Kidney Week

Abstract: FR-OR59

Genetic Determinants of Serum Calcification Propensity and Mortality Risk in CKD

Session Information

• Findings from Landmark Trials, Other Kidney Trials, and Observational Studies
  November 05, 2021 | Location: Simulive, Virtual Only
  Abstract Time: 04:30 PM - 06:00 PM

Category: CKD (Non-Dialysis)

• 2101 CKD (Non-Dialysis): Epidemiology, Risk Factors, and Prevention

Authors

• de Haan, Amber, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands

Amber de Haan, MD

• Ahmadizar, Fariba, Erasmus MC, Rotterdam, Zuid-Holland, Netherlands

Fariba Ahmadizar,

• Van der Most, Peter Johannes, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands

Peter Johannes Van der Most,

• Kamali, Zoha, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands

Zoha Kamali,

• Ani, Alireza, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands

Alireza Ani,

• Bakker, Stephan J.L., Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands

Stephan J.L. Bakker,

• Snieder, Harold, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands

Harold Snieder,

• Kavousi, Maryam, Erasmus MC, Rotterdam, Zuid-Holland, Netherlands

Maryam Kavousi,

• Pasch, Andreas, Calcisco AG, Bern, Switzerland

Andreas Pasch,

• Eijgelsheim, Mark, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands

Mark Eijgelsheim,

• De Borst, Martin H., Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands

Martin H. De Borst,

Background

Serum calciprotein particle maturation time (T₅₀), a measure of calcification propensity, is associated with cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). Here, we aimed to identify genetic loci for serum T₅₀ and examine whether these loci are linked with adverse outcomes.

Methods

We performed a genome-wide association study (GWAS) of serum T₅₀ in 2,739 community-dwelling individuals of mostly European descent. Subsequently, we used the community-based Rotterdam study (RS) to examine the association between the identified variants and all-cause mortality in the general population and in a subgroup of CKD patients, applying multivariate logistic regression analysis.

Results

We identified three independent genome-wide significant single nucleotide polymorphism (SNPs), rs4917 (p=1.72 x 10^-101), rs2077119 (p=3.34 x 10^-18), and rs9870756 (p=3.10 x 10^-8) in the AHSG gene encoding fetuin-A. The three SNPs together explained 18.3% of the variation in serum T₅₀. Quantitative trait locus analysis revealed that all three SNPs have effects detectable at blood protein level of fetuin-A. Associations with outcomes were studied in 8,556 RS participants (age 65.1±9.9 y, 57% female, 63% hypertension, BMI 27.3±4.2 kg/m²), of whom 833 had CKD (age 75.5±8.7 y, 59% female, 85% hypertension, BMI 27.7±4.1 kg/m²). The minor allele of rs9870756, linked with a reduced T₅₀ and thus a higher calcification propensity, was significantly associated with a higher risk of all-cause mortality, both in the general population [OR (95% CI)=1.14 (1.00-1.30)] and in the CKD subgroup [OR (95% CI)=1.60 (1.05-2.42)]. In the fully adjusted model, the minor allele of rs9870756 was only associated with all-cause mortality in the CKD subgroup [OR (95% CI)=1.93 (1.21-3.08)]. The other two variants were not associated with all-cause mortality.

Conclusion

We identified three independent SNPs in the fetuin-A gene as strong genetic determinants of calcification propensity. The minor allele of rs9870756 was significantly associated with a higher risk of all-cause mortality in CKD patients. Our findings connect genetic susceptibility to calcification with adverse outcome in CKD patients.

Funding

• Commercial Support –