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.
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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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