Association of G-protein β3 subunit C825T variant (Gβ3S) and heart valve abnormalities in obese patients treated with fenfuramine-phentermine

Abstract

Obesity is associated with serious health risks, including an increased incidence of heart disease, stroke, and hypertension. Appetite-suppressant medications such as fenfluramine-phentermine (fen-phen) have been used for several decades to treat obesity. Recently, fen-phen has been suggested to increase the incidence of cardiac valvulopathy. Among potential mechanisms, increased signal transduction by G protein coupled receptors such as the serotonin receptor (5HT1C) may be important. We hypothesized that patients with the C825T polymorphism would be at higher risk for fen-phen associated disease, because the 825T allele is associated with the generation of a novel splice variant, enhanced intracellular signal transduction, and arterial hypertension. We reevaluated 33 patients who were treated with fen-phen during a randomized crossover trial in 1983. All patients had no history of heart disease at the onset of the original study. During reevaluation each patient completed a questionnaire, underwent cardiac auscultation, had a complete echocardiographic evaluation, and Gβ3S C825T allele genotyping. Fifteen age-matched untreated obese patients served as controls. A significant association between the 825T allele and obesity was observed (TT+TC = 85.4% in this group of obese patients, compared to 25% prevalence in the general population [Siffert, Nat. Genet 18:45,1998]) similar to results reported by Siffert (J Am Soc Nephrol 10:1921,1999). There was no difference in the prevalence of 825T allele among patients with cardiac valvulopathy (TT+TC: 6/8 [75.0%]) compared to patients without valvulopathy (TT+TC: 22/25 [88.0%]) in fen-phen treated patients. Prevalence of 825T allele was similar in untreated control patients (TT+TC: 13/15 [86.7%]). The TC genotype was significantly increased among treated patients who developed cardiac valvulopathy (5/8. 62.5%) compared to treated patients without valvulopathy (10/25,40.0%, p < 0.01) or control patients (7/15, 46.7%, p<0.01). This observation, if replicated in larger studies, suggests a genetic contribution to the cardiac effects of fen-phen.