Meta-analysis of type 2 Diabetes in African Americans Consortium

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.Peer reviewe

Preferences regarding Genetic Research Results: Comparing Veterans and Nonveterans Responses

OBJECTIVE: Communicating genetic research results to participants presents ethical challenges. Our objectives were to examine participants’ preferences in receiving future genetic research results and to compare preferences reported by veteran and nonveterans participants. METHODS: Secondary analysis was performed on data collected in 2000–2004 from 1,575 consent forms signed by Mexican-American participants enrolled in 2 genetic family studies (GFS) in San Antonio: The Family Investigation of Nephropathy and Diabetes (FIND) and the Extended FIND (EFIND). The consent forms for these studies contained multiple-choice questions to examine participants’ preferences about receiving their (1) clinical lab results and (2) future genetic research results. The FIND and EFIND databases had information on subjects’ demographic characteristics and some selected clinical variables. We identified veterans using the Veterans Health Administration's (VHA's) centralized data repository. We compared veterans’ and nonveterans’ preferences using Student's t test for continuous variables and χ(2) test for discrete variables. A logistic regression analyzed subjects’ preference for receiving their research results, controlling for other socio-demographic and clinical variables. RESULTS: The sample included 275 (18%) veterans and 1,247 (82%) nonveterans. Our results indicated a strong desire among the majority of participants 1,445 (95%) in getting their clinical lab research results. Likewise, 93% expressed interest in being informed about their future genetic results. There was no significant difference in veterans’ and nonveterans’ preference to disclosure of the research results (χ(2) test; p > 0.05). Regression analysis showed no significant relationship (p = 0.449) between the outcome (receiving research results) and veterans’ responses after controlling for demographics and educational levels. CONCLUSION: Participants believed they would prefer receiving their genetic research results. Veterans are similar to nonveterans in their preferences. Offering genetic research results to participants should be based on well defined and structured plans to enhance interpretation of genetic data

Ablation of the gene encoding p66Shc protects mice against AGE-induced glomerulopathy by preventing oxidant-dependent tissue injury and further AGE accumulation

Aims/hypothesis: AGEs have been implicated in renal disease associated with ageing, diabetes and other age-related disorders. Reactive oxygen species (ROS) promote formation of AGEs, which cause AGE-receptor-mediated ROS generation with activation of signalling pathways leading to tissue injury and further AGE accumulation. ROS generation is regulated by the Src homology 2 domain-containing transforming protein C1 (Shc1) isoform p66Shc, whose deletion has been shown to protect from tissue injury induced by ageing, diabetes, hyperlipidaemia and ischaemia-reperfusion by preventing oxidative stress. This study was aimed at assessing the role of p66Shc in the modulation of oxidative stress and oxidant-dependent renal injury induced by AGEs. Methods: For 10 weeks, male p66 shc knockout (KO) and wild-type (WT) mice were injected with 60 μg/day albumin modified or unmodified by $$N^varepsilon - left( {carboxymethyl} right);text{lysine}$$ (CML). Mice were then killed for the assessment of renal function and structure, as well as systemic and renal tissue oxidative stress. Results: Upon CML injection, KO mice, in contrast to WT mice, showed no or only mild forms of proteinuria, glomerular hypertrophy, mesangial expansion, glomerular sclerosis, renal/glomerular cell apoptosis and extracellular matrix upregulation. Moreover, KO mice had lower circulating and tissue AGEs than WT mice and unchanged plasma isoprostane 8-epi-prostaglandin-F2α levels, renal/glomerular CML, 4-hydroxy-2-nonenal, AGE receptor and NAD(P)H oxidase 4 (NOX4) content (and expression of the corresponding genes), and nuclear factor κB activation (NFκB). Mesangial cells from KO mice exposed to CML showed no or slight increase in ROS levels and NFκB activation, again at variance with WT cells. Conclusions/interpretation: These data indicate that p66Shc participates in the pathogenesis of AGE-dependent glomerulopathy by mediating AGE-induced tissue injury and further AGE formation through ROS-dependent mechanisms involving NFκB activation and upregulation of Nox4 expression and NOX4 production. © 2007 Springer-Verlag