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  1. Article ; Online: A functional genomics pipeline identifies pleiotropy and cross-tissue effects within obesity-associated GWAS loci

    Amelia C. Joslin / Débora R. Sobreira / Grace T. Hansen / Noboru J. Sakabe / Ivy Aneas / Lindsey E. Montefiori / Kathryn M. Farris / Jing Gu / Donna M. Lehman / Carole Ober / Xin He / Marcelo A. Nóbrega

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 15

    Abstract: Many genetic loci have been linked to obesity, but knowledge of their functional mechanisms is limited. Here, the authors perform reporter assays and temporal functional genomics data generation to characterize obesity genetic loci and find that loci ... ...

    Abstract Many genetic loci have been linked to obesity, but knowledge of their functional mechanisms is limited. Here, the authors perform reporter assays and temporal functional genomics data generation to characterize obesity genetic loci and find that loci often harbor multiple functional variants.
    Keywords Science ; Q
    Language English
    Publishing date 2021-09-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Role of miRNA-mRNA Interaction in Neural Stem Cell Differentiation of Induced Pluripotent Stem Cells

    Satish Kumar / Joanne E. Curran / Erica DeLeon / Ana C. Leandro / Tom E. Howard / Donna M. Lehman / Sarah Williams-Blangero / David C. Glahn / John Blangero

    International Journal of Molecular Sciences, Vol 21, Iss 6980, p

    2020  Volume 6980

    Abstract: miRNA regulates the expression of protein coding genes and plays a regulatory role in human development and disease. The human iPSCs and their differentiated progenies provide a unique opportunity to identify these miRNA-mediated regulatory mechanisms. ... ...

    Abstract miRNA regulates the expression of protein coding genes and plays a regulatory role in human development and disease. The human iPSCs and their differentiated progenies provide a unique opportunity to identify these miRNA-mediated regulatory mechanisms. To identify miRNA–mRNA regulatory interactions in human nervous system development, well characterized NSCs were differentiated from six validated iPSC lines and analyzed for differentially expressed (DE) miRNome and transcriptome by RNA sequencing. Following the criteria, moderated t statistics, FDR-corrected p -value ≤ 0.05 and fold change—absolute (FC-abs) ≥2.0, 51 miRNAs and 4033 mRNAs were found to be significantly DE between iPSCs and NSCs. The miRNA target prediction analysis identified 513 interactions between 30 miRNA families (mapped to 51 DE miRNAs) and 456 DE mRNAs that were paradoxically oppositely expressed. These 513 interactions were highly enriched in nervous system development functions (154 mRNAs; FDR-adjusted p -value range: 8.06 × 10 −15 –1.44 × 10 −4 ). Furthermore, we have shown that the upregulated miR-10a-5p, miR-30c-5p, miR23-3p, miR130a-3p and miR-17-5p miRNA families were predicted to down-regulate several genes associated with the differentiation of neurons, neurite outgrowth and synapse formation, suggesting their role in promoting the self-renewal of undifferentiated NSCs. This study also provides a comprehensive characterization of iPSC-generated NSCs as dorsal neuroepithelium, important for their potential use in in vitro modeling of human brain development and disease.
    Keywords human ; induced pluripotent stem cell ; neural stem cell ; miRNA ; mRNA ; gene expression regulation ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 571
    Language English
    Publishing date 2020-09-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Association of HIV-1 Infection and Antiretroviral Therapy With Type 2 Diabetes in the Hispanic Population of the Rio Grande Valley, Texas, USA

    Juan Carlos Lopez-Alvarenga / Dora A. Martinez / Alvaro Diaz-Badillo / Liza D. Morales / Rector Arya / Christopher P. Jenkinson / Joanne E. Curran / Donna M. Lehman / John Blangero / Ravindranath Duggirala / Srinivas Mummidi / Ruben D. Martinez

    Frontiers in Medicine, Vol

    2021  Volume 8

    Abstract: The Rio Grande Valley (RGV) in South Texas has one of the highest prevalence of obesity and type 2 diabetes (T2D) in the United States (US). We report for the first time the T2D prevalence in persons with HIV (PWH) in the RGV and the interrelationship ... ...

