Abstract 14242: Missense Mutation in Adcy8 Linked to Myocardial Infarction
Background: Our group established a collection of myocardial infarction (MI)-families with 2-5 affected first- and second-degree relatives. Identification of the underlying mutations may help to further explain the complex etiology of MI. Thus, we were able to narrowing down substantially the region which might carry the underlying mutation.
Methods: We first performed a genome-wide linkage analysis with 805 microsatellites on 25 families (596 individuals) and narrow down the linkage signal in one of the families (23 individuals) by genotyping the Affymetrix 10K array. Subsequent whole exome sequencing was carried out in two affected cousins in this family using the Agilent SureSelect 38 Mb Kit.
Results: We found a linkage peak in one of the families on chromosome 8q24 spanning approximately 12 Mb (LOD=2.4 (p=0.0004)). Overall, sequencing in two affected members identified 26 potential deleterious mutations (missense and nonsense mutations) in the whole exome. In the region on chromosome 8q24 only one potential disease-causing mutation was found. This valine to isoleucine exchange (p.V602I) in the gene adenylyl cyclase 8 (ADCY8) cosegregates with the disease in the family, each affected member (n=6) carried the variant. The mutation p.V602I was not found in 2,722 CAD cases and 3,036 controls. ADCY8 encodes adenylate cyclase, a membrane bound enzyme that catalyzes the formation of cyclic AMP from ATP in a calcium dependent fashion. The functional role of the gene in atherosclerosis remains elusive.
Conclusion: A combination of linkage analysis and whole exome sequencing identified a mutation in ADCY8 leading to Mi and thus a gene hitherto not related to the disease. The functionality of this gene with regard to the disease remains unclear. Further experiments to establish the role of ADCY8 in CAD/MI are ongoing.
- © 2012 by American Heart Association, Inc.