Human and Molecular Genetics Center

Anderson, United States

Human and Molecular Genetics Center

Anderson, United States
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Smith E.M.,Human and Molecular Genetics Center | Smith E.M.,University of Warwick | Zhang Y.,Human and Molecular Genetics Center | Baye T.M.,Human and Molecular Genetics Center | And 12 more authors.
Journal of Lipid Research | Year: 2010

In our analysis of a quantitative trait locus (QTL) for plasma triglyceride (TG) levels [logarithm of odds (LOD) = 3.7] on human chromosome 7q36, we examined 29 single nucleotide polymorphisms (SNPs) across INSIG1, a biological candidate gene in the region. Insulin-induced genes (INSIG s) are feedback mediators of cholesterol and fatty acid synthesis in animals, but their role in human lipid regulation is unclear. In our cohort, the INSIG1 promoter SNP rs2721 was associated with TG levels (P = 2 × 10 3 in 1,560 individuals of the original linkage cohort, P = 8 × 10 4 in 920 unrelated individuals of the replication cohort, combined P = 9.9 × 10 6). Individuals homozygous for the T allele had 9% higher TG levels and 2-fold lower expression of INSIG1 in surgical liver biopsy samples when compared with individuals homozygous for the G allele. Also, the T allele showed additional binding of nuclear proteins from HepG2 liver cells in gel shift assays. Finally, the variant rs7566605 in INSIG2, the only homolog of INSIG1, enhances the effect of rs2721 (P = 0.00117). The variant rs2721 alone explains 5.4% of the observed linkage in our cohort, suggesting that additional, yet-undiscovered genes and sequence variants in the QTL interval also contribute to alterations in TG levels in humans. Copyright © 2010 by the American Society for Biochemistry and Molecular Biology, Inc.

Bergom C.,Cancer Center | Bergom C.,Medical College of Wisconsin | Hauser A.D.,Cancer Center | Hauser A.D.,Medical College of Wisconsin | And 15 more authors.
Journal of Biological Chemistry | Year: 2016

The small GTPase DiRas1 has tumor-suppressive activities, unlike the oncogenic properties more common to small GTPases such as K-Ras and RhoA. Although DiRas1 has been found to be a tumor suppressor in gliomas and esophageal squamous cell carcinomas, the mechanisms by which it inhibits malignant phenotypes have not been fully determined. In this study, we demonstrate that DiRas1 binds toSmgGDS,a protein that promotes the activation of several oncogenic GTPases. In silico docking studies predict that DiRas1 binds to SmgGDS in a manner similar to other small GTPases. SmgGDS is a guanine nucleotide exchange factor for RhoA, but we report here that SmgGDS does not mediate GDP/ GTP exchange on DiRas1. Intriguingly, DiRas1 acts similarly to a dominant-negative small GTPase, binding to SmgGDS and inhibitingSmgGDSbinding to other small GTPases, including K-Ras4B, RhoA, and Rap1A. DiRas1 is expressed in normal breast tissue, but its expression is decreased in most breast cancers, similar to its family member DiRas3 (ARHI). DiRas1 inhibits RhoA- And Smg- GDS-mediated NF-kB transcriptional activity in HEK293T cells. We also report that DiRas1 suppresses basal NF-kB activation in breast cancer and glioblastoma cell lines. Taken together, our data support a model in which DiRas1 expression inhibits malignant features of cancers in part by nonproductively binding to SmgGDS and inhibiting the binding of other small GTPases to SmgGDS. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Flister M.J.,Human and Molecular Genetics Center | Hoffman M.J.,Human and Molecular Genetics Center | Lemke A.,Human and Molecular Genetics Center | Prisco S.Z.,Human and Molecular Genetics Center | And 9 more authors.
Circulation: Cardiovascular Genetics | Year: 2015

Background-Genome-wide association studies are powerful tools for nominating pathogenic variants, but offer little insight as to how candidate genes affect disease outcome. Such is the case for SH2B adaptor protein 3 (SH2B3), which is a negative regulator of multiple cytokine signaling pathways and is associated with increased risk of myocardial infarction (MI), but its role in post-MI inflammation and fibrosis is completely unknown. Methods and Results-Using an experimental model of MI (left anterior descending artery occlusion/reperfusion injury) in wild-type and Sh2b3 knockout rats (Sh2b3em2Mcwi), we assessed the role of Sh2b3 in post-MI fibrosis, leukocyte infiltration, angiogenesis, left ventricle contractility, and inflammatory gene expression. Compared with wild-type, Sh2b3em2Mcwi rats had significantly increased fibrosis (2.2-fold; P<0.05) and elevated leukocyte infiltration (>2-fold; P<0.05), which coincided with decreased left ventricle fractional shortening (-Δ11%; P<0.05) at 7 days post left anterior descending artery occlusion/reperfusion injury. Despite an increased angiogenic potential in Sh2b3em2Mcwi rats (1.7-fold; P<0.05), we observed no significant differences in left ventricle capillary density between wild-type and Sh2b3em2Mcwi rats. In total, 12 genes were significantly elevated in the post left anterior descending artery occluded/reperfused hearts of Sh2b3em2Mcwi rats relative to wild-type, of which 3 (NLRP12, CCR2, and IFNγ) were significantly elevated in the left ventricle of heart failure patients carrying the MI-associated rs3184504 [T] SH2B3 risk allele. Conclusions-These data demonstrate for the first time that SH2B3 is a crucial mediator of post-MI inflammation and fibrosis. © 2015 American Heart Association, Inc.

