Foundation For Biomedical Research Research Articles

Thiamine-modified metabolic reprogramming of human pluripotent stem cell-derived cardiomyocyte under space microgravity

During spaceflight, the cardiovascular system undergoes remarkable adaptation to microgravity and faces the risk of cardiac remodeling. Therefore, the effects and mechanisms of microgravity on cardiac morphology, physiology, metabolism, and cellular biology need to be further investigated. Since China started constructing the China Space Station (CSS) in 2021, we have taken advantage of the Shenzhou-13 capsule to send human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) to the Tianhe core module of the CSS. In this study, hPSC-CMs subjected to space microgravity showed decreased beating rate and abnormal intracellular calcium cycling. Metabolomic and transcriptomic analyses revealed a battery of metabolic remodeling of hPSC-CMs in spaceflight, especially thiamine metabolism. The microgravity condition blocked the thiamine intake in hPSC-CMs. The decline of thiamine utilization under microgravity or by its antagonistic analog amprolium affected the process of the tricarboxylic acid cycle. It decreased ATP production, which led to cytoskeletal remodeling and calcium homeostasis imbalance in hPSC-CMs. More importantly, in vitro and in vivo studies suggest that thiamine supplementation could reverse the adaptive changes induced by simulated microgravity. This study represents the first astrobiological study on the China Space Station and lays a solid foundation for further aerospace biomedical research. These data indicate that intervention of thiamine-modified metabolic reprogramming in human cardiomyocytes during spaceflight might be a feasible countermeasure against microgravity.

Anti-PD-1 antibodies recognizing the membrane-proximal region are agonists that can stimulate immunosuppressive activity of PD-1

Abstract The success of immunoenhancing anti-PD-1 blocking antibodies in cancer treatment indicates the biological significance of PD-1-dependent immunoregulation in the human immune system. Active stimulation of PD-1 is potentially an effective approach in treating various inflammatory disorders; however, agonistic anti-PD-1 antibodies stimulating the immunosuppressive activity are not clearly defined. Here, by assessing the biological activities of anti-human PD-1 mAbs, we have identified functional anti-PD-1 agonists in the antibody group recognizing the membrane-proximal extracellular region (MPER). MPER recognition was characteristic to anti-PD-1 agonist mAbs and distinct from blocking mAbs binding to the membrane-distal region of PD-1. The agonistic activity was mediated by Fc receptor-dependent co-ligation of PD-1 molecules. In vivo anti-inflammatory efficacy of the PD-1 agonist in murine disease models suggests its clinical potential to various inflammatory disorders including autoimmune diseases. Meiji Seika Pharma, Co., Ltd. Foundation for Biomedical Research and Innovation at Kobe

NLM's sponsorship of research in biomedical informatics (1985-2016).

The U.S. National Library of Medicine’s (NLM) funding for biomedical informatics research in the 1980s and 1990s focused on clinical decision support systems, which were also the focus of research for Donald A.B. Lindberg M.D. prior to becoming NLM’s director. The portfolio of projects expanded over the years. At NLM, Dr. Lindberg supported various large infrastructure programs that enabled biomedical informatics research, as well as investigator-initiated research projects that increasingly included biotechnology/bioinformatics and health services research. The authors review NLM’s sponsorship of research during Dr. Lindberg’s tenure as its Director. NLM’s funding significantly increased in the 2000’s and beyond. Authors report an analysis of R01 topics from 1985–2016 using data from NIH RePORTER. Dr. Lindberg’s legacy for biomedical informatics research is reflected by the research NLM supported under his leadership. The number of R01s remained steady over the years, but the funds provided within awards increased over time. A significant amount of NLM funds listed in RePORTER went into various types of infrastructure projects that laid a solid foundation for biomedical informatics research over multiple decades.

NLM's Sponsorship of Research in Biomedical Informatics (1985-2016).

