfunctional glucocorticoid receptor may add to the adverse health effects of excessive cortisol concentrations. In a previous study, comprising Anglo-Celtic descent with a strong hereditability for hypertension and formerly designed to test the relationship between GRL and essential hypertension, the authors found an association between the Ser363 variant and elevated body mass index (BMI).2 However, no association or linkage with hypertension was detected.3 This lack of effect on blood pressure has been reported previously in a Dutch cohort.4 The authors fail to provide valuable pieces of information regarding previously published observations. The fact is that the only studies indicating an association between the Ser363 variant and obesity, measured as BMI, is that of Lin et al2 and Huizenga et al.4 In the referenced study of the Newcastle Heart Project,5 a significant association of the Ser allele was detected with increased waist-to-hip ratio (WHR) and not BMI in white men. To see an association with WHR in this report the authors needed to correct for a number of other factors that associate with central obesity, hence the multivariate approach (Christopher P.F. Redfern, personal communication, 2001). More importantly, however, is that a majority of studies indicates that the ATT to GTT point variation in exon 2 of the GRL is neither associated with obesity nor with obesity-related metabolic and circulatory perturbations.6 The Asn363Ser variant is located in the transactivation ( 1) domain, and phosphorylation of serine residues is important in DNA binding by glucocorticoid receptors (GRs). However, a series of studies clearly indicates that this variant lacks any effect on the function of the receptor in vitro.4,7–9 Still, Lin et al1 suggest that the underlying mechanism for the observed association with CAD might be that “adipocytes having the S363 variant of GR could be more sensitive to glucocorticoids. . . .” During the past decade, mutations affecting liability to obesity have been discovered at a phenomenal rate.10 The current literature linking obesity to genetic variants is teeming with reports of associations that cannot be replicated. Explanations for this lack of reproducibility are well rehearsed and typically include poor study design, incorrect assumptions about the underlying genetic architecture, and simple overinterpretation of data. In this regard, the authors of this paper apply a case-control strategy of association study for characterizing the genetic contribution to CAD and obesity. This approach, however, is inherently more susceptible to identifying gene variants that prove to be spuriously associated with diseases.11 Furthermore, findings beyond the study design and study objective are most likely to be misleading and spurious in nature.2 Although publication is a crucial portion of the scientific process, investigators and editors should be encouraged to avoid publishing non–hypothesis-driven results, especially in excellent journals,2 to prevent their unfortunate persistence into the present time.