JOSE CARLOS FLOREZ

..We use the lessons learned from this extensive body of evidence to illustrate general implications for the genetic analysis of complex traits...

..Finally, a strategy for the analogous discovery of insulin resistance genes is proposed...

..Similarly, whether genetic information will help guide therapeutic decisions must be tested in adequately designed and rigorously conducted clinical trials...

..These variants do not have a detectable impact on diabetes incidence or response to metformin or lifestyle modification in the Diabetes Prevention Program...

..We tested whether this variant modified the effect of metformin in the Diabetes Prevention Program (DPP), in which metformin reduced diabetes incidence by 31% in volunteers with impaired glucose tolerance...

..Here, we offer a contemporary overview of the field in its current state, identify potential obstacles, and highlight future directions...

..Susceptibility to type 2 diabetes may be conferred by genetic variants having modest effects on risk. Genome-wide fixed marker arrays offer a novel approach to detect these variants...

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..We therefore examined the effects of these variants on diabetes incidence and response to interventions in the Diabetes Prevention Program (DPP), in which a lifestyle intervention or metformin treatment was compared with placebo...

..Over the last few months, genome-wide association studies have contributed significantly to our understanding of the genetic architecture of type 2 diabetes. If and how this information will impact clinical practice is not yet clear...

..Nominally significant differences in quantitative traits are consistent with statistical noise. We conclude that common genetic variation at IDE is unlikely to confer clinically significant risk of type 2 diabetes in Caucasians...

..Common variants in the gene that encodes the transcription factor 7-like 2 (TCF7L2) have been strongly associated with type 2 diabetes. This highly reproducible association may uncover novel mechanisms of glycemic pathophysiology...

..However, other nearby variants might account for the putative association signal...

..The common P12A polymorphism in PPARG (a target for thiazolidinedione medications) has been consistently associated with type 2 diabetes...

..We conclude that the KLF11 A347S and T220M mutations do not contribute to increased risk of diabetes in European-derived populations and that the Q62R polymorphism has, at best, a minor effect on diabetes risk...

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..We set out to confirm the association of ENPP1 K121Q with hyperglycemia, expand this association to insulin resistance traits, and determine whether the association stems from K121Q or another variant in linkage disequilibrium with it...

..DESIGN, SETTING, PARTICIPANTS, AND OUTCOME: We genotyped ENPP1 K121Q in 3548 DPP participants and performed Cox regression analyses using genotype, intervention, and interactions as predictors of diabetes incidence...

..We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits...

..003) but not with increased insulin resistance. These results suggest that TCF7L2 variants may act through insulin secretion to increase the risk of type 2 diabetes...

..We can apply these lessons to future investigation so as to improve our understanding of the genetic basis of type 2 diabetes...

..6 [0.42-0.88], P = 0.007). However, these findings are not supported by other studies. We did not observe a reproducible association between these three ENPP1 variants and BMI or type 2 diabetes...

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..15 [1.05-1.26], P = 0.001). Despite genotyping 9,000 people and >95% power to reproduce the estimated OR from the recent meta-analysis, we were unable to replicate the association of the IRS-1 G972R polymorphism with type 2 diabetes...

..To use genome-wide fixed marker arrays and improved analytical tools to detect genetic associations with type 2 diabetes in a carefully phenotyped human sample...

..We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency...

..05). These data suggest that the 2q24 locus may influence the T2D risk by affecting glucose metabolism and insulin resistance...

..Such interactions might also influence trait-locus associations and may be useful to consider in diabetes genome-wide association studies...

..We therefore conducted a new meta-analysis that includes novel unpublished data from the ENPP1 Consortium and recent negative findings from large association studies to address the contribution of K121Q to type 2 diabetes...

..Using comprehensive linkage disequilibrium mapping, we genotyped single nucleotide polymorphisms (SNPs) in ADIPOQ to evaluate the association of common variants with adiponectin levels and risk of diabetes...

..We tested the hypothesis that knowledge of these loci allows better prediction of risk than knowledge of common phenotypic risk factors alone...

..Using comprehensive linkage disequilibrium mapping, we genotyped tag single nucleotide polymorphisms (SNPs) in RETN and tested associations with plasma resistin levels, risk of diabetes, and glycemic traits...

..An improved understanding of genetic mechanisms should allow us to test whether behavioral or pharmacologic therapies can be tailored and thus the tremendous disease burden inflicted by type 2 diabetes alleviated...

..Several nominal associations of variants in PRKAA2 and PRKAB1 with BMI appear to be consistent with statistical noise...

..We conclude that physicians can deliver prenatal diagnoses of DS in a sensitive manner that can be appreciated by expectant parents...

..To highlight recent type 2 diabetes (T2D)-associated genetic discoveries and their potential for clinical application...

..DS remains the most common chromosomal condition, occurring in 1 of every 733 births, with the majority of children still diagnosed postnatally...

..Finally, the current list of genetic loci that are related to T2DM does not seem to offer greater predictive value in determining diabetes risk than do commonly used phenotypic risk factors and family history...

..We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA₁(c) levels...

..This proposal should serve as the foundation for a large pharmacogenomics trial designed to evaluate the feasibility of genetically-tailored therapy in T2DM. ..

..In addition, this pilot study will lay the groundwork for a long-term, outcomes-based pharmacogenetic clinical trial. ..

..In the DPP, we will test the association of select variants with baseline diabetes-related quantitative traits, incidence of metabolic outcomes, response to the lifestyle intervention, and the effects of metformin and troglitazone. ..

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