The U.S. National Library of Medicine's (NLM) funding for biomedical informatics research in the 1980s and 1990s focused on clinical decision support systems, which were also the focus of research for Donald A.B. Lindberg M.D. prior to becoming NLM's director. The portfolio of projects expanded over the years. At NLM, Dr. Lindberg supported various large infrastructure programs that enabled biomedical informatics research, as well as investigator-initiated research projects that increasingly included biotechnology/bioinformatics and health services research. The authors review NLM's sponsorship of research during Dr. Lindberg's tenure as its Director. NLM's funding significantly increased in the 2000's and beyond. Authors report an analysis of R01 topics from 1985-2016 using data from NIH RePORTER. Dr. Lindberg's legacy for biomedical informatics research is reflected by the research NLM supported under his leadership. The number of R01s remained steady over the years, but the funds provided within awards increased over time. A significant amount of NLM funds listed in RePORTER went into various types of infrastructure projects that laid a solid foundation for biomedical informatics research over multiple decades.

Optimal Criteria for G3 (Poorly Differentiated) Stage II Colon Cancer: Prospective Validation in a Randomised Controlled Study (SACURA Trial)

Background: Grade 3 (G3, poorly differentiated) is an important treatment-decision factor in stage II colon cancer, but no unified diagnostic criteria are established. According to previous studies, an intra-tumoural poorly differentiated area with no glandular formation (POR) that fills the microscopic field of a 40× objective lens was an essential factor that defined G3. We aimed to prospectively validate this in a randomised controlled study of adjuvant chemotherapy (SACURA trial). Methods: Between 2006 and 2010, we enrolled 991 patients with stage II colon cancer from 123 institutions. POR was quantitatively graded according to the 40× objective lens rule and the intensity of poorly differentiated clusters (GradePOR). The prognostic power of GradePOR was compared with that of the conventional tumour grade based on the predominant histology rule (Gradeconv). Findings: According to GradePOR, 313, 526 and 152 tumours were classified as G1POR, G2POR and G3POR, respectively, and the 5-year relapse-free survival (RFS) rates were 91·1%, 82·9%, and 74·7%, respectively (P < 0·0001). When G3POR and G3conv were alternatively added to the standard prognostic model consisting of eight conventional factors, only G3POR was a significant factor for RFS (P = 0·040, Wald test). The adverse impact of G3POR on RFS was greater in the microsatellite stable (MSS)/microsatellite instability (MSI)-low subset (hazard ratio [HR], 2·61; 95% confidence interval [CI], 1·81–3·77) compared with that in the full analysis set (HR, 1·93; 95% CI, 1·34–2·77). In the MSS/MSI-low subset, the 5-year RFS rate of patients with G3POR tumours in the adjuvant chemotherapy group achieved greater improvement (9·1%) than the surgery-alone group (HR, 0·65; 95% CI, 0·34–1·24). Interpretation: The validated prognostic value of the least differentiation policy with the 40× objective lens rule may be highlighted as the diagnostic criterion for G3 in the adjuvant treatment setting for stage II colon cancer, particularly for MSS/MSI-low tumours. Trial Registration: ClinicalTrials.gov NCT00392899 Funding: This study was supported by the Foundation for Biomedical Research and Innovation at Kobe, Translational Research Center for Medical Innovation (TRI), under the funding contract with Taiho Pharmaceutical Co. Ltd., Japan. Declaration of Interests: MI has received consulting fees from Taiho Pharmaceutical Co. Ltd., BristolMyers Squibb and Merck Serono Co. Ltd; honoraria from Taiho, Chugai Pharmaceutical Co. Ltd., and Yakult Honsha Co. Ltd. HM has received consulting fees from Otsuka Pharmaceutical Factory, Inc. and Sysmex Co.; honoraria from Taiho, Chugai, Yakult Honsha, Daiichi Sankyo Co. Ltd., Astellas Pharma Inc. NT has received research funding from Taiho, Chugai, and Yakult Honsha; honoraria from Taiho, Chugai, Takeda Pharmaceutical Co. Ltd., Merck Serono. YS has received honoraria from Taiho, Chugai and Yakult Honsha. KT has received honoraria from Taiho and Takeda. KK has received consulting fees from Taiho and Chugai; honoraria from Taiho, Chugai, Bristol-Myers, Merck Serono and Otsuka. MW has received research funding from Taiho, Chugai, Yakult Honsha, Johnson and Johnson K. K. and Covidien Japan Co. Ltd. YK has received honoraria from Taiho and Chugai. H. Ueno has received honoraria from Taiho, Chugai, Yakult Honsha, BristolMyers and Daiichi Sankyo. TI has received research funding from Taiho; honoraria from Chugai. H. Uetake has received consulting fees, research funding, and honoraria from Taiho, Chugai, Takeda, Bristol-Myers and Merck Serono. SM has no competing interest. ST has received consulting fees from Taiho, Daiichi Sankyo and Solasia Pharma K. K.; research funding from Daiichi Sankyo, Yakult Honsha and Kureha Co. Ltd.; honoraria from Daiichi Sankyo. KS has received consultant fees, research funding and honoraria from Taiho, Chugai, Takeda, Yakult Honsha, Daiichi Sankyo, Bristol-Myers, Merck Serono, and Pfizer Co. Ltd. Ethics Approval Statement: The study protocol was approved by the Institutional Review Boards of each participating institution and was conducted in accordance with the tenets of the Declaration of Helsinki and comparable Japanese ethical standards. Furthermore, written informed consent was obtained from all study participants.