    Abstract The Rio Grande Valley (RGV) in South Texas has one of the highest prevalence of obesity and type 2 diabetes (T2D) in the United States (US). We report for the first time the T2D prevalence in persons with HIV (PWH) in the RGV and the interrelationship between T2D, cardiometabolic risk factors, HIV-related indices, and antiretroviral therapies (ART). The PWH in this study received medical care at Valley AIDS Council (VAC) clinic sites located in Harlingen and McAllen, Texas. Henceforth, this cohort will be referred to as Valley AIDS Council Cohort (VACC). Cross-sectional analyses were conducted using retrospective data obtained from 1,827 registries. It included demographic and anthropometric variables, cardiometabolic traits, and HIV-related virological and immunological indices. For descriptive statistics, we used mean values of the quantitative variables from unbalanced visits across 20 months. Robust regression methods were used to determine the associations. For comparisons, we used cardiometabolic trait data obtained from HIV-uninfected San Antonio Mexican American Family Studies (SAMAFS; N = 2,498), and the Mexican American population in the National Health and Nutrition Examination Survey (HHANES; N = 5,989). The prevalence of T2D in VACC was 51% compared to 27% in SAMAFS and 19% in HHANES, respectively. The PWH with T2D in VACC were younger (4.7 years) and had lower BMI (BMI 2.43 units less) when compared to SAMAFS individuals. In contrast, VACC individuals had increased blood pressure and dyslipidemia. The increased T2D prevalence in VACC was independent of BMI. Within the VACC, ART was associated with viral load and CD4+ T cell counts but not with metabolic dysfunction. Notably, we found that individuals with any INSTI combination had higher T2D risk: OR 2.08 (95%CI 1.67, 2.6; p < 0.001). In summary, our results suggest that VACC individuals may develop T2D at younger ages independent of obesity. The high burden of T2D in these individuals necessitates rigorously designed longitudinal studies to ...
    Keywords South Texas ; AIDS ; type 2 diabetes ; HIV ; Mexican Americans ; antiretroviral treatment ; Medicine (General) ; R5-920
    Subject code 310
    Language English
    Publishing date 2021-07-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Serum carotenoids and Pediatric Metabolic Index predict insulin sensitivity in Mexican American children

    Srinivas Mummidi / Vidya S. Farook / Lavanya Reddivari / Joselin Hernandez-Ruiz / Alvaro Diaz-Badillo / Sharon P. Fowler / Roy G. Resendez / Feroz Akhtar / Donna M. Lehman / Christopher P. Jenkinson / Rector Arya / Jane L. Lynch / Jose A. Canas / Ralph A. DeFronzo / Daniel E. Hale / John Blangero / Juan Carlos Lopez-Alvarenga / Ravindranath Duggirala / Jairam K. P. Vanamala

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 11

    Abstract: Abstract High concentrations of carotenoids are protective against cardiometabolic risk traits (CMTs) in adults and children. We recently showed in non-diabetic Mexican American (MA) children that serum α-carotene and β-carotene are inversely correlated ... ...

    Abstract Abstract High concentrations of carotenoids are protective against cardiometabolic risk traits (CMTs) in adults and children. We recently showed in non-diabetic Mexican American (MA) children that serum α-carotene and β-carotene are inversely correlated with obesity measures and triglycerides and positively with HDL cholesterol and that they were under strong genetic influences. Additionally, we previously described a Pediatric Metabolic Index (PMI) that helps in the identification of children who are at risk for cardiometabolic diseases. Here, we quantified serum lycopene and β-cryptoxanthin concentrations in approximately 580 children from MA families using an ultraperformance liquid chromatography-photodiode array and determined their heritabilities and correlations with CMTs. Using response surface methodology (RSM), we determined two-way interactions of carotenoids and PMI on Matsuda insulin sensitivity index (ISI). The concentrations of lycopene and β-cryptoxanthin were highly heritable [h2 = 0.98, P = 7 × 10–18 and h2 = 0.58, P = 1 × 10–7]. We found significant (P ≤ 0.05) negative phenotypic correlations between β-cryptoxanthin and five CMTs: body mass index (− 0.22), waist circumference (− 0.25), triglycerides (− 0.18), fat mass (− 0.23), fasting glucose (− 0.09), and positive correlations with HDL cholesterol (0.29). In contrast, lycopene only showed a significant negative correlation with fasting glucose (− 0.08) and a positive correlation with HDL cholesterol (0.18). Importantly, we found that common genetic influences significantly contributed to the observed phenotypic correlations. RSM showed that increased serum concentrations of α- and β-carotenoids rather than that of β-cryptoxanthin or lycopene had maximal effects on ISI. In summary, our findings suggest that the serum carotenoids are under strong additive genetic influences and may have differential effects on susceptibility to CMTs in children.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Acanthosis nigricans as a composite marker of cardiometabolic risk and its complex association with obesity and insulin resistance in Mexican American children.

