Two MAGIC Papers Provide Insight into Diabetes Genetics and Response to Insulin
Researchers in the Meta-Analyses of Glucose and Insulin Related Traits Consortium (MAGIC) have recently published the results of two meta-analyses related to the genetic basis of glucose regulation, response to insulin and risk of developing diabetes.
Rather than being the work of a single laboratory group, these results have come from the efforts of a great many researchers in a wide variety of locations. Commenting on the nature of the studies, Professor Francis S. Collins, Director at the NIH (MD, USA) and an author on both papers, had this to say: “The findings from these ambitious, large-scale studies represent an enormous achievement in international cooperation involving hundreds of researchers and many thousands of individuals who contributed genetic samples for the study.”
Of the two papers, one was a general attempt to detect the association of genetic variants with several different factors related to glucose and its regulation, taking in studies ranging from simple measurements of glucose and insulin levels to those examining β-cell function and insulin resistance. Combining the results of 21 genome-wide association studies (GWAS) related to glucose levels, insulin levels and β-cell function across a total of over 46,000 individuals, the initial meta-analysis isolated 25 loci of interest. Upon further analysis of studies which included over 75,000 individuals, this selection was narrowed down to 16 loci associated with fasting glucose and β-cell function, and two loci associated with fasting insulin and insulin resistance. Of these, nine were newly associated with fasting glucose and one with fasting insulin. As well as this, six loci were newly associated with Type 2 diabetes.
Given the positions of these loci, genes that they are likely to influence are associated with such functions as glucose sensing, circadian regulation and signal transduction, among others.
“We were delighted that we were able to find so many SNPs associated with raised levels of glucose, but amazed that we found only one strong association with levels of insulin”, admitted corresponding author Dr Inês Barroso (Wellcome Trust Sanger Institute, Cambridge, UK). He remained upbeat, however, continuing; “We don‘t think this is a technical difference, but that the genetics is telling us that the two measures, insulin and glucose, have different architectures, with fewer genes, rarer variants or greater environmental influence affecting insulin resistance.”
The second paper was concerned with glucose levels 2 h after oral glucose challenge, and combined nine GWAS in its initial analysis, including results from over 15,000 individuals. Having identified 29 loci of interest, a subsequent analysis found that genetic variants at the GIPR, VPS13C and ADCY5 loci were all associated with the original 2 h glucose level, while GIPR status affected several other diabetes-relevant measurements, such as insulin secretion and response to incretin. Despite this, as summarized in the paper, “only the ADCY5 locus was found to be associated with Type 2 diabetes”.
Sources: Dupuis J, Langenberg C, Prokopenko I et al.: New genetic loci implicated in fasting glucose homeostasis and their impact on Type 2 diabetes risk. Nat. Genet. 42, 105–116 (2010); Saxena R, Hivert M, Langenberg C et al.: Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat. Genet. 42, 142–148 (2010).
Association of Common Genetic Variants with Disease may be ‘Synthetic‘, Driven by Rarer Linked Alleles
As a tool for gathering genomic data and associating it with phenotype, genome-wide association studies have provided a massive amount of data on potential relationships between SNPs and disease. Despite this wealth of information, however, pinning down the actual variation for which SNPs are the indicator has proven difficult. According to a group carrying out research at the Duke Institute for Genome Sciences and Policy (NC, USA), the reason why the mechanisms behind the thousands of associations discovered so far have proven to be so elusive could be a simple one: “It may be because we have been looking in the wrong place.”
This suggestion, made by Professor David Goldstein, explains the recent efforts of his group at the Duke Institute, where they have been creating and analyzing simulated genealogical trees in order to determine the distribution of the true causes of variation across a genome.
Using data from sufferers of genetically linked hearing loss and sickle-cell anemia, the group claims to have demonstrated that the rare mutations, which actually cause such disorders, can create ‘blocks‘ of synthetic associations across a genome that could lead to the disorders being seen as associated with common variations, a ‘synthetic association‘.
As the first author of the paper Samuel Dickson (Duke Institute for Genome Sciences and Policy) summarized: “We showed that not only is it possible that rare variants are behind many of the results of recent findings, but that there are likely to be many more to be found as researchers shift their focus to methods that will find rare variants.”
The paper concludes “this possibility requires careful consideration in the interpretation and follow up of GWAS signals.”
Source: Dickson SP, Wang K, Krantz I, Hakonarson H, Goldstein DB: Rare variants create synthetic genome-wide associations. PLoS Biol. 8(1), E1000294 (2010).
