• Mapping study yields novel insights into

    From ScienceDaily@1:317/3 to All on Mon May 2 22:30:42 2022
    Mapping study yields novel insights into DNA-protein connection, paving
    way for researchers to target new treatments

    Date:
    May 2, 2022
    Source:
    Johns Hopkins University Bloomberg School of Public Health
    Summary:
    DNA-to-protein mapping could help researchers understand some
    health disparities.



    FULL STORY ==========================================================================
    A new genetic mapping study led by researchers at the Johns Hopkins
    Bloomberg School of Public Health traces links between DNA variations and thousands of blood proteins in two large and distinct populations. The
    results should help researchers better understand the molecular causes
    of diseases and identify proteins that could be targeted to treat these diseases.


    ==========================================================================
    The study included more than 9,000 Americans of European or African
    ancestry, and generated maps of DNA-to-protein links for both groups. The
    study is thought to be the first of its kind to include two large and ancestrally distinct population cohorts. Proteins play a critical role in cellular function, and changes in protein mechanisms -- often regulated
    by DNA variations -- can lead to disease. DNA-to-protein mapping could
    help explain differences in the rates of some diseases in the two groups
    and help researchers understand some health disparities.

    The study appears May 2 in Nature Genetics.

    Researchers have been mapping the molecular roots of human diseases for
    decades through so-called genetic mapping studies. The best known is the genome-wide association study (GWAS). A GWAS typically links variations
    in DNA to disease risk by analyzing the DNA of subjects -- often tens
    or hundreds of thousands of individuals at a time -- along with their
    history of a given disease. This uncovers statistical associations
    linking the disease to specific DNA variations.

    Missing from the GWAS picture: Most of the disease-linked DNA
    variants identified by GWAS analysis do not lie within protein-coding
    genes. Researchers therefore assumed that many -- even most --
    disease-linked DNA variants affect proteins indirectly, by regulating one
    or more steps in the gene-to-protein production process, thereby altering protein levels. Linking diseases directly to proteins, researchers can
    better understand the roots of disease -- and also identify protein
    targets for disease prevention and treatments.

    "This relatively new kind of mapping study provides a wealth of
    information that will allow researchers to test for potential links of
    proteins on various types of health outcomes--risk of cancers, heart
    disease, severe COVID -- and help to develop or repurpose therapeutic
    drugs," says study senior author Nilanjan Chatterjee, PhD, Bloomberg Distinguished Professor in the Department of Biostatistics at the
    Bloomberg School.



    ==========================================================================
    To demonstrate the DNA-protein mapping's application, the researchers
    used it to identify an existing rheumatoid arthritis drug as a plausible
    new treatment for the common joint-pain disorder known as gout.

    The study was a collaboration between Chatterjee's team and the research
    group of Josef Coresh, MD, George W. Comstock Professor in the Bloomberg School's Department of Epidemiology and one of the paper's co-authors,
    and colleagues at several institutions.

    The analysis covered 7,213 Americans of European ancestry and 1,871
    African Americans in the long-running Atherosclerosis Risk in Communities (ARIC) study, headed by Coresh; and 467 African Americans from the African American Study of Kidney Disease and Hypertension (AASK). In both of these studies, the research teams had sequenced the genomes of the participants
    and recorded bloodstream levels of thousands of distinct proteins.

    For their mapping study, Chatterjee's team analyzed the ARIC and AASK
    genomic data to identify more than two thousand common DNA variations
    that lie close to the genes encoding many of these proteins and correlate
    with the proteins' bloodstream levels.

    "The value of knowing about these DNA variants that predict certain
    protein levels is that we can then examine much larger GWAS datasets to
    see if those same DNA variants are linked to disease risks," Chatterjee
    says.



    ========================================================================== Using a European-American dataset, they found that it predicted several proteins whose levels would influence the risk of gout or bloodstream
    levels of the gout-related chemical urate. These proteins included the interleukin 1 receptor antagonist (IL1RN) protein, which appears to lower
    gout risk -- a finding that suggests the existing rheumatoid arthritis
    drug anakinra, which mimics IL1RN, as a plausible new therapy for gout.

    Having data from both white and Black Americans allowed the researchers
    to map protein-linked DNA variants more finely than if they had been
    restricted to one or the other. The African-ancestry models generated
    in the study will allow future analyses of how different populations'
    genetic backgrounds might contribute to differences in disease rates.

    "We know that prostate cancer risk, for example, is higher in African
    American men, so in principle, one could combine prostate cancer GWAS
    data on African Americans with our protein data to identify proteins
    that contribute to elevated prostate cancer risk in that population," Chatterjee says.

    The team has made its datasets and protein prediction models publicly
    available online so researchers can use the resource. Chatterjee's team
    and collaborators anticipate doing further studies in the ARIC and AASK cohorts, as well as in other diverse cohorts, to gather information
    on proteins and other factors that influence the DNA-to-disease chain
    of causality.

    "Plasma proteome analyses in individuals of European and African ancestry identify cis-pQTLs and models for proteome-wide association studies"
    was co- authored by first authors Jingning Zhang and Diptavo Dutta,
    and by Anna Ko"ttgen, Adrienne Tin, Pascal Schlosser, Morgan Grams,
    Benjamin Harvey, CKDGen Consortium, Bing Yu, Eric Boerwinkle, Josef
    Coresh, and Nilanjan Chatterjee.

    The analysis of this project was supported by a RO1 grant from the
    National Human Genome Research Institute at the National Institutes
    of Health (1 R01 HG010480-01). Additional NIH grants supporting
    this research include R01 HL134320, R01 AR073178, R01 DK124399, and
    HL148218. The Atherosclerosis Risk in Communities study has been
    funded in whole or in part by the National Heart, Lung, and Blood
    Institute; National Institutes of Health; Department of Health and
    Human Services (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I).


    ========================================================================== Story Source: Materials provided by Johns_Hopkins_University_Bloomberg_School_of_Public Health. Note:
    Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Jingning Zhang, Diptavo Dutta, Anna Ko"ttgen, Adrienne Tin, Pascal
    Schlosser, Morgan E. Grams, Benjamin Harvey, Bing Yu, Eric
    Boerwinkle, Josef Coresh, Nilanjan Chatterjee. Plasma proteome
    analyses in individuals of European and African ancestry identify
    cis-pQTLs and models for proteome-wide association studies. Nature
    Genetics, 2022; DOI: 10.1038/s41588-022-01051-w ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/05/220502125402.htm

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