Epigenetic Markers in Human Diseases

The human genome project (HGP) provided important information about structure, organization and predicted function of 2.85 billion nucleotides in the DNA sequence, which is the foundation for biomedical research, genetic diagnosis and evolutionary genomics [1]. However, the genetic basis of complex disorders as diabetes, cardiovascular diseases, Alzheimer, schizophrenia, autoimmune diseases and cancer, remains unclear. The multifactorial nature of these diseases involves an intricate gene network and environmental influences that reprogram the genome and hinders the knowledge of the mechanisms involved in its pathophysiology.

Chaperones and Beyond as Key Players in Pluripotency Maintenance

Pluripotency is orchestrated by distinct players and chaperones and their partners have emerged as pivotal molecules in proteostasis control to maintain stemness. The proteostasis network consists of diverse interconnected pathways that function dynamically according to the needs of the cell to quality control and maintain protein homeostasis. The proteostasis machinery of pluripotent stem cells (PSCs) is finely adjusted in response to distinct stimuli during cell fate commitment to determine successful organism development. Growing evidence has shown different classes of chaperones regulating crucial cellular processes in PSCs. Histones chaperones promote proper nucleosome assembly and modulate the epigenetic regulation of factors involved in PSCs’ rapid turnover from pluripotency to differentiation. The life cycle of pluripotency proteins from synthesis and folding, transport and degradation is finely regulated by chaperones and co-factors either to maintain the stemness status or to cell fate commitment. Here, we summarize current knowledge of the chaperone network that govern stemness and present the versatile role of chaperones in stem cells resilience. Elucidation of the intricate regulation of pluripotency, dissecting in detail molecular determinants and drivers, is fundamental to understanding the properties of stem cells in order to provide a reliable foundation for biomedical research and regenerative medicine.

The Japan Statin Treatment Against Recurrent Stroke (J-STARS): A Multicenter, Randomized, Open-label, Parallel-group Study

BackgroundAlthough statin therapy is beneficial for the prevention of initial stroke, the benefit for recurrent stroke and its subtypes remains to be determined in Asian, in whom stroke profiles are different from Caucasian. This study examined whether treatment with low-dose pravastatin prevents stroke recurrence in ischemic stroke patients. MethodsThis is a multicenter, randomized, open-label, blinded-endpoint, parallel-group study of patients who experienced non-cardioembolic ischemic stroke. All patients had a total cholesterol level between 4.65 and 6.21mmol/L at enrollment, without the use of statins. The pravastatin group patients received 10mg of pravastatin/day; the control group patients received no statins. The primary endpoint was the occurrence of stroke and transient ischemic attack (TIA), with the onset of each stroke subtype set to be one of the secondary endpoints. FindingAlthough 3000 patients were targeted, 1578 patients (491 female, age 66.2years) were recruited and randomly assigned to pravastatin group or control group. During the follow-up of 4.9±1.4years, although total stroke and TIA similarly occurred in both groups (2.56 vs. 2.65%/year), onset of atherothrombotic infarction was less frequent in pravastatin group (0.21 vs. 0.64%/year, p=0.0047, adjusted hazard ratio 0.33 [95%CI 0.15 to 0.74]). No significant intergroup difference was found for the onset of other stroke subtypes, and for the occurrence of adverse events. InterpretationAlthough whether low-dose pravastatin prevents recurrence of total stroke or TIA still needs to be examined in Asian, this study has generated a hypothesis that it may reduce occurrence of stroke due to larger artery atherosclerosis. FundingThis study was initially supported by a grant from the Ministry of Health, Labour and Welfare, Japan. After the governmental support expired, it was conducted in collaboration between Hiroshima University and the Foundation for Biomedical Research and Innovation.

