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Wang, Thomas

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Wang

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Thomas

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Wang, Thomas
Author's Publications: search.filters.isAuthorOfPublication.5dc50a2e-f779-4dad-8d6e-4230e66e7ccf

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    Metabolite Profiles During Oral Glucose Challenge
    (American Diabetes Association, 2013) Ho, Jennifer E.; Larson, Martin G.; Vasan, Ramachandran S.; Ghorbani, Anahita; Cheng, Susan; Rhee, Eugene; Florez, Jose; Clish, Clary B.; Gerszten, Robert; Wang, Thomas
    To identify distinct biological pathways of glucose metabolism, we conducted a systematic evaluation of biochemical changes after an oral glucose tolerance test (OGTT) in a community-based population. Metabolic profiling was performed on 377 nondiabetic Framingham Offspring cohort participants (mean age 57 years, 42% women, BMI 30 kg/m2) before and after OGTT. Changes in metabolite levels were evaluated with paired Student t tests, cluster-based analyses, and multivariable linear regression to examine differences associated with insulin resistance. Of 110 metabolites tested, 91 significantly changed with OGTT (P ≤ 0.0005 for all). Amino acids, β-hydroxybutyrate, and tricarboxylic acid cycle intermediates decreased after OGTT, and glycolysis products increased, consistent with physiological insulin actions. Other pathways affected by OGTT included decreases in serotonin derivatives, urea cycle metabolites, and B vitamins. We also observed an increase in conjugated, and a decrease in unconjugated, bile acids. Changes in β-hydroxybutyrate, isoleucine, lactate, and pyridoxate were blunted in those with insulin resistance. Our findings demonstrate changes in 91 metabolites representing distinct biological pathways that are perturbed in response to an OGTT. We also identify metabolite responses that distinguish individuals with and without insulin resistance. These findings suggest that unique metabolic phenotypes can be unmasked by OGTT in the prediabetic state.
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    Distinct Metabolomic Signatures Are Associated with Longevity in Humans
    (2015) Cheng, Susan; Larson, Martin G.; McCabe, Elizabeth L.; Murabito, Joanne M.; Rhee, Eugene; Ho, Jennifer E.; Jacques, Paul F.; Ghorbani, Anahita; Magnusson, Martin; Souza, Amanda L.; Deik, Amy A.; Pierce, Kerry A.; Bullock, Kevin; O’Donnell, Christopher J.; Melander, Olle; Clish, Clary B.; Vasan, Ramachandran S.; Gerszten, Robert; Wang, Thomas
    Alterations in metabolism influence lifespan in experimental models, but data in humans are lacking. Here we use liquid chromatography/mass spectrometry to quantify 217 plasma metabolites and examine their relation to longevity in a large cohort of men and women. In 647 individuals followed for up to 20 years, higher concentrations of the citric acid cycle intermediate, isocitrate, and the bile acid, taurocholate, are associated with lower odds of longevity, defined as attaining 80 years of age. In a larger cohort of 2,327 individuals with metabolite data available, higher concentrations of isocitrate but not taurocholate are also associated with worse cardiovascular health at baseline, as well as risk of future cardiovascular disease and death. None of the metabolites identified are associated with cancer risk. Our findings suggest that some, but not all, metabolic pathways to human longevity are dependent on modifying risk for the two most common causes of death.
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    Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study
