Project Grant R01HL173869

MULTI-OMIC CHARACTERIZATION OF COPD IN FEMALES - ABSTRACT COPD IS THE FOURTH LEADING CAUSE OF DEATH FOR WOMEN IN THE UNITED STATES, WHICH HAS A STRONG GENETIC BASIS. STUDIES HAVE DEMONSTRATED THE HERITABILITY OF COPD TO BE ~40%. DESPITE THE ENORMOUS BURDEN OF COPD, THERE ARE STILL NO PHARMACOLOGIC THERAPIES THAT SLOW PROGRESSION OF DISEASE OR REDUCE MORTALITY, INDICATING THE NEED FOR A BETTER UNDERSTANDING OF THE GENETIC BASIS OF THE DISEASE. NOTABLY, COPD SHOWS SEX DIFFERENCES IN DISEASE PREVALENCE, PATHOLOGY, AND SYMPTOMS. ALTHOUGH HISTORICALLY THOUGHT TO AFFECT PRIMARILY MEN, THE RISK OF COPD IN WOMEN HAS INCREASED OVER TIME DUE TO GROWING PREVALENCE OF SMOKING AND EXPOSURE TO HARMFUL POLLUTANTS. THUS, OVER THE PAST DECADE, AGE-ADJUSTED PREVALENCE OF COPD HAS BEEN CONSISTENTLY HIGHER IN WOMEN THAN IN MEN. MOREOVER, WOMEN REPORT GREATER BREATHLESSNESS AT SIMILAR DEGREES OF AIRFLOW OBSTRUCTION AND EMPHYSEMA SEVERITY, AND EXPERIENCE >25% MORE EXACERBATIONS THAN MEN. DESPITE THE SEX DIFFERENCES, MOST OMICS STUDIES OF COPD COMBINE BOTH SEXES TOGETHER AND LARGE-SCALE FEMALE SPECIFIC COPD STUDIES ARE LACKING. IN THIS APPLICATION, WE PROPOSE NOVEL APPROACHES TO CONDUCT FEMALE-SPECIFIC GWAS, BORROWING STRENGTH FROM SUMMARY STATISTICS FROM LARGE SEX-COMBINED GWAS OF COPD. WE WILL ALSO GENERATE SINGLE CELL RNASEQ DATA FROM FEMALE LUNG AND INTEGRATE CELL TYPE SPECIFIC EQTLS WITH GWAS TO IDENTIFY RISK GENES. BESIDES, WE WILL ASSEMBLE A LARGE MULTI-ANCESTRY PLASMA PROTEOMICS DATASET, GENERATE FEMALE SPECIFIC PQTLS, AND USE THEM TO IDENTIFY COPD BIOMARKERS. RESULTS FROM THIS STUDY WILL BRING NOVEL INSIGHTS INTO THE MECHANISMS OF COPD IN FEMALES AND IDENTIFY PROTEIN BIOMARKERS TO AID IN THE DIAGNOSIS.