Animal extremists' threats to neurologic research continue: Neuroreality II.

In 1995, Landau et al.1 documented the prevailing threats to animal research in “Neuroreality I,” which emphasized the importance of incorporating an understanding of biomedical research within the educational system. Two decades later, the threat against research involving animals has not receded but rather has escalated. It is therefore time to revisit these important issues. According to the Foundation for Biomedical Research, illegal incidents against researchers using animals rose from 6–27 events per year (1993–1997) to 76–103 per year (2003–2006).2 This has occurred against the backdrop of exponential growth in neuroscience research and understanding of neurologic disease pathogenesis leading to innovative treatment strategies. These advances have occurred as a direct outgrowth of the seminal contributions of animal investigations. Therefore, the alarming trend of these direct attacks requires an appropriate response.

Integrating ethics into science education and research: report of the presidential commission for the study of bioethical issues.

The 2013 BRAIN Research Initiative calls for the integration of ethics into medical education and all levels of research, from hypothesis generation to evaluation, which promises to provide an ethical foundation for all future biomedical research.

568P - Tumor Location and Histological Type Related to Intratumoral Expression of 5-Fu Metabolizing Enzymes in Stage III Colon Cancer: a Multicenter, Prospective Cohort Study [B-Cast Study

ABSTRACT Aim: Several oral 5-FU derivatives with different properties are used in adjuvant therapy for colon cancer in Japan. The B-CAST study is a prospective cohort study aimed efficacy prediction of 5-FU derivatives, through evaluating the intratumoral biomarker expressions and treatment outcome. We evaluated relationships between the relevant biomarker expressions and patient characteristics, as baseline analysis of the study. Methods: The frozen specimens of patients with stage III colon cancer who received postoperative adjuvant chemotherapy were examined. The expressions of TP, DPD, EGFR, and VEGF protein and TP, DPD, TS and OPRT mRNA were evaluated by using ELISA and qRT-PCR, respectively. Patients were divided into subgroups according to the biomarker expression levels by using a tree-based regression model with baseline patient characteristics as explanatory factors. Results: Among 2128 patients from the 217 institutions enrolled between Apr. 2009 and Mar. 2012, 2018 were used for analysis. The protein and mRNA expressions were successfully estimated in 100% and 89% of the examined samples, respectively. The logarithmic values of expressions of all examined biomarkers followed normal distributions. In the tree-based model, tumor was the most relevant variable to explain the expression of TP protein and OPRT mRNA (p Conclusions: This large cohort study revealed considerable degrees of correlations between location as well as histological type and the intratumoral expression of TP, DPD, TS, OPRT, and VEGF. The results would provide useful information for future studies in personalization of chemotherapy using 5-FU derivatives. Disclosure: M. Ishiguro: B-CAST study is conducted as a part of joint research of Tokyo Medical and Dental University and the Foundation for Biomedical Research and Innovation (FBRI), with funding from FBRI. All authors declare no relevant competing interest.All other authors have declared no conflicts of interest.

