The ABO gene encodes a glycosyltransferase, which adds sugars (N-acetylgalactos-amine for A and ?-D- galactose for B) to the H antigen substrate. Single nucleotide variants in the ABO gene affect the function of this glycosyltransferase at the molecular level by altering the specificity and efficiency of this enzyme for these specific sugars. Characterizing variation in ABO is important in transfusion and transplantation medicine because variants in ABO have significant consequences with regard to recipient compatibility. Additionally, variation in the ABO gene has been associated with cardiovascular disease risk (e.g., myocardial infarction) and quantitative blood traits (e.g., von Willebrand factor (VWF) Factor VIII (FVIII) and Intercellular Adhesion molecule 1 (ICAM-1). Relating ABO genotypes to actual blood antigen phenotype requires the analysis of haplotypes. My plan is to explore the variation (single nucleotide, insertion and deletions, and structural variation) in the ABO gene using a dataset enriched for heart, lung and blood related diseases (including both African-Americans and European-Americans) from the NHLBI Exome Sequencing Project (ESP) dataset. I will also determine the haplotype structure of the ABO gene and, potentially, increase the accuracy of blood type and subtype calling using the variation in the ESP dataset. Using these haplotype calls, I will explore at least one outcome dataset available in the ESP, early onset myocardial infarction, and a quantitative trait linked to cardiovascular risk where measures are available for the ESP dataset. This work will provide training in areas that are important to my future efforts to explore genotype-phenotype associations in underrepresented populations.
Precise matching has successfully eliminated major life-threatening transfusion reactions. However, adverse outcomes due to donor/recipient antigen mismatches still occur, particularly in chronically transfused patients. My proposal will focus on exploring genetic variation in a key blood group gene, ABO, and will create a new framework for a clinical ABO genotyping system using next-generation sequence (NGS) data. One of the major outcomes of my work will be to provide new insights that: (1) will allow clinicians to call the ABO blood group from NGS data to reduce the risk of adverse reactions and (2) will refine our knowledge for genotype- phenotype correlation in human cardiovascular disease.