Elsevier

American Heart Journal

Volume 168, Issue 1, July 2014, Pages 96-102.e2
American Heart Journal

Clinical Investigation
Genetics
Polymorphism of the cystatin C gene in patients with acute coronary syndromes: Results from the PLATelet inhibition and patient Outcomes study

https://doi.org/10.1016/j.ahj.2014.03.010Get rights and content

Purpose

Elevated cystatin C concentration is an independent risk factor for cardiovascular (CV) events in patients with acute coronary syndromes. Genetic polymorphisms in CST3 influence cystatin C levels, but their relationship to outcomes is unclear.

Methods

We measured cystatin C concentrations in plasma, obtained within 24 hours of admission, in 16,279 acute coronary syndrome patients from the PLATO trial. In 9,978 patients, we performed a genome-wide association study with up to 2.5 million single nucleotide polymorphisms. Single nucleotide polymorphisms affecting cystatin C levels were evaluated in relation to the first occurrence of myocardial infarction (MI) or CV death within 1 year using Cox regression analysis.

Results

Several single nucleotide polymorphisms were associated with cystatin C levels, most significantly rs6048952 (P = 7.82 × 10−16) adjacent to CST3. Median cystatin C concentrations per genotype were 0.85 mg/L (A/A), 0.80 mg/L (A/G), and 0.73 mg/L (G/G). Modeled as additive, the allelic effect, multivariable adjusted, was −0.045 mg/L per G allele for rs6048952.

The multivariable adjusted c-statistic regarding the combined end point (CV death or MI) was 0.6735. Adding cystatin C or genotype-adjusted cystatin C levels resulted in c-statistics of 0.6761 and 0.6758, respectively.

The multivariable adjusted hazard ratios per G allele at rs6048952 in the entire population were 0.94 (95% CI 0.83–1.06) for CV death or MI and 0.88 (95% CI 0.71–1.08) for CV death.

Conclusions

Genetic polymorphisms affect cystatin C concentrations independently of kidney function. However, the polymorphisms were not observed to be associated with outcome, nor did they improve risk prediction or discriminative models.

Section snippets

Background

Chronic kidney disease (CKD) affects approximately 13% of American adults, and the prevalence of CKD is increasing.1 Identification of patients with CKD is important as decreased glomerular filtration rate (GFR) is associated with greater risk for cardiovascular (CV) morbidity and mortality.2, 3 Cystatin C, a low-molecular-weight cysteine protease inhibitor, is used as a biomarker reflecting the GFR as it is synthesized in all nucleated cells at a constant rate and is freely filtered in the

Study population

The PLATO trial (NCT00391872) evaluated 18,624 patients with ACS randomized to receive either ticagrelor or clopidogrel treatment in addition to optimal medical therapy and optional coronary revascularization.10, 11 A predefined genetic substudy was conducted in which genetic and biomarker information as well as clinical characteristics and outcomes was recorded.10 The details of the substudy program have been published previously.10, 11 Baseline blood samples were collected before the

Results

Overall, 9,978 individuals (3,982 in the discovery set and 5,996 in the replication set) passed quality control and were included in the genome-wide association analysis. The number of SNPs that were extracted from the HumanOmni2.5 BeadChip (phase I) was 2,379,855 with an average call rate of 99.58% (phase I), whereas 951,117 SNPs were extracted from the HumanOmniExpressExome BeadChip with an average call rate of 99.77% (phase II). After filtration, 1,586,429 SNPs in phase I and 649,761 SNPs in

Discussion

Decreased GFR is independently associated with CV morbidity and mortality.2, 3 Currently, the most accurate estimation of the GFR might be achieved by using both creatinine and cystatin C based estimates,18 although the combination did not provide any better risk prediction in our hands than considering either marker alone in the current ACS population.19 In this study, we evaluated genetic polymorphisms on cystatin C concentrations and showed that genetic variants (rs6048952 and rs16985615)

Conclusion

The current study identified genetic polymorphisms, close to CST3, which affect cystatin C concentrations independently of kidney function. These genetic polymorphisms were, however, not related to clinical outcome and genetic information did not improve multivariable predictive or discriminatory models compared with using only the plasma cystatin C concentration in an ACS population. We found no evidence, therefore, that cystatin C affects CV risk, other than by reflecting the kidney function.

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