Pharmacogenetics in type 2 diabetes: precision medicine or discovery tool?

Florez, José C.

doi:10.1007/s00125-017-4227-1

Cited by 53 publications

(35 citation statements)

References 57 publications

(54 reference statements)

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“…Having established that searching for genetic determinants of metformin response is sensible, it becomes worthwhile to articulate the main goals of pharmacogenetic inquiry (see Text box) [24]. One goal is to use genetic variation to stratify patients into likely responders and non-responders, so as to tailor therapy to those most likely to benefit.…”

Section: The Genetic Approach As a Potential Solutionmentioning

confidence: 99%

“…The strongest association (odds of achieving the glycaemic target, 1.6) was detected at SNP rs11212617; this signal was followed up in an independent set of 1783 GoDARTS and 1113 UKPDS participants, achieving genome-wide statistical significance. Other groups have reproduced this finding in participants with established type 2 diabetes [51]; however, the DPP has not been able to detect an association of this SNP with diabetes incidence or change in quantitative glycaemic traits in participants with impaired glucose tolerance [52], a failure that may be caused by insufficient statistical power or the intriguing possibility that pharmacogenetic interactions may diverge at different stages of the disease process [24]. …”

Section: Second Phase: Gwasmentioning

confidence: 99%

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The pharmacogenetics of metformin

Florez

2017

Diabetologia

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Despite its widespread use as the first-line agent for the treatment of type 2 diabetes, it has become clear that metformin does not work optimally for everyone. Elucidating who are the likely metformin responders and non-responders is hampered by our limited knowledge of its precise molecular mechanism of action. One approach to achieve the related goals of stratifying patients into response subgroups and identifying the molecular targets of metformin involves the deployment of agnostic genome-wide approaches in cohorts of appropriate size to attain sufficient statistical power. While candidate gene studies have shed some light on the role of genetic variation in influencing metformin response, genome-wide association studies are beginning to provide additional insight that is unconstrained by prior knowledge. To fully realise their potential, much larger samples need to be assembled via international collaboration, preferably involving the academic community, government and the pharmaceutical industry.

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Section: The Genetic Approach As a Potential Solutionmentioning

confidence: 99%

Section: Second Phase: Gwasmentioning

confidence: 99%

The pharmacogenetics of metformin

Florez

2017

Diabetologia

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“…Initial candidate gene approaches focused on SLC22A1 (encoding the organic cation transporter 1) or SLC47A1 (encoding the multidrug and toxin extrusion 1) have failed to produce a definite picture of the genetic determinants of metformin response. 108 GWASs have identified two metformin response loci (ATM and SLC2A2). The ATM (ataxia telangiectasia mutated) locus, located in a large linkage disequilibrium block on chromosome 11 that includes a total of seven potential candidate genes, has been associated with glycemic response to metformin.…”

Section: Does Omic Information Make a Difference For Treatment?mentioning

confidence: 99%

Precision medicine in diabetes: an opportunity for clinical translation

Merino

Florez

2018

Annals of the New York Academy of Sciences

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Metabolic disorders present a public health challenge of staggering proportions. In diabetes, there is an urgent need to better understand disease heterogeneity, clinical trajectories, and related comorbidities. A pressing and timely question is whether we are ready for precision medicine in diabetes. Some biological insights that have emerged during the last decade have already been used to direct clinical decision making, especially in monogenic forms of diabetes. However, much work is necessary to integrate high-dimensional explorations into complex disease architectures, less penetrant biological alterations, and broader phenotypes, such as type 2 diabetes. In addition, for precision medicine to take hold in diabetes, reproducibility, interpretability, and actionability remain key guiding objectives. In this review, we examine how mounting data sets generated during the last decade to understand biological variability are now inspiring new venues to clarify diabetes nosology and ultimately translate findings into more effective prevention and treatment strategies.

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“…Defining subgroups using molecular testing is much more difficult in T2DM, as it is a polygenic disorder and the clinical phenotype reflects environmental as well as genetic influences [11]. One approach for precision medicine in T2DM is to categorise patients based on differential responses to drugs, and to then investigate the molecular underpinnings of each subgroup using next-generation sequencing platforms and gene arrays.…”

Section: Precision Diabetes In T2dmmentioning

confidence: 99%

Precision Diabetes Is Slowly Becoming a Reality

Mohan

Radha

2019

Med Princ Pract

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The concept of precision medicine is becoming increasingly popular. The use of big data, genomics and other “omics” like metabolomics, proteomics and transcriptomics could make the dream of personalised medicine become a reality in the near future. As far as polygenic forms of diabetes like type 2 and type 1 diabetes are concerned, interesting leads are emerging, but precision diabetes is still in its infancy. However, with regard to monogenic forms of diabetes like maturity-onset diabetes of the young and neonatal diabetes mellitus, rapid strides have been made and precision diabetes has already become part of the clinical tools used at advanced diabetes centres. In patients with some monogenic form of diabetes, if the appropriate gene defects are identified, insulin injections can be stopped and be replaced by oral sulphonylurea drugs. In the coming years, rapid advances can be expected in the field of precision diabetes, thereby making the control of diabetes more effective and hopefully leading to prevention of its complications and improvement of the quality of life of people afflicted with diabetes.

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Pharmacogenetics in type 2 diabetes: precision medicine or discovery tool?

Cited by 53 publications

References 57 publications

The pharmacogenetics of metformin

The pharmacogenetics of metformin

Precision medicine in diabetes: an opportunity for clinical translation

Precision Diabetes Is Slowly Becoming a Reality

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