    Juan C Lopez-Alvarenga / Geetha Chittoor / Solomon F D Paul / Sobha Puppala / Vidya S Farook / Sharon P Fowler / Roy G Resendez / Joselin Hernandez-Ruiz / Alvaro Diaz-Badillo / David Salazar / Doreen D Garza / Donna M Lehman / Srinivas Mummidi / Rector Arya / Christopher P Jenkinson / Jane L Lynch / Ralph A DeFronzo / John Blangero / Daniel E Hale /
    Ravindranath Duggirala

    PLoS ONE, Vol 15, Iss 10, p e

    2020  Volume 0240467

    Abstract: Aim Acanthosis nigricans (AN) is a strong correlate of obesity and is considered a marker of insulin resistance (IR). AN is associated with various other cardiometabolic risk factors (CMRFs). However, the direct causal relationship of IR with AN in ... ...

    Abstract Aim Acanthosis nigricans (AN) is a strong correlate of obesity and is considered a marker of insulin resistance (IR). AN is associated with various other cardiometabolic risk factors (CMRFs). However, the direct causal relationship of IR with AN in obesity has been debated. Therefore, we aimed to examine the complex causal relationships among the troika of AN, obesity, and IR in Mexican Americans (MAs). Methods We used data from 670 non-diabetic MA children, aged 6-17 years (49% girls). AN (prevalence 33%) severity scores (range 0-5) were used as a quasi-quantitative trait (AN-q) for analysis. We used the program SOLAR for determining phenotypic, genetic, and environmental correlations between AN-q and CMRFs (e.g., BMI, HOMA-IR, lipids, blood pressure, hs-C-reactive protein (CRP), and Harvard physical fitness score (PFS)). The genetic and environmental correlations were subsequently used in mediation analysis (AMOS program). Model comparisons were made using goodness-of-fit indexes. Results Heritability of AN-q was 0.75 (p<0.0001). It was positively/significantly (p<0.05) correlated with traits such as BMI, HOMA-IR, and CRP, and negatively with HDL-C and PFS. Of the models tested, indirect mediation analysis of BMI→HOMA-IR→AN-q yielded lower goodness-of-fit than a partial mediation model where BMI explained the relationship with both HOMA-IR and AN-q simultaneously. Using complex models, BMI was associated with AN-q and IR mediating most of the CMRFs; but no relationship between IR and AN-q. Conclusion Our study suggests that obesity explains the association of IR with AN, but no causal relationship between IR and AN in Mexican American children.
    Keywords Medicine ; R ; Science ; Q
    Subject code 796
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Transcriptomic identification of ADH1B as a novel candidate gene for obesity and insulin resistance in human adipose tissue in Mexican Americans from the Veterans Administration Genetic Epidemiology Study (VAGES).

    Deidre A Winnier / Marcel Fourcaudot / Luke Norton / Muhammad A Abdul-Ghani / Shirley L Hu / Vidya S Farook / Dawn K Coletta / Satish Kumar / Sobha Puppala / Geetha Chittoor / Thomas D Dyer / Rector Arya / Melanie Carless / Donna M Lehman / Joanne E Curran / Douglas T Cromack / Devjit Tripathy / John Blangero / Ravindranath Duggirala /
    Harald H H Göring / Ralph A DeFronzo / Christopher P Jenkinson

    PLoS ONE, Vol 10, Iss 4, p e

    2015  Volume 0119941

    Abstract: Type 2 diabetes (T2D) is a complex metabolic disease that is more prevalent in ethnic groups such as Mexican Americans, and is strongly associated with the risk factors obesity and insulin resistance. The goal of this study was to perform whole genome ... ...

