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Principal Investigator: LUISA N BORRELL
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $700,325
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Asthma is the most common chronic disorder of children, with an estimated 300 million cases worldwide and
with significant increases in incidence since the early 1980s. In the United States (U.S.), asthma prevalence,
morbidity, mortality, and drug response vary substantially among racial and ethnic groups. While asthma was
previously regarded as being a single clinical entity with a number of diagnostic criteria, it is now widely
recognized that asthma represents multiple different pathobiological and clinical subtypes, which may underlie
observed racial and ethnic variation. Furthermore, an individual's risk of developing asthma reflects a summation
of genetic as well as various clinical risk factors. Importantly, clinical risk factors are not randomly distributed
across racial and ethnic groups, and certain populations are more burdened than others.
Our goal in this work is to identify cell types, genes, and pathways altered by exposure to clinical risk factors,
thereby improving mechanistic understanding of asthma subtypes and elucidating the underlying networks by
which these risk factors affect asthma disparities. To achieve this goal, we will determine the epigenetic profiles
of patients with and without known asthma risk factors (Aim 1), identify common and unique epigenetic profiles
associated with known and novel clinical asthma subtypes (Aim 2), and examine the contribution of common
and unique epigenetic changes to the association of clinical risk factors with clinical asthma subtypes (Aim 3).
We hypothesize that DNA methylation will provide the bridge that ties clinical risk factors with asthma
disease subtypes and that this relationship may be modified by self-identified race/ethnicity and genetic ancestry
thereby contributing to asthma disparities. Strong preliminary data from our group and others have shown that
methylation, a long lasting but dynamic measure of cellular states, is highly correlated with exposure to clinical
asthma risk factors, including early life respiratory infection, obesity, and maternal history of asthma. To execute
this research program, we have assembled an interdisciplinary team with complementary expertise in
epidemiology, clinical asthma, genetics, epigenetics, and statistical methods. Our team will study a unique cohort
of minority children at the extremes of asthma prevalence and mortality (high risk Puerto Ricans and African
Americans, and low risk Mexican Americans), who have existing demographic data, clinical exposures,
genotypes, and RNA/DNA sequences. To our knowledge, there are no other groups within or outside the U.S.
with populations as detailed as ours that are large enough to be well powered for these analyses. Therefore, we
are the only group with the population needed and track record to successfully complete this project.
Findings from our work will help: (i) provide the clinical and biomedical research communities with the largest
methylation dataset on minority children produced to date, with a substantially increased value due to existing
clinical, socio-environmental, and genetic data, (ii) improve risk profiling, especially for minority children, and (iii)
precisely treat patients by selecting interventions using epigenetic markers accounting for clinical risk factors.
Terms: <0-11 years old><Accounting><Address><Admixture><Affect><African American><African American group><African American individual><African American people><African American population><African Americans><Afro American><Afroamerican><Air Pollution><Airway infections><Algorithms><Allergic Disease><Allergic asthma><American><Asthma><Biological Markers><Biomedical Research><Blood Eosinophil><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Serum><Blood leukocyte><Bronchial Asthma><Bronchial-Dilating Agents><Bronchodilator Agents><Bronchodilators><Chicanas><Chicanos><Child><Child Youth><Children (0-21)><Chronic Disease><Chronic Illness><Clinical><Clinical Research><Clinical Study><Collaborations><Communities><Complex><Cytosine><DNA Methylation><DNA Sequence><Data><Data Set><Death Rate><Disease><Disorder><Disparities><Disparity><Drugs><Environment><Environmental Epidemiology><Environmental Factor><Environmental Risk Factor><Eosinophilic Granulocyte><Eosinophilic Leukocyte><Epidemiology><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Ethnic Group><Ethnic Origin><Ethnic People><Ethnic Population><Ethnic individual><Ethnicity><Ethnicity People><Ethnicity Population><Exposure to><Extrinsic asthma><Family Medical History><Family Medical History Epidemiology><Family history of><Funding><Genes><Genetic><Genetic predisposing factor><Genomics><Genotype><Goals><Guanine><Heterogeneity><Hispanic><History><IgE><Immune response><Immunoglobulin E><Immunological response><Incidence><Individual><Intervention><Intervention Strategies><Latino><Leukocytes><Leukocytes Reticuloendothelial System><Life><Marrow Eosinophil><Marrow Neutrophil><Marrow leukocyte><Measures><Mediating><Mediation><Medication><Methylation><Mexican><Mexican Americans><Morbidity><Morbidity - disease rate><Negotiating><Negotiation><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Non-Polyadenylated RNA><Obesity><Outcome><Participant><Pathway interactions><Patient Selection><Peripheral><Pharmaceutical Preparations><Phenotype><Phosphates><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Prevalence><Puerto Rican><RNA><RNA Gene Products><RNA Sequences><Race><Races><Racial Group><Recording of previous events><Research><Respiratory Disease><Respiratory Infections><Respiratory System Disease><Respiratory System Disorder><Respiratory Tract Infections><Ribonucleic Acid><Risk><Risk Factors><Science><Serum><Site><Social Environment><Spirometry><Statistical Methods><Testing><Tobacco smoke><United States><Variant><Variation><White Blood Cells><White Cell><Work><adiposity><adolescent minority><atopic asthma><bio-markers><biologic marker><biomarker><cell type><chronic disorder><clinical effect><clinical epidemiology><clinical risk><clinical subtypes><cohort><corpulence><diagnostic criteria><disease subgroups><disease subtype><disorder subtype><disparities in race><disparity due to race><disparity in ethnic><disparity in health><drug/agent><entire genome><environmental risk><eosinophil><epidemiologic><epidemiological><epigenetic biomarker><epigenetic marker><epigenetic variation><epigenetically><epigenomics><ethnic based disparity><ethnic disadvantage><ethnic disparity><ethnic identity><ethnic inequality><ethnic inequity><ethnic minority><ethnic subgroup><ethnicity disparity><ethnicity group><extrinsic allergic asthma><full genome><functional genomics><genetic risk factor><genome scale><genome-wide><genomewide><genomic data><genomic data-set><genomic dataset><health disparity><high risk><histories><host response><immune system response><immunoresponse><improved><inequality due to race><inequity due to race><inherited factor><inorganic phosphate><interventional strategy><kids><lumen dilator><methylation pattern><minority children><minority youth><mortality><mortality rate><mortality ratio><neutrophil><novel><pathway><patient profile><pediatric minority><power analysis><profiles in patients><programs><race based disparity><race based inequality><race based inequity><race disparity><race related disparity><race related inequality><race related inequity><racial><racial background><racial disparity><racial inequality><racial inequity><racial minority><racial origin><racial population><racial subgroup><racially unequal><response><skin prick test><social climate><social context><social epidemiology><social factors><socioenvironment><socioenvironmental><statistic methods><therapeutic target><white blood cell><white blood corpuscle><whole genome><young minority><youngster>