A pregnancy case report of alagille syndrome; expression of NOTCH signaling in the placenta

A pregnancy case report of alagille syndrome; expression of NOTCH signaling in the placenta

Interview: Enriching The Pore

Professor Hagan Bayley speaks to Hannah Stanwix, Assistant Commissioning Editor Professor Hagan Bayley received his Bachelor of Arts degree in Chemistry from the University of Oxford (Oxford, UK) in 1974. He holds a PhD in Chemistry from Harvard University (MA, USA) and completed a postdoctoral fellowship at the Massachusetts Institute of Technology (MA, USA). In 1981, Professor Bayley moved to Columbia University (NY, USA) as an Assistant Professor of Biochemistry. He subsequently worked at the Worcester Foundation for Biomedical Research (MA, USA) and in 1997, Professor Bayley moved to Texas A&amp;M University (TX, USA) to become a Professor of Chemistry and Head of the Department of Medical Biochemistry &amp; Genetics. Professor Bayley returned to the University of Oxford in 2003 and is currently the Professor of Chemical Biology. Professor Bayley is a Fellow of the American Association for the Advancement of Science, a Fellow of the Society of Biology (London, UK) and a Fellow of the Royal Society (London, UK). He has received numerous awards including the Royal Society of Chemistry 2009 Chemistry World Entrepreneur of the Year. Professor Bayley is the founder of Oxford Nanopore Technologies Ltd., a private company based in Oxford (UK). Professor Bayley has authored over 150 peer-reviewed papers, over 40 book chapters and review articles, as well as numerous patents.

Interview: Personal Account of the Discovery of a New Disease Using Next-Generation Sequencing

Gholson Lyon speaks to Natalie Harrison, Commissioning Editor Gholson J Lyon, MD, PhD, is a research scientist at the Center for Applied Genomics at The Children’s Hospital of Philadelphia and at the Utah Foundation for Biomedical Research (UFBR). He is also an adjunct assistant professor of Psychiatry at New York University School of Medicine. He is a board-certified child, adolescent and adult psychiatrist. He earned an MPhil in Genetics, working with Nobel laureate Martin Evans in Cambridge, UK, then received a PhD and MD through the Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program. He has published peer-reviewed papers in biochemistry, genetics, pharmacology and molecular biology. In addition to his research interest in neuropsychiatric illnesses, Dr Lyon is focusing on the discovery of rare previously undiscovered Mendelian diseases. Recently Dr Lyon and a team of international researchers used a new disease-variant finding tool (variant annotation, analysis and search tool [VAAST]) to identify the cause of an extremely rare X-linked genetic disorder that is lethal in infancy. The disease-causing mutation is in the NAA10 gene. Affecting only males, the mutation causes an aged appearance, facial abnormalities, developmental delay and cardiac arrhythmias, among other conditions. The team studied a family in Utah with a history of several boys with these symptoms who died in infancy, and analyzed DNA from five boys in the family. They are tentatively calling the disease Ogden syndrome, reflecting the family’s city of residence. This study is one of the first times in which next-generation sequencing has been used to help identify and confirm the genetic etiology of a previously unknown and unreported disease. Dr Lyon answers some questions below regarding this work.

Erratum: Corrigendum: Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47

Nat. Genet. 43, 246–252 (2011); published online 6 February 2011; corrected after print 11 August 2011 In the version of this article initially published, an affiliation was missing for two authors, Maria Gazouli and Nicholas P. Anagnou. They are also affiliated with the Foundation for Biomedical Research of the Academy of Athens in Athens, Greece.