    (2015) Vimaleswaran, Karani S; Cavadino, Alana; Berry, Diane J; Jorde, Rolf; Dieffenbach, Aida Karina; Lu, Chen; Alves, Alexessander Couto; Heerspink, Hiddo J Lambers; Tikkanen, Emmi; Eriksson, Joel; Wong, Andrew; Mangino, Massimo; Jablonski, Kathleen A; Nolte, Ilja M; Houston, Denise K; Ahluwalia, Tarunveer Singh; van der Most, Peter J; Pasko, Dorota; Zgaga, Lina; Thiering, Elisabeth; Vitart, Veronique; Fraser, Ross M; Huffman, Jennifer E; de Boer, Rudolf A; Schöttker, Ben; Saum, Kai-Uwe; McCarthy, Mark I; Dupuis, Josée; Herzig, Karl-Heinz; Sebert, Sylvain; Pouta, Anneli; Laitinen, Jaana; Kleber, Marcus E; Navis, Gerjan; Lorentzon, Mattias; Jameson, Karen; Arden, Nigel; Cooper, Jackie A; Acharya, Jayshree; Hardy, Rebecca; Raitakari, Olli; Ripatti, Samuli; Billings, Liana K; Lahti, Jari; Osmond, Clive; Penninx, Brenda W; Rejnmark, Lars; Lohman, Kurt K; Paternoster, Lavinia; Stolk, Ronald P; Hernandez, Dena G; Byberg, Liisa; Hagström, Emil; Melhus, Håkan; Ingelsson, Erik; Mellström, Dan; Ljunggren, Östen; Tzoulaki, Ioanna; McLachlan, Stela; Theodoratou, Evropi; Tiesler, Carla M T; Jula, Antti; Navarro, Pau; Wright, Alan F; Polasek, Ozren; Hayward, Caroline; Wilson, James F; Rudan, Igor; Salomaa, Veikko; Heinrich, Joachim; Campbell, Harry; Price, Jacqueline F; Karlsson, Magnus; Lind, Lars; Michaëlsson, Karl; Bandinelli, Stefania; Frayling, Timothy M; Hartman, Catharina A; Sørensen, Thorkild I A; Kritchevsky, Stephen B; Langdahl, Bente Lomholt; Eriksson, Johan G; Florez, Jose; Spector, Tim D; Lehtimäki, Terho; Kuh, Diana; Humphries, Steve E; Cooper, Cyrus; Ohlsson, Claes; März, Winfried; de Borst, Martin H; Kumari, Meena; Kivimaki, Mika; Wang, Thomas; Power, Chris; Brenner, Hermann; Grimnes, Guri; van der Harst, Pim; Snieder, Harold; Hingorani, Aroon D; Pilz, Stefan; Whittaker, John C; Järvelin, Marjo-Riitta; Hyppönen, Elina
    Summary Background: Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk. Methods: In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium. Findings: In phenotypic analyses (up to n=49 363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (β per 10% increase, −0·12 mm Hg, 95% CI −0·20 to −0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97−0·99; p=0·0003), but not with decreased diastolic blood pressure (β per 10% increase, −0·02 mm Hg, −0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of −0·10 mm Hg in systolic blood pressure (−0·21 to −0·0001; p=0·0498) and a change of −0·08 mm Hg in diastolic blood pressure (−0·15 to −0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96−0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of −0·29 mm Hg in diastolic blood pressure (−0·52 to −0·07; p=0·01), a change of −0·37 mm Hg in systolic blood pressure (−0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87–0·97; p=0·002). Interpretation Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study.
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    Loss of the epigenetic mark, 5-Hydroxymethylcytosine, correlates with small cell/nevoid subpopulations and assists in microstaging of human melanoma
    (Impact Journals LLC, 2015) Lee, Jonathan J.; Cook, Martin; Mihm, Martin; Xu, Shuyun; Zhan, Qian; Wang, Thomas; Murphy, George; Lian, Christine
    Melanomas in the vertical growth phase (VGP) not infrequently demonstrate cellular heterogeneity. One commonly encountered subpopulation displays small cell/nevoid morphology. Although its significance remains unknown, such subpopulations may pose diagnostic issues when faced with differentiating such changes from associated nevus or mistaking such regions for nevic maturation (pseudomaturation). That ‘loss’ of the epigenetic biomarker, 5-hydroxymethylcytosine (5-hmC), is a hallmark for melanoma and correlates with virulence prompted us to explore the diagnostic utility and biological implications of 5-hmC immunohistochemistry (IHC) in melanomas with small cell/nevoid subpopulations. Fifty-two cases were included in this study, including melanomas with small cell/nevoid subpopulations (MSCN) or melanomas with pre-existing nevus (MPEN). Semiquantitative and computer-validated immunohistochemical analyses revealed invariable, uniform loss of 5-hmC in the conventional melanoma component. By contrast, the nevic components in MPEN cases demonstrated strong nuclear immunopositivity. In MSCN cases, there was partial to complete loss of 5-hmC restricted to these nevoid areas. Based on recent data supporting tight correlation between 5-hmC loss and malignancy, our findings indicate a potential ‘intermediate’ biological nature for small cell/nevoid subpopulations. Because 5-hmC assisted in differentiating such regions from associated nevus, the use of 5-hmC as an adjunct to microstaging in difficult cases showing VGP heterogeneity should be further explored.