New US FDA Warfarin Label Refers to Pharmacogenomically Guided Dosage Table
Although the US FDA label for warfarin has included mention of pharmacogenetic considerations since 2007, when it was changed to indicate that dosage prescriptions should be modified for patients possessing certain variants of the CYP29C and VKORC1 genes, it was not considered appropriate at that time to include any more specific instructions on the matter without the support of evidence from studies that were then still in progress.
This state of affairs was not welcomed by certain industry representatives, who felt that the labels were insufficiently informative for prescribing doctors. The new label, by directing doctors to “consider these ranges in choosing the initial dose” and referring to a set of maintenance dose examples for a variety of genotypes, has certainly addressed that issue.
Following the conclusion of studies into warfarin dosing algorithms, the new labeling information, revealed on the 22nd of January, has the potential to bring personalized, pharmacogenomic testing further into the mainstream of prescription and treatment. Nevertheless, there have been concerns expressed that without stronger language than a ‘recommendation to consider‘, this new labeling information may not lead to increased uptake of genetic testing.
In response, Dr Lawrence Lesko, director of the FDA Office of Clinical Pharmacology and Biopharmaceutics explained that “the purpose of the label is to inform healthcare providers how to use a medicine safely and effectively. The label is not intended to dictate the practice of medicine as it occurs between a physician and individual patient.”
Moving on to discuss cases such as HLA-B*5701 and its interaction with the antiretroviral drug abacavir, which are considered to be far more clear cut, he continued “In some cases, it is self-evident that a test is needed. ‘Demanding‘ the patients be tested would be redundant.”
Source: GenomeWeb: Pharmacogenomic Reporter press release: www.genomeweb.com/dxpgx/fda-updates-warfarin-labeling-pgx-guided-dosing-ranges
RON Found to Mediate Resistance to Chemotherapy and Apoptosis in Pancreatic Cancer
Recepteur d‘origine nantais (RON) is a tyrosine kinase receptor that is known to be overexpressed in most pancreatic cancers. Recent research from a group led by Professor Andrew Lowy at Moores Cancer Center (University of California, San Diego, CA, USA) using mouse and human cells in a mouse model suggests that the silencing of RON can lead to pancreatic cancer becoming sensitized to gemcitabine, and vulnerable to natural apoptosis mechanisms.
Pancreatic cancer is difficult to detect and often difficult to treat effectively, making research into the processes that support and maintain its survival extremely relevant. As a known KRAS effector, RON has been observed to be involved with cancer migration and resistance to apoptosis, regulating the expression of cancer-survival genes such as STAT3 and Bcl-2. These factors, along with its overexpression in many pancreatic cancers, led to Professor Lowy‘s investigation of its mechanism. As he explained “To understand how to treat pancreatic cancer tumors, we need to better understand their circuitry and behavior”.
To examine the role of RON in pancreatic cancer, the researchers attempted to silence its expression in order to examine what effect this would have. The method of silencing used was via the introduction of RON-targeted shRNA to the cancer cells, which bound to RON mRNA and prevented expression. With RON out of the picture, the cells were observed to be much more susceptible to apoptosis and to treatment with gemcitabine, a nucleoside analog chemotherapeutic agent commonly used against pancreatic cancer.
Although it is unsurprising that many of the cancer cells being studied eventually bypassed RON silencing by activating alternative mechanisms to evade apoptosis, such as overexpression of EGFR, some resisted the treatment by reactivating RON itself, becoming resistant to the shRNA silencing.
Despite this eventual resistance to treatment, RON-based cancer treatment may well have its place as part of a combination therapy. On this line of thought, Professor Lowry suggested: “If we can learn to predict the results of RON-directed therapy, maybe we can combine it with an EGFR-directed therapy, for example, to take away tumor escape routes.”
With regard to the clinical validity of these findings, it was demonstrated that RON signaling is involved in a transcriptional program present in both human pancreatic cancer cells (inserted subcutaneously as xenografts) and cell lines derived from murine premalignant pancreatic intraepithelial neoplasia (PanIN). In terms of novelty, “This is the first demonstration that RON-directed therapy in an animal model can sensitize tumors to chemotherapy”, claimed Professor Lowy.
This in vivo and in vitro evidence strongly suggests that the results from this series of experiments could be applied to pancreatic cancer in humans.
Source: Logan-Collins J, Thomas RM, Yu P et al.: Silencing of RON receptor signaling promotes apoptosis and gemcitabine sensitivity in pancreatic cancers. Cancer Res. 70(3), 1130–1140 (2010).