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

Abstract

The serotonin 5-HT(2C) 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 (BMI > or = 30) and 104 non-obese (BMI < or = 25) 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.