Abstract
Background: There is limited information regarding genetic contributions to atherosclerotic aortic calcification, an important predictor of cardiovascular disease. Methods: We conducted a genome-wide association study (GWAS) meta-analysis with subsequent replication analysis to define single nucleotide polymorphisms (SNPs) associated with abdominal (AAC) or thoracic aortic calcification (TAC). AAC and TAC were quantified using multi-detector computed tomography. SNPs were assayed by Illumina or Affymetrix arrays and imputation at the cohort level was performed using data from the 1000 Genomes project. Results: 9417 individuals of European descent from four cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) consortium were included in the AAC discovery analysis and 8422 individuals from five cohorts in the TAC discovery analysis. SNPs achieving genome-wide significance were tested for replication in four additional cohorts with Hispanic-American (HA) and African-American (AA) participants. Two regions contained SNPs associated at a genome-wide level for AAC (p<5.0x10 -8 , Table), the HDAC9 (chromosome 7, 6 SNPs) and RAP1GAP (chromosome 1, 2 SNPs) genetic loci. All six HDAC9 SNPs were associated with AAC in HA. Among these, rs2107595 was associated with AAC both in HA (p=2.8x10 -6 ) and in AA (p=0.01). SNPs in RAP1GAP were not associated with AAC in the replication analysis. No SNPs were associated with TAC at the genome-wide threshold. SNPs in the HDAC9 locus were associated with other forms of calcification (coronary artery calcification) as well as clinically apparent coronary heart disease (p<0.05). Conclusions: SNPs in the HDAC9 locus are associated with the presence of AAC in participants of European descent. This association was replicated in other ethnic groups in the United States. These findings suggest a novel role for HDAC9 in the development of abdominal aortic calcification.
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