It has been argued that the limited genetic diversity and reduced allelic heterogeneity observed in isolated founder populations facilitates discovery of loci contributing to both Mendelian and complex disease. A strong founder effect, severe isolation, and substantial inbreeding have dramatically reduced genetic diversity in natives from the island of Kosrae, Federated States of Micronesia, who exhibit a high prevalence of obesity and other metabolic disorders. We hypothesized that genetic drift and possibly natural selection on Kosrae might have increased the frequency of previously rare genetic variants with relatively large effects, making these alleles readily detectable in genome-wide association analysis. However, mapping in large, inbred cohorts introduces analytic challenges, as extensive relatedness between subjects violates the assumptions of independence upon which traditional association test statistics are based. We performed genome-wide association analysis for 15 quantitative traits in 2,906 members of the Kosrae population, using novel approaches to manage the extreme relatedness in the sample. As positive controls, we observe association to known loci for plasma cholesterol, triglycerides, and C-reactive protein and to a compelling candidate loci for thyroid stimulating hormone and fasting plasma glucose. We show that our study is well powered to detect common alleles explaining ≥5% phenotypic variance. However, no such large effects were observed with genome-wide significance, arguing that even in such a severely inbred population, common alleles typically have modest effects. Finally, we show that a majority of common variants discovered in Caucasians have indistinguishable effect sizes on Kosrae, despite the major differences in population genetics and environment.

The therapeutic potential of administering stem cells to promote angiogenesis and myocardial tissue regeneration after infarction has recently been demonstrated. Given the advantages of using embryonic stem cells and mouse models of myocardial infarction for furthering the development of this therapeutic approach, the purpose of this study was to determine if embryonic stem cells could be loaded with superparamagnetic iron oxide (SPIO) particles and imaged in a mouse model of myocardial infarction over time using MRI. Mouse embryonic stem cells were labeled with SPIO particles. When incubated with 11.2, 22.4, and 44.8 g Fe/ml of SPIO particles, cells took up increasing amounts of iron oxide. Embryonic stem cells loaded with SPIO compared to unlabeled cells had similar viability and proliferation profiles for up to 14 days. Free SPIO injected into infarcted myocardium was not observable within 12 hr after injection. After injection of three 10-l aliquots of 10 7 SPIO-loaded cells/ml into infarcted myocardium, MRI demonstrated that the mouse embryonic stem cells were observable and could be seen for at least 5 weeks after injection. The therapeutic potential of administration of adult stem cells in animal models of ischemic injury has recently been demonstrated by several investigators (1-3). These studies demonstrated that regional blood flow and capillary density was significantly higher and cardiac function was improved compared to control animals. The ability to track stem cells in vivo will greatly facilitate the development of this therapeutic modality. Two recent studies have demonstrated the ability to use MRI to track iron-labeled adult stem cells in pigs in the setting of myocardial infarction (MI) (4,5). In one study, mesenchymal cells were harvested from the bone marrow of swine, labeled with dextran-coated superparamagnetic iron oxide (SPIO) particles, and injected locally in a pig model of MI. In the second study, adult stem cells with myogenic potential were harvested from skeletal muscle of swine, labeled with SPIO particles, and injected into myocardial tissue using a percutaneous catheter.The previous studies used adult mesenchymal stem cells; however, there are advantages in using embryonic stem (ES) cells for research and eventual clinical application. Unlike primary adult stem cells, ES cells can be engineered to express other factors such as angiogenic growth factors or other proteins that might promote myocardial tissue regeneration. In clinical settings such as MI, the availability of sufficient numbers of cells at or near the onset of MI seems more likely to be feasible with ES cells than with adult stem cells. Several recent studies specifically demonstrated this therapeutic potential of using ES cells for transplantation in animal models for a variety of human diseases (6 -8), including their ability to limit myocardial tissue injury after infarction (9,10).Some of the advantages of performing these studies in mice, as opposed to other, larger animals, include the ability to perform stud...

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