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Sökning: onr:"swepub:oai:lup.lub.lu.se:72cac14a-bfb1-4c22-b4a0-a3edd2c9d336" > Probing the Virtual...

Probing the Virtual Proteome to Identify Novel Disease Biomarkers

Mosley, Jonathan D., (författare)
Vanderbilt University
Benson, Mark D., (författare)
Brigham and Women's Hospital, Boston, Beth Israel Deaconess Medical Center
Smith, J. Gustav, (författare)
Forskargrupper vid Lunds universitet, Lund University Research Groups, Lunds universitet, Lund University, Molecular Epidemiology and Cardiology, Molecular Epidemiology and Cardiology, Skåne University Hospital
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Melander, Olle, (författare)
Forskargrupper vid Lunds universitet, Lund University Research Groups, Lunds universitet, Lund University, Kardiovaskulär forskning - hypertoni, Cardiovascular Research - Hypertension, Skåne University Hospital
Ngo, Debby, (författare)
Harvard University, Massachusetts General Hospital
Shaffer, Christian M., (författare)
Vanderbilt University
Ferguson, Jane F., (författare)
Vanderbilt University
Herzig, Matthew S., (författare)
Beth Israel Deaconess Medical Center
McCarty, Catherine A., (författare)
University of Minnesota
Chute, Christopher G., (författare)
Johns Hopkins University
Jarvik, Gail P., (författare)
University of Washington
Gordon, Adam S., (författare)
University of Washington
Palmer, Melody R., (författare)
University of Washington
Crosslin, David R., (författare)
University of Washington
Larson, Eric B., (författare)
Kaiser Permanente Research Institute, University of Washington
Carrell, David S., (författare)
Kaiser Permanente Research Institute
Kullo, Iftikhar J., (författare)
Mayo Clinic Minnesota
Pacheco, Jennifer A., (författare)
Northwestern University
Peissig, Peggy L., (författare)
Marshfield Clinic
Brilliant, Murray H., (författare)
Marshfield Clinic
Kitchner, Terrie E., (författare)
Marshfield Clinic
Linneman, James G., (författare)
Marshfield Clinic
Namjou, Bahram, (författare)
Cincinnati Children's Hospital Medical Center, University of Cincinnati
Williams, Marc S., (författare)
Geisinger Health System
Ritchie, Marylyn D., (författare)
University of Pennsylvania
Borthwick, Kenneth M., (författare)
Geisinger Health System
Kiryluk, Krzysztof, (författare)
Columbia University
Mentch, Frank D., (författare)
The Children's Hospital of Philadelphia
Sleiman, Patrick M., (författare)
The Children's Hospital of Philadelphia
Karlson, Elizabeth W., (författare)
Harvard University, Brigham and Women's Hospital, Boston
Verma, Shefali S., (författare)
University of Pennsylvania
Zhu, Yineng, (författare)
Boston University
Vasan, Ramachandran S., (författare)
Boston University
Yang, Qiong, (författare)
Boston University
Denny, Josh C., (författare)
Vanderbilt University
Roden, Dan M., (författare)
Vanderbilt University
Gerszten, Robert E., (författare)
Beth Israel Deaconess Medical Center
Wang, Thomas J., (författare)
Vanderbilt University
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2018
Engelska 13 s.
Ingår i: Circulation. - Lippincott Williams and Wilkins. - 1524-4539. ; 138:22, s. 2469-2481
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • BACKGROUND: Proteomic approaches allow measurement of thousands of proteins in a single specimen, which can accelerate biomarker discovery. However, applying these technologies to massive biobanks is not currently feasible because of the practical barriers and costs of implementing such assays at scale. To overcome these challenges, we used a "virtual proteomic" approach, linking genetically predicted protein levels to clinical diagnoses in >40 000 individuals. METHODS: We used genome-wide association data from the Framingham Heart Study (n=759) to construct genetic predictors for 1129 plasma protein levels. We validated the genetic predictors for 268 proteins and used them to compute predicted protein levels in 41 288 genotyped individuals in the Electronic Medical Records and Genomics (eMERGE) cohort. We tested associations for each predicted protein with 1128 clinical phenotypes. Lead associations were validated with directly measured protein levels and either low-density lipoprotein cholesterol or subclinical atherosclerosis in the MDCS (Malmö Diet and Cancer Study; n=651). RESULTS: In the virtual proteomic analysis in eMERGE, 55 proteins were associated with 89 distinct diagnoses at a false discovery rate q<0.1. Among these, 13 associations involved lipid (n=7) or atherosclerosis (n=6) phenotypes. We tested each association for validation in MDCS using directly measured protein levels. At Bonferroni-adjusted significance thresholds, levels of apolipoprotein E isoforms were associated with hyperlipidemia, and circulating C-type lectin domain family 1 member B and platelet-derived growth factor receptor-β predicted subclinical atherosclerosis. Odds ratios for carotid atherosclerosis were 1.31 (95% CI, 1.08-1.58; P=0.006) per 1-SD increment in C-type lectin domain family 1 member B and 0.79 (0.66-0.94; P=0.008) per 1-SD increment in platelet-derived growth factor receptor-β. CONCLUSIONS: We demonstrate a biomarker discovery paradigm to identify candidate biomarkers of cardiovascular and other diseases.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Kardiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)

Nyckelord

atherosclerosis
biomarkers
electronic health records
proteomics

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