Targeted Deep Resequencing Identifies Coding Variants in the PEAR1 Gene That Play a Role in Platelet Aggregation

• Published in: PloS one Vol. 8; no. 5; p. e64179
• Main Authors: Kim, Yoonhee, Suktitipat, Bhoom, Yanek, Lisa R., Faraday, Nauder, Wilson, Alexander F., Becker, Diane M., Becker, Lewis C., Mathias, Rasika A.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.05.2013; Public Library of Science (PLoS)
• Subjects: Adenosine; Adenosine diphosphate; African Americans; Agglomeration; Alleles; Aspirin; ATPases; Biology; Black or African American - genetics; Blood; Blood platelets; Cardiovascular disease; Chromosome 1; Cohort Studies; Collagen; Coronary vessels; DNA sequencing; Drug dosages; Epinephrine; Exons - genetics; Family medical history; Female; Genes; Genetic Predisposition to Disease; Genetics; Genome-Wide Association Study; Genomes; Genomics; Heart attacks; High-Throughput Nucleotide Sequencing - methods; Humans; Linkage Disequilibrium - genetics; Male; Medical research; Medicine; Middle Aged; Minority & ethnic groups; Mutation; Open Reading Frames - genetics; Platelet aggregation; Platelet Aggregation - genetics; Polymorphism, Single Nucleotide - genetics; Receptors, Cell Surface - genetics; Researchers; Review boards; Studies; White People - genetics; United States > US; Maryland; Baltimore Maryland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0064179

Platelet aggregation is heritable, and genome-wide association studies have detected strong associations with a common intronic variant of the platelet endothelial aggregation receptor1 (PEAR1) gene both in African American and European American individuals. In this study, we used a sequencing approach to identify additional exonic variants in PEAR1 that may also determine variability in platelet aggregation in the GeneSTAR Study. A 0.3 Mb targeted region on chromosome 1q23.1 including the entire PEAR1 gene was Sanger sequenced in 104 subjects (45% male, 49% African American, age = 52±13) selected on the basis of hyper- and hypo- aggregation across three different agonists (collagen, epinephrine, and adenosine diphosphate). Single-variant and multi-variant burden tests for association were performed. Of the 235 variants identified through sequencing, 61 were novel, and three of these were missense variants. More rare variants (MAF<5%) were noted in African Americans compared to European Americans (108 vs. 45). The common intronic GWAS-identified variant (rs12041331) demonstrated the most significant association signal in African Americans (p = 4.020×10(-4)); no association was seen for additional exonic variants in this group. In contrast, multi-variant burden tests indicated that exonic variants play a more significant role in European Americans (p = 0.0099 for the collective coding variants compared to p = 0.0565 for intronic variant rs12041331). Imputation of the individual exonic variants in the rest of the GeneSTAR European American cohort (N = 1,965) supports the results noted in the sequenced discovery sample: p = 3.56×10(-4), 2.27×10(-7), 5.20×10(-5) for coding synonymous variant rs56260937 and collagen, epinephrine and adenosine diphosphate induced platelet aggregation, respectively. Sequencing approaches confirm that a common intronic variant has the strongest association with platelet aggregation in African Americans, and show that exonic variants play an additional role in platelet aggregation in European Americans.