Interview with Rohina Rubicz, Winner of the 2010 Gabriel W. Lasker Prize

An international jury composed of Guido Barbujani (Italy), David Caramelli (Italy), Roberto Macchiarelli (France), John Relethford (U.S.A.), and Alan Goodman (U.S.A.) selected the article entitled Genetic Architecture of a Small, Recently Aggregated Aleut Population: Bering Island, Russia by Rohina Rubicz, Mark Zlojutro, Guangyun Sun, Victor Spitsyn, Ranjan Deka, Kristin Young, and Michael Crawford as the best contribution to the 82 volume of Human Biology (2010). This research paper appeared in a special double issue, entitled Origins of the Populations of the Aleutian Islands guest edited byMichael Crawford, DixieWest (both at theUniversity of Kansas, Manhattan, Kansas), and Dennis O’Rourke (University of Utah, Salt Lake City, Utah). Rohina Rubicz is a postdoctoral researcher at the Texas Biomedical Research Institute (formerly the Southwest Foundation for Biomedical Research), San Antonio, Texas. She received her Ph.D. in biological anthropology (population genetics) in 2007 from the University of Kansas. As a graduate student she used molecular genetic markers (mitochondrial, Y chromosome, and autosomal DNA) to investigate questions concerning the peopling of the Americas, the co-evolution of genes and languages (Rubicz et al. 2002), and the origins of Aleuts and their relationship to other North American and Siberian populations (Rubicz et al. 2003; Zlojutro et al. 2006). Rohina’s current research applies statistical genetic methods to the study of complex phenotypes, including the role of host genetics in susceptibility to infectious disease, and the relationship between infection and risk factors for chronic diseases of aging (i.e., cardiovascular disease and diabetes) in Mexican Americans. She also continues her work in population genetics, with a recent publication on genetic substructure among the peoples of Beringia (Rubicz et al. 2010).

Interview with Rohina Rubicz, Winner of the 2010 Gabriel W.Lasker Prize

Interview with Rohina Rubicz, Winner of the 2010 Gabriel W.Lasker Prize Franz Manni* Keywords Aleuts, Bering Island, genetic drift, admixture, population genetics An international jury composed of Guido Barbujani (Italy), David Caramelli (Italy), Roberto Macchiarelli (France), John Relethford (U.S.A.), and Alan Goodman (U.S.A.) selected the article entitled Genetic Architecture of a Small, Recently Aggregated Aleut Population: Bering Island, Russia by Rohina Rubicz, Mark Zlojutro, Guangyun Sun, Victor Spitsyn, Ranjan Deka, Kristin Young, and Michael Crawford as the best contribution to the 82nd volume of Human Biology (2010). This research paper appeared in a special double issue, entitled Origins of the Populations of the Aleutian Islands guest edited by Michael Crawford, Dixie West (both at the University of Kansas, Manhattan, Kansas), and Dennis O'Rourke (University of Utah, Salt Lake City, Utah). Rohina Rubicz is a postdoctoral researcher at the Texas Biomedical Research Institute (formerly the Southwest Foundation for Biomedical Research), San Antonio, Texas. She received her Ph.D. in biological anthropology (population genetics) in 2007 from the University of Kansas. As a graduate student she used molecular genetic markers (mitochondrial, Y chromosome, and autosomal DNA) to investigate questions concerning the peopling of the Americas, the co-evolution of genes and languages (Rubicz et al. 2002), and the origins of Aleuts and their relationship to other North American and Siberian populations (Rubicz et al. 2003; Zlojutro et al. 2006). Rohina's current research applies statistical genetic methods to the study of complex phenotypes, including the role of host genetics in susceptibility to infectious disease, and the relationship between infection and risk factors for chronic diseases of aging (i.e., cardiovascular disease and diabetes) in Mexican Americans. She also continues her work in population genetics, with a recent publication on genetic substructure among the peoples of Beringia (Rubicz et al. 2010). Franz Manni: Dear Rohina, first of all, let me congratulate you for this prize given to the first author of the best article in a volume of the Journal! Even though it is not an easy task as the article is rather complex, would you mind summarizing it for those readers who did not go through it yet? [End Page 337] Click for larger view View full resolution Figure 1. Dr. Rohina Rubicz, winner of the 2010 Gabriel W. Lasker Prize. Photo courtesy of Aaron Clark. Rohina Rubicz: Thank you, it is a great honor to receive this recognition of our work. Briefly, the article investigates genetic consequences of the founding of the community of Bering Island (in the Commander Islands, Russia) by Aleuts relocated from Alaska, and subsequent historic events, including intermarriages with Russians. This resulted in a loss of diversity of mitochondrial DNA (mtDNA) lineages due to founder effect on the maternal side. Meanwhile, on the paternal side the opposing evolutionary force of gene flow introduced non-native Y chromosome lineages into the population. Based on admixture results of autosomal data, ancestral contributions to the mixed Aleut component of the Bering Island community are approximately 60% Aleut and 40% Russian. These molecular genetic data, along with classic genetic marker data compiled from the literature, are discussed within the context of the documented history and demography of this population. FM: How did you become interested in Bering Island? RR: When I first started out in anthropological genetics, as a graduate student working with Dr. Michael Crawford, my research focused on the origins and evolution of the inhabitants of the Aleutian archipelago, Alaska. According to archaeological evidence (Laughlin 1980; Knecht and Davis 2001) this region is believed to have been first settled from the east approximately 9,000 years ago. My work involved characterizing the mtDNA diversity of the modern Aleut [End Page 338] population. In this way I identified 26 different maternal lineages, belonging exclusively to mtDNA haplogroups A2 and D2. Analyses indicated that they are most closely related genetically to the peoples of the Chukchi Peninsula in northeastern Siberia, and Aleut-specific sublineages are dated to approximately 5,400 BP (Rubicz et al. 2003; Zlojutro et al. 2006). We further developed this project to look at the impact of historical events on Aleut genetic diversity, which included the founding of the Bering Island...

