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Abstract: FR-OR59

Genetic Determinants of Serum Calcification Propensity and Mortality Risk in CKD

Session Information

Category: CKD (Non-Dialysis)

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

Authors

  • de Haan, Amber, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • Ahmadizar, Fariba, Erasmus MC, Rotterdam, Zuid-Holland, Netherlands
  • Van der Most, Peter Johannes, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • Kamali, Zoha, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • Ani, Alireza, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • Bakker, Stephan J.L., Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • Snieder, Harold, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • Kavousi, Maryam, Erasmus MC, Rotterdam, Zuid-Holland, Netherlands
  • Pasch, Andreas, Calcisco AG, Bern, Switzerland
  • Eijgelsheim, Mark, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • De Borst, Martin H., Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
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