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

Background: Serum calciprotein particle maturation time (T ₅₀), a measure of vascular calcification propensity, is associated with cardiovascular morbidity and mortality. We aimed to identify genetic loci associated with serum T ₅₀ and study their association with cardiovascular disease and mortality. Methods: We performed a genome-wide association study of serum T ₅₀ 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 T ₅₀ on cardiovascular outcomes. Finally, we examined associations between T ₅₀ loci and cardiovascular outcomes in 8,566 community-dwelling participants in the Rotterdam study. Results: 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 T ₅₀. MR did not demonstrate a causal effect of T ₅₀ on cardiovascular outcomes in the general population. Patient-level analyses revealed that the minor allele of rs9870756, which explained 9.1% of variation in T ₅₀, 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)]. Conclusions: We identified three SNPs in the AHSG gene that explained 18.3% of variability in serum T ₅₀ levels. Only one SNP was associated with cardiovascular outcomes, particularly in individuals with type 2 diabetes or chronic kidney disease.