期刊
FRONTIERS IN CARDIOVASCULAR MEDICINE
卷 8, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fcvm.2021.809717
关键词
calcification propensity; serum T-50; GWAS; cardiovascular disease; population genetics; AHSG; fetuin-A
资金
- stimulate public-private partnerships [RVO/6320, IMAGEN/LSHM20009]
- Dutch Kidney Foundation [E.033]
- Erasmus MC University Medical Center and Erasmus University Rotterdam
- Netherlands Organization for Scientific Research (NWO)
- Netherlands Organization for Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly (RIDE)
- Netherlands Genomics Initiative (NGI)
- Ministry of Education, Culture and Science
- Ministry of Health, Welfare and Sports
- European Commission (DG XII)
- Municipality of Rotterdam
This study identified three SNPs in the AHSG gene associated with serum T-50 variability, with one SNP being associated with cardiovascular outcomes, particularly in individuals with type 2 diabetes or chronic kidney disease.
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 x 10(-101)), rs2077119 (p = 3.34 x 10(-18)), and rs9870756 (p = 3.10 x 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.
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