Localization of genes for V+LDL plasma cholesterol levels on two diets in the opossum Monodelphis domestica

Plasma cholesterol levels among individuals vary considerably in response to diet. However, the genes that influence this response are largely unknown. Non-HDL (V+LDL) cholesterol levels vary dramatically among gray, short-tailed opossums fed an atherogenic diet, and we previously reported that two quantitative trait loci (QTLs) influenced V+LDL cholesterol on two diets. We used hypothesis-free, genome-wide linkage analyses on data from 325 pedigreed opossums and located one QTL for V+LDL cholesterol on the basal diet on opossum chromosome 1q [logarithm of the odds (LOD) = 3.11, genomic P = 0.019] and another QTL for V+LDL on the atherogenic diet (i.e., high levels of cholesterol and fat) on chromosome 8 (LOD = 9.88, genomic P = 5 x 10(-9)). We then employed a novel strategy involving combined analyses of genomic resources, expression analysis, sequencing, and genotyping to identify candidate genes for the chromosome 8 QTL. A polymorphism in ABCB4 was strongly associated (P = 9 x 10(-14)) with the plasma V+LDL cholesterol concentrations on the high-cholesterol, high-fat diet. The results of this study indicate that genetic variation in ABCB4, or closely linked genes, is responsible for the dramatic differences among opossums in their V+LDL cholesterol response to an atherogenic diet.

The Digest/The Wire

The Digest/The Wire

Quantitative Loci Regulating Plasma Levels of γ Glutamyl Transferase and Albumin and Their Genetic Correlations with Cardiovascular Risk Factors

gamma Glutamyl transferase (GGT) and albumin (ALB) are two markers of liver function. These two proteins have been associated with non-alcoholic fatty liver disease and cardiovascular disease. The objectives of this study were to explore the genetic factors that influence variation in the plasma levels of GGT and ALB and to evaluate their genetic correlations with cardiovascular risk factors. Baboons from the Southwest National Primate Research Center at the Southwest Foundation for Biomedical Research, San Antonio, TX, were used as an animal model. The baboons were fed a standard monkey chow diet ad libitum. Fasting plasma concentrations of GGT, ALB, triglycerides, total cholesterol and LDL cholesterol were measured in 350 pedigreed adult baboons by standard assay procedures. A maximum likelihood-based variance decomposition approach implemented in the computer program SOLAR was used to conduct genetic analyses. The heritabilities of GGT (h(2) = 0.55; P < 0.0001) and ALB (h(2) = 0.42; P < 0.01) were significant. No statistically significant associations were found between GGT and the cardiovascular-related phenotypes. Genetic correlations between ALB and total cholesterol, LDL cholesterol and triglycerides were significant. A QTL (LOD = 2.8) for GGT plasma levels was identified on the baboon homologue of human chromosome 22 between markers D22S304 and D22S280. A QTL (LOD = 2.3) near marker D10S1432 was detected on the baboon homologue of human chromosome 10 for ALB. These results imply that variations in the plasma levels of GGT and ALB are under significant genetic regulation and that a common genetic component influences ALB and cardiovascular risk factor phenotypes.