    Abstract Type 2 diabetes (T2D) is a complex metabolic disease that is more prevalent in ethnic groups such as Mexican Americans, and is strongly associated with the risk factors obesity and insulin resistance. The goal of this study was to perform whole genome gene expression profiling in adipose tissue to detect common patterns of gene regulation associated with obesity and insulin resistance. We used phenotypic and genotypic data from 308 Mexican American participants from the Veterans Administration Genetic Epidemiology Study (VAGES). Basal fasting RNA was extracted from adipose tissue biopsies from a subset of 75 unrelated individuals, and gene expression data generated on the Illumina BeadArray platform. The number of gene probes with significant expression above baseline was approximately 31,000. We performed multiple regression analysis of all probes with 15 metabolic traits. Adipose tissue had 3,012 genes significantly associated with the traits of interest (false discovery rate, FDR ≤ 0.05). The significance of gene expression changes was used to select 52 genes with significant (FDR ≤ 10(-4)) gene expression changes across multiple traits. Gene sets/Pathways analysis identified one gene, alcohol dehydrogenase 1B (ADH1B) that was significantly enriched (P < 10(-60)) as a prime candidate for involvement in multiple relevant metabolic pathways. Illumina BeadChip derived ADH1B expression data was consistent with quantitative real time PCR data. We observed significant inverse correlations with waist circumference (2.8 x 10(-9)), BMI (5.4 x 10(-6)), and fasting plasma insulin (P < 0.001). These findings are consistent with a central role for ADH1B in obesity and insulin resistance and provide evidence for a novel genetic regulatory mechanism for human metabolic diseases related to these traits.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2015-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

    Julia K. Goodrich / Moriel Singer-Berk / Rachel Son / Abigail Sveden / Jordan Wood / Eleina England / Joanne B. Cole / Ben Weisburd / Nick Watts / Lizz Caulkins / Peter Dornbos / Ryan Koesterer / Zachary Zappala / Haichen Zhang / Kristin A. Maloney / Andy Dahl / Carlos A. Aguilar-Salinas / Gil Atzmon / Francisco Barajas-Olmos /
    Nir Barzilai / John Blangero / Eric Boerwinkle / Lori L. Bonnycastle / Erwin Bottinger / Donald W. Bowden / Federico Centeno-Cruz / John C. Chambers / Nathalie Chami / Edmund Chan / Juliana Chan / Ching-Yu Cheng / Yoon Shin Cho / Cecilia Contreras-Cubas / Emilio Córdova / Adolfo Correa / Ralph A. DeFronzo / Ravindranath Duggirala / Josée Dupuis / Ma Eugenia Garay-Sevilla / Humberto García-Ortiz / Christian Gieger / Benjamin Glaser / Clicerio González-Villalpando / Ma Elena Gonzalez / Niels Grarup / Leif Groop / Myron Gross / Christopher Haiman / Sohee Han / Craig L. Hanis / Torben Hansen / Nancy L. Heard-Costa / Brian E. Henderson / Juan Manuel Malacara Hernandez / Mi Yeong Hwang / Sergio Islas-Andrade / Marit E. Jørgensen / Hyun Min Kang / Bong-Jo Kim / Young Jin Kim / Heikki A. Koistinen / Jaspal Singh Kooner / Johanna Kuusisto / Soo-Heon Kwak / Markku Laakso / Leslie Lange / Jong-Young Lee / Juyoung Lee / Donna M. Lehman / Allan Linneberg / Jianjun Liu / Ruth J. F. Loos / Valeriya Lyssenko / Ronald C. W. Ma / Angélica Martínez-Hernández / James B. Meigs / Thomas Meitinger / Elvia Mendoza-Caamal / Karen L. Mohlke / Andrew D. Morris / Alanna C. Morrison / Maggie C. Y. Ng / Peter M. Nilsson / Christopher J. O’Donnell / Lorena Orozco / Colin N. A. Palmer / Kyong Soo Park / Wendy S. Post / Oluf Pedersen / Michael Preuss / Bruce M. Psaty / Alexander P. Reiner / Cristina Revilla-Monsalve / Stephen S. Rich / Jerome I. Rotter / Danish Saleheen / Claudia Schurmann / Xueling Sim / Rob Sladek / Kerrin S. Small / Wing Yee So / Timothy D. Spector / Konstantin Strauch / Tim M. Strom / E. Shyong Tai / Claudia H. T. Tam / Yik Ying Teo / Farook Thameem / Brian Tomlinson / Russell P. Tracy / Tiinamaija Tuomi / Jaakko Tuomilehto / Teresa Tusié-Luna / Rob M. van Dam / Ramachandran S. Vasan / James G. Wilson / Daniel R. Witte / Tien-Yin Wong / AMP-T2D-GENES Consortia / Noël P. Burtt / Noah Zaitlen / Mark I. McCarthy / Michael Boehnke / Toni I. Pollin / Jason Flannick / Josep M. Mercader / Anne O’Donnell-Luria / Samantha Baxter / Jose C. Florez / Daniel G. MacArthur / Miriam S. Udler

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 15

    Abstract: Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess ... ...

    Abstract Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.
    Keywords Science ; Q
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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