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Genomas Study Links Genes to Increased BMI, Edema in Diabetics Treated With Avandia, Actos

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A Genomas study has uncovered several genes that could identify individuals at risk for increased body-mass index and edema after being treated with the diabetes drugs Avandia and Actos.

The study, published in the February issue of Clinica Chimica Acta, identified “physiogenomic associations … suggesting mechanistic links between adenosine signaling and BMI, and between vascular permeability and drug-induced edema.”

“The findings are being used to develop a DNA-guided decision support system for diabetic pharmacotherapy,” Genomas said in a statement. The study was co-authored by investigators from the Joslin Diabetes Center Affiliate at the Hospital of Central Connecticut, Hartford Hospital, and Yale University School of Medicine.

Genomas CEO Gualberto Ruaño told Pharmacogenomics Reporter this week that the company plans to conduct larger validating studies to home in on these genes and possibly launch a test in 2011.

Actos, made by Takeda, and Avandia, manufactured by GlaxoSmithKline, are thiazolidinedine drugs that came under regulatory scrutiny in 2007 after a meta-analysis published by Cleveland Clinic cardiologist Steven Nissen in the New England Journal of Medicine associated Avandia with a 43 percent increase in heart attacks and a 64 percent increase in cardiovascular death.

Despite GSK’s challenges to Nissen’s analysis, the US Food and Drug Administration on June 6 of that year requested that Avandia and Actos’ label carry a black box warning about congestive heart failure [see PGx Reporter 07-11-2007 ].

The study published in Clinica Chimica Acta, meantime, is a retrospective analysis of 87 patients taking Actos or Avandia, known generically as pioglitazone and rosiglitazone, respectively.

The researchers performed a physiogenomic analysis on 384 SNPs from 222 cardiometabolic and neuroendocrine genes in order to relate patients’ responses to the drugs with the genes of interest. Of the SNPs tested, 25 yielded statistically significant associations with BMI or edema.

“For BMI, the strongest associations were found with SNPs among genes involved in energy homeostasis, adiposity, glucose metabolism, and lipid metabolism,” Genomas said in a statement. “For edema, associations were found among the genes involved in vascular inflammation or regulation, lipid metabolism and glucose metabolism.”

In the study, the five most significant gene associations between BMI and SNPs were ADORA1, PKM2, ADIPOR2, UCP2, and APOH. For edema, the five most significant gene associations were NPY, GYS, CCL2, OLR1, and GHRH. “After accounting for multiple comparisons, ADORA1 was significantly associated with BMI at a false discovery rate (FDR) of b10 percent,” the study authors wrote in the paper.

According to Ruaño, Genomas’ next steps will be to validate these gene associations in a second and third trial with the Joslin Diabetes Center Affiliate, and file patents on the genes of interest. The company plans to eventually extend partnerships with other hospitals in Connecticut.

In the study, genotyping was performed with Illumina’s BeadArray platform and GoldenGate assay. However, Genomas has not yet decided on what platform a commercialized test would run.

“The technologies you use for research are different than what you use for clinical launch … [due to] regulatory aspects, proficiency testing, and how you validate the assay,” Ruaño said. “We as a company we are evaluating the clinical launch technology for all of our products.”

The study around TZD drugs is Genomas’ newest program. “We don’t have any expectations of going to market in 2009 or 2010,” Ruaño said. “The launch for this product will be in 2011.”

“TZDs have been observed to have side effects of weight gain and abdominal obesity, which exacerbate the diabetic condition itself, and cause edema and exacerbate congestive heart failure in certain patients,” Genomas said in a statement. “Individuals vary in their risk and there is no known method for predicting such side effects.

“FDA-mandated ‘black box’ warnings on the drug labels underscore the urgent need to better understand the mechanisms underlying these potentially serious side effects,” the company continued. “Uncertainties surrounding the use of these drugs may place patients at risk, reduce patient compliance, burden medical management and increase healthcare costs.”

Genomas also plans to launch predictive genetic tests for statins and psychotropic drugs by the end of the year or in early 2010, Ruaño said.

Researchers from the company and Hartford Hospital published findings in Personalized Medicine last month suggesting that patients with major depressive disorders who carry combinations of the CYP2C9, CYP2C19, and CYP2D6 genes have limited ability to metabolize at least 14 psychotropic medications [see PGx Reporter 01-07-2009 ].

The potential for increased cardiovascular risks with Avandia and Actos has garnered the attention of other players in the genetic-testing industry. In 2007, Perlegen announced that it has collected more than 3,000 DNA samples from diabetic patients treated with the two TZD drugs and planned to analyze the genetic variability associated with adverse events tied to this class of medications.

GSK is also conducting two long-term diabetes studies designed to provide additional information about Avandia’s association with increased cardiovascular risks. The results from these studies are expected this year.

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