An Islet-Targeted Genome-Wide Association Scan Identifies Novel Genes Implicated in Cytokine-Mediated Islet Stress in Type 2 XXXX .

@entity1 @entity32 @entity2175 @entity70628 @entity2426 @entity28 @entity6 @entity19 @entity70626 @entity409 @entity70627 @entity46951 @entity70624 @entity70623 @entity70625 @entity1893 @entity4334 @entity413
Genome-wide association studies in @entity1 @entity2175 ( @entity2175 ) have renewed interest in the pancreatic islet as a contributor to @entity2175 risk. @entity32 resulting from @entity28 is a risk factor for @entity2175 and a possible trigger of b-cell failure. In this study, microarray data were collected from @entity19 islets after overnight treatment with cytokines at concentrations consistent with the chronic low-grade @entity32 in @entity2175 . Genes with a cytokine-induced change of >2-fold were then examined for associations between single @entity4334 polymorphisms and the acute insulin response to @entity413 (AIRg) using data from the Genetics Underlying @entity6 in Hispanics (GUARDIAN) Consortium. Significant evidence of association was found between AIRg and single nucleotide polymorphisms in @entity70623 (5q31.3), @entity70624 (6p25.3), @entity70625 (3q27.1), @entity46951 (1q42.3), @entity70626 (11p13), @entity70627 (8q21.3), and @entity70628 (7q21.12). To assess the potential relevance to islet function, @entity19 islets were exposed to conditions modeling low-grade @entity32 , mitochondrial stress, @entity1893 ( @entity1893 ) stress, glucotoxicity, and lipotoxicity. RT-PCR revealed that one or more forms of stress significantly altered expression levels of all genes except @entity70623 . @entity2426 -induced @entity1893 stress up-regulated both @entity70626 and @entity70625 . Three genes confirmed microarray predictions of significant cytokine sensitivity: @entity70624 was down-regulated 3.3-fold by cytokines, @entity70627 was up-regulated 1.5- to 3-fold by all stressors, and @entity70628 was profoundly cytokine sensitive (167-fold up-regulation). Three genes were thus closely associated with low-grade @entity32 in @entity19 islets and also with a marker for islet function (AIRg) in a @entity6 -prone @entity1 population. This islet-targeted genome-wide association scan identified several previously unrecognized candidate genes related to @entity409 during the development of @entity2175 .
