Interface between Pharmacotherapy and Genes in Human Obesity

Abstract

Obesity is a polygenic chronic condition, and dysregulation in multiple underlying energy balance processes drives the obese phenotype. Lifestyle changes can be difficult to sustain long term, and anti-obesity drugs can be an advantageous component of a successful weight loss plan. However, due to lack of efficacy or adverse safety profiles, there is currently a limited selection of anti-obesity drugs on the market. This, coupled with the notable interindividual variability in efficacy of approved treatments, represents a significant unmet medical need. In this review, we will highlight this variability in weight loss response to these existing anti-obesity compounds and discuss how underpinning genetic variation is associated with weight loss outcomes. Existing research in the field of pharmacogenomics and obesity drugs will be highlighted, as will possibilities for future focus. We will conclude by exploring examples of successful pharmacogenomics studies, and also by asking how pharmacogenomics can be built into the drug development pipeline for the benefit of patients and pharmaceutical companies alike.

Current review of genetics of human obesity: from molecular mechanisms to an evolutionary perspective

“…This new field focuses on the study of polymorphisms within one or more candidate genes for associations with pharmacologic phenotypes. So, common polymorphisms may alter the response to pharmacotherapy affecting drug metabolism, drug transport or drug targets (Cascorbi et al 2013;O´Connor and Swick 2013). Relating to obesity, at least 35 loci were validated as being associated with BMI and the advent of GWAS and next generation sequencing will likely lead to the identification of additional genetic biomarkers.…”

A candidate-gene association study of topiramate-induced weight loss in obese patients with and without type 2 diabetes mellitus

“…Patients carrying the C/C (n = 23), C/T (n = 200), and T/T (n = 356) genotypes lost 6.8, 6.9, and 8.1% of their body weight, respectively. The variant rs266729 in ADIPOQ has been previously associated with obesity, T2D, and sibutramine efficacy [60,61], and other SNPs, rs518147 and rs3813929, in HTR2C have been associated with antipsychotic-induced weight gain and Table 4 Analyses for placebo response All SNPs are intronic, except rs6758386, which is intergenic and rs1042048, which is in an untranslated region. A 1 , allele 1 (the minor allele); A 2 , allele 2; Chr, chromosome; MAF (allele 1), minor allele frequency; unadj, unadjusted.…”

Precision Medicine for Obesity

“…[88][89][90] Three silent SNPs in the gene encoding the pancreatic lipase were shown to influence the efficacy of orlistat. 91 In the same way, 13 SNPs have been strongly associated with weight or BMI changes secondary to antipsychotic medications use. 92…”

“…Within this field, as described earlier, few genetic variants that affect the individual's susceptibility for antiobesity medications' adverse effects and/or weight loss response have been identified and could be used to maximize response to treatment in clinical practice. [88][89][90][91]103 Furthermore, in spite of the available evidence on the effect of certain genetic variants on the predisposition to gain weight with some medications, more research is needed to develop specific guidelines. 92 • Microbiomics: The gut microbiota plays a crucial role in energy homeostasis and feeding behavior.…”