Abstract 3933: Genetic Linkage of Aortic Valve Sclerosis and Mitral Annular Calcification: The HyperGEN Study
Background: Aortic valve sclerosis (AVS) and mitral annular calcification (MAC) are associated with adverse cardiovascular outcomes. It remains unclear whether genetic factors contribute to the susceptibility to AVS or MAC.
Methods and Results: Echocardiograms and genotyping were performed in hypertensive siblings who participated in the Hypertension Genetic Epidemiology Network (HyperGEN) Study. Genome-wide affected sibpair nonparametric linkage analysis was conducted using the allele-sharing model method implemented in the MERLIN computer program. 1,871 hypertensive siblings from 858 families (1,014 sibships) were evaluated for AVS and/or MAC. Of these, 68 families (78 sibships) contained at least two affected siblings who were affected with at least one type of valve calcification (142 affected siblings in total). All the three traits showed modest degree of familial aggregation, with sibling recurrence risk (Ks, SD) and sibling recurrence risk ratio (λs, 95% CI) being 0.25 (0.035) and 2.31 (1.72~3.11) for AVS, 0.25 (0.035) and 1.78 (1.36~2.33) for MAC, and 0.31 (0.030) and 1.52 (1.24~1.85) for AVS and/or MAC, respectively. Affected sibpair linkage analysis revealed the highest LOD score (3.14) in chromosome 16 at 105.6 cM for AVS. Other chromosomal regions with LOD score≥1.9 were found in chromosomes 19 (at 48.0 cM, LOD score=2.88), 16 (at 130.4 cM, LOD score=2.63), 1 (at 251.7 cM, LOD score=2.12) and 2 (at 251.9 cM, LOD score=2.03) for AVS and chromosome 13 (at 85.0 cM, LOD score=2.12) for AVS and/or MAC. There was no LOD≥1.9 for MAC.
Conclusion: Our study shows strong linkage of AVS to chromosome 16q22.1-q22.3 and suggestive linkage to chromosome 19p13.11-p11 and identifies several other promising genomic regions that may contain specific susceptibility loci for valve calcification. Studies are underway to identify the specific genes contained in these chromosomal regions that are responsible for the observed linkage results.