1. Pharmacogenomics: Genotype specific response to a weight loss drug Paper by Hauner et al. Pharmacogenetics 2003; 13(8): 453-459 Presented by: Payal Sipahimalani

2. The drug: Sibutramine Chemical name: Sibutramine hydrochloride monohydrate Used for management of obesity (BMI≥30kg/m 2 ) Mode of action: Inhibits uptake of serotonin, dopamine and norepinephrine Side effects may include headache, dry mouth, anorexia, constipation, insomnia, dizziness, nausea, nervousness, dyspepsia, increase in blood pressure and heart rate.

3. Sibutramine Variability in response Reasons unknown Ideally: want to be able to identify responders

4. This study G-protein  3 subunit gene (GNB3) C825T polymorphism –Alternative splicing –Truncated, but functional protein variant –Increased signal transduction –Associated with obesity Association between C825T status and treatment outcome?

5. Study design Previous study: 348 subjects (BMI: 30 - 40) –174 = sibutramine group –174 = placebo group Weight loss after 54 weeks This study: Genotyped the C825T polymorphism – pyrosequencing –111 individuals

6. Genotype distribution 825T frequency = 35.1% in entire group Higher than in non-obese subjects OverallSibutraminePlacebo TT1587 TC481929 CC482523

7. Sibutramine vs. placebo Figure 1: Weight loss after 54 weeks Mean weight loss: Sibutramine 10.3 + 1.0 kg Placebo 5.0 + 1.5 kg Therefore, significantly greater weight loss with sibutramine.

8. Placebo group Weight loss in: TT = 7.8kg TC = 6.9kg CC = 2.7kg Genotype specific difference in weight loss T allele carriers: 4.3 + 2.0 kg greater than CC

9. Sibutramine group TT and TC – no additional effect with drug CC – strong effect (P=0.003) Figure 3: Genotype specific weight loss with sibutramine treatment vs. placebo. 15.6 7.8 6.9 10.2 7.1 9.6 2.7

10. Sibutramine vs. Placebo Odds Ratios (95% Confidence Intervals) OverallCC 5% weight loss3.5 (1.6-8.1)6.8 (1.8-25.6) 10% weight loss2.9 (1.2-6.8)9.6 (1.7-53.8)

11. Long term effects Two years after study termination: No overall advantage of sibutramine over placebo ≥ 5% weight loss –Placebo group: greater in T carriers –Sibutramine group: greater in CC individuals.

12. Summary and Conclusions Polymorphism  drug response? 825T allele of GNB3 –associated with obesity –Increased weight loss without drug Sibutramine –increased overall weight loss –Genotype specific weight loss (C>T)

13. Mechanism of action 825T allele = intracellular signalling = response to drugs Not here!!! set-point for body weight– easily shifted up or down Handle stress better? CC individuals defend body weight set point.

14. Future directions Side effects  genotype? Are psychological mechanisms of weight control allele specific? Other polymorphic genes involved in body weight regulation? Predict outcome of non-pharmacological and pharmacological programmes of weight loss.

15. Critique Ethnicity –variation in frequency of polymorphism –other effects? Sample size Graphs and tables

16. Discussion Side effects and the lawsuit Long term effect?

17. G Protein Signal Transduction

18. Pyrosequencing