Pharmacogenetics: potential role in the treatment of diabetes and obesity

Abstract

Background-Common genetic variation is associated with increased risk of common metabolic diseases such as type 1 and type 2 diabetes, and obesity. Increasing experience with genetic association studies has led to an understanding of the large sample sizes required to detect a weak to moderate genetic predisposition to disease, the need to reproduce such associations in independent cohorts, and the statistical criteria required to detect a true association. This approach has been used successfully to identify disease-associated gene variation usually in representative populations of large numbers.Objective-To review the current understanding of how common genetic variation influences predisposition to, and treatment of, metabolic disease. Methodology-Review of scientific literature.Results-While there has been progress in understanding how genetic variation predisposes to diabetes and obesity, and how candidate genes may alter drug response, several caveats limit the interpretation and significance of pharmacogenetic studies published to date: those caveats typically include relatively small numbers of participants and choice of endpoints in determining gene-associated differences in response, which may not be clinically significant or relevant as a biomarker or predictor of a desired clinical effect. The genetic variants studied at a given locus are often limited in number and may not represent a comprehensive map of the region under study.Conclusions-The pharmacogenetic associations in diabetes and obesity that have been reported to date have had limited impact on the choice of individual treatments. We perceive, however, that this field is in its infancy in these multifactorial metabolic diseases, and with further advances and future drug intervention trials designed in a way that allows a more clear interpretation of the impact of genetic variation on differences in drug response in obesity and diabetes, it is anticipated that pharmacogenetics will have a significant impact on individualizing medical care.

Frequency of MDR1 single nucleotide polymorphisms in a Jordanian population, including a novel variant

“…Targeting therapies to patients who are most likely to benefit with minimal adverse events will improve patient care and facilitate the approval of new, innovative medicines (Roses, 2008;Katz and Bhathena, 2009). Furthermore, advances in pharmacogenetic working models is associated with superior individualized care for patients suffering from every condition, especially those with cancer (van Schaik, 2008), cardiovascular diseases (D' Andrea et al, 2008), asthma (Hawkins and Peters, 2008), diabetes (Vella and Camilleri, 2008), and psychiatric or neurological disorders (Kadiev et al, 2008). In this study, we scanned the MDR1 coding sequences to identify variations.…”

A model of GLP-1 action on insulin secretion in nondiabetic subjects

“…However, there has been some suggestion that there is interindividual heterogeneity in response to GLP-1, raising the possibility that some individuals may benefit more from such therapy than others earlier in the disease (25,31). Given the potential expense and side effects from such intervention, it would be reasonable to develop a quantitative measure of GLP-1-induced insulin secretion that can be used to examine differences in individual response to this hormone.…”

Interface between Pharmacotherapy and Genes in Human Obesity

“…This has a substantial impact on potential therapeutic efficacy of pharmacological treatments which often target a single specific energy balance regulatory mechanism. Additionally, common genetic variation may alter the response to pharmacotherapy even if this variation is not associated with the risk of developing the disease itself [24] . Indeed, the weight loss response to drug treatments for obesity varies considerably.…”

“…exenatide or other GLP-1 analogues) [24] . For example, a heterozygous GLP-1R missense polymorphism that resulted in a substitution of threonine 149 by methionine (T149M) and which was associated with diabetes has been identified [65] and studied in vitro [66] .…”