Abstract
Background: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.Methods: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.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 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)].Conclusions: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.
Highlights
Arterial calcification is associated with an increased risk of cardiovascular morbidity and mortality in the general population, independent of traditional cardiovascular risk factors such as hypertension, smoking, and dyslipidemia [1,2,3]
We recently reported an association between a lower T50 and a higher risk of cardiovascular mortality in the general population, which was more pronounced in patients with type 2 diabetes (T2D) at baseline [15]
T50 Genome-wide association studies (GWASs) in 2,739 Prevention of REnal and Vascular ENd-stage Disease (PREVEND) participants revealed 171 genetic variants in a single locus on chromosome 3 that were genome-wide significantly associated with serum T50 (Supplementary Table 1)
Summary
Arterial calcification is associated with an increased risk of cardiovascular morbidity and mortality in the general population, independent of traditional cardiovascular risk factors such as hypertension, smoking, and dyslipidemia [1,2,3]. Calcification propensity can be quantified in serum using the T50-test, which evaluates the transformation time from primary to secondary calciprotein particles (CPPs) in supersaturating conditions of calcium and phosphate [6]. Calcium and phosphate precipitation in serum is prevented by the formation of primary CPPs. Primary CPPs can spontaneously transform into secondary CPPs, which can induce calcification in vascular smooth muscle cells [7]. 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
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