Flister M.J.,Human and Molecular Genetics Center | Flister M.J.,Medical College of Wisconsin | Prisco S.Z.,Human and Molecular Genetics Center | Prisco S.Z.,Medical College of Wisconsin | And 12 more authors.
Hypertension | Year: 2012

Previous studies have identified multiple blood pressure and renal disease quantitative trait loci located on rat chromosome 12. In the present study, we narrowed blood pressure loci using a series of overlapping Dahl salt-sensitive/Mcwi (SS)-12 Brown Norway (BN) congenic lines. We found that transferring 6.1 Mb of SS chromosome 12 (13.4-19.5 Mb) onto the consomic SS-12 background significantly elevated blood pressure on 1% NaCl (146 ± 6 versus 127 ± 1 mm Hg; P<0.001) and 8% NaCl diets (178 ± 7 versus 144 ± 2 mm Hg; P<0.001). Compared with the SS-12 consomic, these animals also had significantly elevated albumin (218 ± 31 versus 104 ± 8 mg/d; P<0.001) and protein excretion (347 ± 41 versus 195 ± 12 mg/d; P<0.001) on a 1% NaCl diet. Elevated blood pressure, albuminuria, and proteinuria coincided with greater renal and cardiac damage, demonstrating that SS allele(s) within the 6.1 Mb congenic interval are associated with strong cardiovascular disease phenotypes. Sequence analysis of the 6.1 Mb congenic region revealed 12 673 single nucleotide polymorphisms between SS and BN rats. Of these polymorphisms, 293 lie within coding regions, and 18 resulted in nonsynonymous changes in conserved genes, of which 5 were predicted to be potentially damaging to protein function. Syntenic regions in human chromosome 7 have also been identified in multiple linkage and association studies of cardiovascular disease, suggesting that genetic variants underlying cardiovascular phenotypes in this congenic strain can likely be translated to a better understanding of human hypertension. © 2012 American Heart Association, Inc.

Chen Y.-G.,The Jackson Laboratory | Chen Y.-G.,Max e National Research Center for Juvenile Diabetes | Chen Y.-G.,Human and Molecular Genetics Center | Chen Y.-G.,Medical College of Wisconsin | And 3 more authors.
Genes and Immunity | Year: 2012

Previous studies using gene-targeted mutant mice revealed several molecules important for the development or function of invariant natural killer T (iNKT) cells. However, these gene knockout mice represent cases that are rare in humans. Thus, it remains unclear how naturally occurring allelic variants of these genes or others regulate the numerical and functional diversity of iNKT cells in both mice and humans. Studies in humans are mostly limited to iNKT cells in peripheral blood (PB). It is not known if the relative distribution of iNKT cells between PB and other lymphoid organs is correlated or under common genetic control. To initially address these questions, we analyzed iNKT cells in the spleen, thymus and PB of 38 inbred mouse strains. Percentages of iNKT cells in these three anatomical sites varied significantly in a strain-dependent manner. The correlation between PB and spleen was moderate, and none was observed between PB and thymus. Similarly, proportions of the CD4-expressing subset of iNKT cells differed significantly among inbred strains. The percentages of CD4-positive iNKT cells displayed a strong correlation between PB and spleen, although it remained poor between PB and thymus. Genome-wide association studies across strains identified only partially overlapping loci associated with variability of iNKT cell frequencies within and between differing anatomical sites. © 2012 Macmillan Publishers Limited All rights reserved.

Tsaih S.-W.,Human and Molecular Genetics Center | Holl K.,Human and Molecular Genetics Center | Holl K.,Medical College of Wisconsin | Jia S.,Human and Molecular Genetics Center | And 25 more authors.
Genetics | Year: 2014

The genetic basis of type 2 diabetes remains incompletely defined despite the use of multiple genetic strategies. Multiparental populations such as heterogeneous stocks (HS) facilitate gene discovery by allowing fine mapping to only a few megabases, significantly decreasing the number of potential candidate genes compared to traditional mapping strategies. In the present work, we employed expression and sequence analysis in HS rats (Rattus norvegicus) to identify Tpcn2 as a likely causal gene underlying a 3.1-Mb locus for glucose and insulin levels. Global gene expression analysis on liver identified Tpcn2 as the only gene in the region that is differentially expressed between HS rats with glucose intolerance and those with normal glucose regulation. Tpcn2 also maps as a cis-regulating expression QTL and is negatively correlated with fasting glucose levels. We used founder sequence to identify variants within this region and assessed association between 18 variants and diabetic traits by conducting a mixed-model analysis, accounting for the complex family structure of the HS. We found that two variants were significantly associated with fasting glucose levels, including a nonsynonymous coding variant within Tpcn2. Studies in Tpcn2 knockout mice demonstrated a significant decrease in fasting glucose levels and insulin response to a glucose challenge relative to those in wild-type mice. Finally, we identified variants within Tpcn2 that are associated with fasting insulin in humans. These studies indicate that Tpcn2 is a likely causal gene that may play a role in human diabetes and demonstrate the utility of multiparental populations for positionally cloning genes within complex loci. © 2014 by the Genetics Society of America.

