Genetic Determinants of Serum Calcification Propensity and Cardiovascular Outcomes in the General Population

Serum calciprotein particle maturation time (T₅₀), a measure of vascular calcification propensity, is associated with cardiovascular morbidity and mortality. We aimed to identify genetic loci associated with serum T₅₀ and study their association with cardiovascular disease and mortality.

We performed a genome-wide association study of serum T₅₀ in 2,739 individuals of European descent participating in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, followed by a two-sample Mendelian randomization (MR) study to examine causal effects of T₅₀ on cardiovascular outcomes. Finally, we examined associations between T₅₀ loci and cardiovascular outcomes in 8,566 community-dwelling participants in the Rotterdam study.

We identified three independent genome-wide significant single nucleotide polymorphism (SNPs) in the AHSG gene encoding fetuin-A: rs4917 (p = 1.72 × 10^-101), rs2077119 (p = 3.34 × 10^-18), and rs9870756 (p = 3.10 × 10^-8), together explaining 18.3% of variation in serum T₅₀. MR did not demonstrate a causal effect of T₅₀ on cardiovascular outcomes in the general population. Patient-level analyses revealed that the minor allele of rs9870756, which explained 9.1% of variation in T₅₀, was associated with a primary composite endpoint of all-cause mortality or cardiovascular disease [odds ratio (95% CI) 1.14 (1.01-1.28)] and all-cause mortality alone [1.14 (1.00-1.31)]. The other variants were not associated with clinical outcomes. In patients with type 2 diabetes or chronic kidney disease, the association between rs9870756 and the primary composite endpoint was stronger [OR 1.40 (1.06-1.84), relative excess risk due to interaction 0.54 (0.01-1.08)].

We identified three SNPs in the AHSG gene that explained 18.3% of variability in serum T₅₀ levels. Only one SNP was associated with cardiovascular outcomes, particularly in individuals with type 2 diabetes or chronic kidney disease.