A 5-HT2C receptor promoter polymorphism (HTR2C-759C/T) is associated with obesity in women, and with resistance to weight loss in heterozygotes

The serotonin 5-HT2C receptor (HTR2C) helps regulate appetite and body weight. An HTR2C promoter polymorphism (-759C/T) has been associated with obesity and with weight gain in response to antipsychotic (neuroleptic) drugs. We studied this polymorphism in 120 obese women (BMIgreater than or equal to30) and 104 non-obese (BMIless than or equal to25) women. The C allele was commoner in the obese group (OR=1.72 [95% CI, 1.13-2.64], P=0.008). Ninety-five of the obese women participated in a randomized trial of psychological treatments for weight loss. Among these women, heterozygotes lost less weight during the trial than did homozygotes (6.8 vs. 9.7 kg; P=0.047) and weighed more 6 months (90.1 vs. 83.6 kg; P=0.006) and 12 months (91.8 vs. 84.6 kg; P=0.009) later. Heterozygotes also had higher triglyceride levels than homozygotes. C/C subjects in the obesity trial did not differ from T/T subjects in terms of weight loss or triglycerides. In a separate RT-PCR study of 43 subjects, we found that HTR2C mRNA abundance in frontal cortex was unaffected by -759C/T status. Our data extend the evidence that HTR2C promoter variation may be a risk factor for obesity and, perhaps through heterosis, influences weight loss by obese women. Pharmacogenetic testing of HTR2C promoter variants may be valuable when evaluating anti-obesity drugs which act directly or indirectly on the receptor. (C) 2003 Wiley-Liss, Inc.