Genome-wide association and linkage analysis of histidine-rich glycoprotein identifies common variants associated with plasma histidine-rich glycoprotein concentrations

Background: The plasma protein histidine-rich glycoprotein (HRG) interacts with multiple plasma ligands with various roles in coagulation, immunity, and angiogenesis. Through its inhibition of factor XIIa, HRG regulates the contact pathway of blood coagulation. Plasma HRG concentrations are highly heritable and vary widely, which may impact HRG function. Objectives: To determine the genetic factors contributing to HRG variability. Methods: Plasma HRG concentrations were measured in a healthy sibling cohort of 1152 subjects and a second healthy cohort of 2304 individuals of Irish descent. We performed genome-wide association study and meta-analysis on the European subset of these cohorts. Using the sibling subset of the 2 cohorts (n = 934 in 460 sibships), we explored linkage patterns to identify additional signals associated with variation in HRG concentrations that may be driven by rare variants. Two HRG missense variants associated with decreased HRG concentrations were expressed in vitro. Results: Narrow-sense heritability was estimated at 69%. Meta-analysis identified an association between HRG concentrations and 2 independent signals at the HRG locus. Variants at these chromosome 3 loci collectively explained 45% of the variation in HRG concentrations. In vitro expression of 2 HRG variants associated with decreased HRG concentrations had no impact on HRG secretion. Linkage analysis of HRG concentrations identified 3 further regions contributing to differences in HRG concentrations. Conclusion: The results of this genome-wide association study, investigating HRG concentration variation in a healthy population, provide new insights into the genetic control of circulating HRG concentrations and generate data for colocalization and Mendelian randomization studies.