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TGen and USC researchers find genetic markers to help fight diabetes
Date:6/16/2009

ere associated with TZD metabolism and the biological effects of TZD, and thereby contribute to the therapeutic response associated with TZD. However, these variants did not fully account for the non-response rate, suggesting that other variants may contribute to TZD response.

To identify other variants that predict response to TZDs, TGen researchers performed a genome-wide analysis of 115,352 single nucleotide polymorphisms, or SNPs (a DNA sequence variation within the more than 3 billion base pairs in the human genome). In addition, the scientists also systematically screened 28 key genes involved in TZD metabolism or PPARG-stimulated pathways.

Of the markers examined, DiStefano and her team identified five critical markers that may predict response to TZD mono-therapy. These markers include variants in a key drug metabolizing gene called cytochrome P450 3A4 and a PPARG-coactivator known as PPARGC1B. Other markers were located in genes associated with PPARG function and include the protein kinase MAP2K6, a potassium inwardly-rectifying channel called KCNJ16, and the farnesoid X receptor (NR1H4).

Together, these markers predicted both response to Actos therapy and improvement in insulin sensitivity in the patients taking the drug.

Dr. DiStefano said the next steps in this research will be to characterize the functional effects of the polymorphisms and assess the effect of these variants in other patients.

"This work may help treat the right people with the right drug, design better drugs that will effectively improve insulin sensitivity for more people, and possibly safeguard against adverse side reactions seen with some members of this drug class,'' she said. Importantly, these findings will enable us to dissect the pharmacogenetics of TZD response, which will expand our understanding of the genetic determinants of insulin resistance and its treatment, provide critical baseline information for the development and impl
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Contact: Steve Yozwiak
syozwiak@tgen.org
602-343-8704
The Translational Genomics Research Institute
Source:Eurekalert

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