Flister M.J.,Human and Molecular Genetics Center | Hoffman M.J.,Human and Molecular Genetics Center | Reddy P.,Human and Molecular Genetics Center | Jacob H.J.,Human and Molecular Genetics Center | And 2 more authors.
Hypertension | Year: 2013

Renin was the first blood pressure (BP) quantitative trait locus mapped by linkage analysis in the rat. Subsequent BP linkage and congenic studies capturing different portions of the renin region have returned conflicting results, suggesting that multiple interdependent BP loci may be residing in the chromosome 13 BP quantitative trait locus that includes Renin. We used SS-13 congenic strains to map 2 BP loci in the Renin region (chr13: 45.2-49.0 Mb). We identified a 1.1-Mb protective Brown Norway region around Renin (chr13: 46.1-47.2 Mb) that significantly decreased BP by 32 mm Hg. The Renin protective BP locus was offset by an adjacent hypertensive locus (chr13: 47.2-49.0 Mb) that significantly increased BP by 29 mm Hg. Sequence analysis of the protective and hypertensive BP loci revealed 1433 and 2063 variants between Dahl salt-sensitive/Mcwi and Brown Norway rats, respectively. To further reduce the list of candidate variants, we regenotyped an overlapping SS-13 congenic strain (S/renrr) with a previously reported BP phenotype. Sequence comparison among Dahl salt-sensitive, Dahl R, and Brown Norway reduced the number of candidate variants in the 2 BP loci by 42% for further study. Combined with previous studies, these data suggest that at least 4 BP loci reside within the 30-cM chromosome 13 BP quantitative trait locus that includes Renin. © 2013 American Heart Association, Inc.

Petri V.,Human and Molecular Genetics Center | Shimoyama M.,Human and Molecular Genetics Center | Hayman G.T.,Human and Molecular Genetics Center | Smith J.R.,Human and Molecular Genetics Center | And 10 more authors.
Database | Year: 2011

The set of interacting molecules collectively referred to as a pathway or network represents a fundamental structural unit, the building block of the larger, highly integrated networks of biological systems. The scientific community's interest in understanding the fine details of how pathways work, communicate with each other and synergize, and how alterations in one or several pathways may converge into a disease phenotype, places heightened demands on pathway data and information providers. To meet such demands, the Rat Genome Database [(RGD)] has adopted a multitiered approach to pathway data acquisition and presentation. Resources and tools are continuously added or expanded to offer more comprehensive pathway data sets as well as enhanced pathway data manipulation, exploration and visualization capabilities. At RGD, users can easily identify genes in pathways, see how pathways relate to each other and visualize pathways in a dynamic and integrated manner. They can access these and other components from several entry points and effortlessly navigate between them and they can download the data of interest. The Pathway Portal resources at RGD are presented, and future directions are discussed. © The Author(s) 2011.

Pabbidi M.R.,University of Mississippi Medical Center | Juncos J.,University of Mississippi Medical Center | Juncos L.,University of Mississippi Medical Center | Renic M.,Medical College of Wisconsin | And 6 more authors.
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2013

This study examined the effects of transfer of a 2.4-Mbp region of rat chromosome 1 (RNO1) from Brown Norway (BN) into fawn-hooded hypertensive (FHH) rats on autoregulation (AR) of cerebral blood flow (CBF) and the myogenic response of middle cerebral arteries (MCAs). AR of CBF was poor in FHH and FHH.1BN AR- congenic strains that excluded the critical 2.4-Mbp region. In contrast, AR was restored in FHH.1BN AR+ congenic strains that included this region. The diameter of MCAs of FHH rats increased from 140 ± 14 to 157 ± 18 μm when transmural pressure was increased from 40 to 140 mmHg, but it decreased from 137 ± 5 to 94 ± 7 μm in FHH.1BN AR+ congenic strains. Transient occlusion of MCAs reduced CBF by 80% in all strains. However, the hyperemic response following ischemia was significantly greater in FHH and AR- rats than that seen in AR+ congenic strains (AR-, 173 ± 11% vs. AR+, 124 ± 5%). Infarct size and edema formation were also significantly greater in an AR- strain (38.6 ± 2.6 and 12.1 ± 2%) than in AR- congenic strains (27.6 ± 1.8 and 6.5 ± 0.9%). These results indicate that there is a gene in the 2.4-Mbp region of RNO1 that alters the development of myogenic tone in cerebral arteries. Transfer of this region from BN to FHH rats restores AR of CBF and vascular reactivity and reduces cerebral injury after transient occlusion and reperfusion of the MCA. © 2013 the American Physiological Society.

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