Genetic variations in G-protein signal pathways influence progression of coronary artery calcification: Results from the Heinz Nixdorf Recall study

Background and aims: Coronary artery calcification (CAC) is one of the most sensitive and specific markers of coronary atherosclerosis and believed to be heritable. We hypothesized that functionally relevant single-nucleotide polymorphisms (SNPs) in the G-protein signal pathway, which have been previously related to coronary artery disease, are associated with CAC progression.

Methods: 3108 participants from the Heinz Nixdorf Recall study with CAC measurements at both baseline (CACb) and 5-year follow-up (CAC5y) were included. We genotyped SNPs rs1042714 (ADRB2), rs6026584 and rs12481583 (GNAS), and rs5443 (GNB3) and defined a priori risk alleles derived from literature data. Regression analyses were applied to measures of 5-year CAC progression, unadjusted, adjusted for age, sex, and adjusted for age, sex, log(CACb+1) as well as for cardiovascular risk factors.

Results: The presence of one or more risk alleles was associated with a 26.9% (95% CI 5.5-52.4) increase in 5-year CAC progression (p = 0.011) and a 29.2% (95% CI 5.9-57.6) accelerated increase of CAC over the 5-year period compared to what was expected with respect to the baseline CAC percentile value (p = 0.012). Each of those risk alleles increased the 5-year CAC progression by 4.4% (95% CI 1.3-7.6, p = 0.006) and resulted in a 4.9% accelerated increase of CAC over the 5-year period (95% CI 1.6-8.4, p = 0.004). These unadjusted data did not change after adjustment.

Conclusions: Genetic variations in the G-protein signal pathway are associated with CAC progression in a cumulative fashion, indicating the importance of the pathway for genetic heritability in CAC progression and coronary artery disease.