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.

We measured cystatin C concentrations in plasma, obtained within 24hours 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.

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 0.85mg/L (A/A), 0.80 mg/L (A/G), and 0.73mg/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.

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.