Abstract 13110: Digenic Mutations in GUCY1A3 and CCT7 Increases Risk of Myocardial Infarction in an Extended Family
Myocardial infarction (MI) is a life-threatening disease, which results from sudden atherothrombotic occlusion of a coronary artery. Most cases of MI occur sporadically, but sometimes the disease clusters in families.
We applied whole-exome sequencing in extended MI families to identify disease-related mutations which might illuminate its pathobiology.
Exome sequencing in three affected cousins of a large MI family was performed. Linkage analysis was carried out using the Affymetrix Human Mapping 10K Array. Using CARDIoGRAM data, comprising 22,233 CAD/MI cases and 64,762 controls, we interrogated the association of common SNPs covering GUCY1A3 and CCT7 with MI or CAD. The α1-subunit-dependent cGMP-forming activity was measured in platelets from affected (digenic mutation carriers and GUCY1A3- and CCT7-only carriers) and unaffected family members. We monitored thrombus formation in arterioles in α1-subunit KO mice in response to a confined focused trauma in the microcirculation.
We identified in an extended MI family heterozygous mutations in two functionally related genes, GUCY1A3 (p.Leu163Phefs*24) and CCT7 (p.Ser525Leu), segregating with MI. Out of 15 affected family members available for genetic analysis, 7 and 11 carried GUCY1A3 and/or CCT7 mutations, respectively (two-locus maximum LOD score of 5.68). Moreover, studying 28,733 MI or coronary artery disease (CAD) cases and 75,028 controls by genome-wide association analysis we identified a SNP in GUCY1A3 as associated with MI/CAD (P <1.74x10-8 for rs7692387). Platelets from digenic mutation carriers contained less sGC protein and consequently reduced NO-induced cGMP formation. α1-subunit KO mice displayed accelerated thrombus formation in the microcirculation upon local trauma.
Starting with a severely affected family, we have identified a link, possibly through accelerated thrombus formation, between impaired sGC dependent NO signaling and MI risk which may also relate to more common forms of the disease. Reversing this defect could provide a novel therapeutic target for reducing risk of MI.
- © 2012 by American Heart Association, Inc.