title: TESTING POPULATION-SPECIFIC QUANTITATIVE TRAIT ASSOCIATIONS FOR CLINICAL OUTCOME RELEVANCE IN A BIOREPOSITORY LINKED TO ELECTRONIC HEALTH RECORDS: LPA AND MYOCARDIAL INFARCTION IN AFRICAN AMERICANS.
abstract: Previous candidate gene and genome-wide association studies have identified common genetic variants in LPA associated with the quantitative trait Lp(a), an emerging risk factor for cardiovascular disease. These associations are population-specific and many have not yet been tested for association with the clinical outcome of interest. To fill this gap in knowledge, we accessed the epidemiologic Third National Health and Nutrition Examination Surveys (NHANES III) and BioVU, the Vanderbilt University Medical Center biorepository linked to de-identified electronic health records (EHRs), including billing codes (ICD-9-CM) and clinical notes, to test population-specific Lp(a)-associated variants for an association with myocardial infarction (MI) among African Americans. We performed electronic phenotyping among African Americans in BioVU≥40 years of age using billing codes. At total of 93 cases and 522 controls were identified in NHANES III and 265 cases and 363 controls were identified in BioVU. We tested five known Lp(a)-associated genetic variants (rs1367211, rs41271028, rs6907156, rs10945682, and rs1652507) in both NHANES III and BioVU for association with myocardial infarction. We also tested LPA rs3798220 (I4399M), previously associated with increased levels of Lp(a), MI, and coronary artery disease in European Americans, in BioVU. After meta-analysis, tests of association using logistic regression assuming an additive genetic model revealed no significant associations (p<0.05) for any of the five LPA variants previously associated with Lp(a) levels in African Americans. Also, I4399M rs3798220 was not associated with MI in African Americans (odds ratio = 0.51; 95% confidence interval: 0.16 - 1.65; p=0.26) despite strong, replicated associations with MI and coronary artery disease in European American genome-wide association studies. These data highlight the challenges in translating quantitative trait associations to clinical outcomes in diverse populations using large epidemiologic and clinic-based collections as envisioned for the Precision Medicine Initiative.
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, 519 Light Hall, 2215 Garland Avenue, Nashville, TN 37232, USA, logandumitrescu@gmail.com.
authors.forename: Logan
authors.initials: L
authors.lastname: Dumitrescu
authors.forename: Kirsten E
authors.initials: KE
authors.lastname: Diggins
authors.forename: Robert
authors.initials: R
authors.lastname: Goodloe
authors.forename: Dana C
authors.initials: DC
authors.lastname: Crawford
mesh_terms: D001741:Black or African American / Q000235:genetics*; D019295:Computational Biology / Q000379:methods / Q000706:statistics & numerical data; D057286:Electronic Health Records / Q000706:statistics & numerical data; D005260:Female; D056726:Genetic Association Studies / Q000706:statistics & numerical data; D006801:Humans; D017270:Lipoprotein(a) / Q000097:blood / Q000235:genetics*; D008297:Male; D009203:Myocardial Infarction / Q000097:blood / Q000235:genetics*; D009749:Nutrition Surveys; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D014481:United States
chemical_list: D017270:Lipoprotein(a)