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

• Published in: Frontiers in cardiovascular medicine 2022-01, Vol.8, p.809717-809717
• Main Authors: de Haan, Amber, Ahmadizar, Fariba, van der Most, Peter J, Thio, Chris H L, Kamali, Zoha, Ani, Alireza, Ghanbari, Mohsen, Chaker, Layal, van Meurs, Joyce, Ikram, M Kamran, van Goor, Harry, Bakker, Stephan J L, van der Harst, Pim, Snieder, Harold, Kavousi, Maryam, Pasch, Andreas, Eijgelsheim, Mark, de Borst, Martin H
• Format: Article
• Language: English
• Subjects: AHSG; calcification propensity; cardiovascular disease; Cardiovascular Medicine; GWAS; population genetics; serum T50
• ISSN: 2297-055X; 2297-055X
• DOI: 10.3389/fcvm.2021.809717

Serum calciprotein particle maturation time (T ), a measure of vascular calcification propensity, is associated with cardiovascular morbidity and mortality. We aimed to identify genetic loci associated with serum T and study their association with cardiovascular disease and mortality. We performed a genome-wide association study of serum T 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 on cardiovascular outcomes. Finally, we examined associations between T 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 gene encoding fetuin-A: rs4917 ( = 1.72 × 10 ), rs2077119 ( = 3.34 × 10 ), and rs9870756 ( = 3.10 × 10 ), together explaining 18.3% of variation in serum T . MR did not demonstrate a causal effect of T 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 , 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 gene that explained 18.3% of variability in serum T levels. Only one SNP was associated with cardiovascular outcomes, particularly in individuals with type 2 diabetes or chronic kidney disease.