title: Polymorphism of the cystatin C gene in patients with acute coronary syndromes: Results from the PLATelet inhibition and patient Outcomes study.
abstract: OBJECTIVE
  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.
authors: Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden; Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden. Electronic address: axel.akerblom@ucr.uu.se.
authors: Axel
authors: A
authors: Akerblom
authors: Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
authors: Niclas
authors: N
authors: Eriksson
authors: Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden; Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden.
authors: Lars
authors: L
authors: Wallentin
authors: Department of Medical Sciences, Center of Excellence, Inflammation, Uppsala University, Uppsala, Sweden.
authors: Agneta
authors: A
authors: Siegbahn
authors: Personalised Healthcare and Biomarkers AstraZeneca Research and Development, Alderley Park, United Kingdom.
authors: Bryan J
authors: BJ
authors: Barratt
authors: Duke Clinical Research Institute, Durham, NC.
authors: Richard C
authors: RC
authors: Becker
authors: Postgraduate Medical School, Grochowski Hospital, Warsaw, Poland.
authors: Andrzej
authors: A
authors: Budaj
authors: AstraZeneca Research and Development, Mölndal, Sweden.
authors: Anders
authors: A
authors: Himmelmann
authors: Medical Department, Hospital Unit West, Herning, Denmark.
authors: Steen
authors: S
authors: Husted
authors: Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom.
authors: Robert F
authors: RF
authors: Storey
authors: Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden; Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors: Asa
authors: A
authors: Johansson
authors: Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden; Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden.
authors: Stefan K
authors: SK
authors: James
mesh_terms: D054058:Acute Coronary Syndrome / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D000368:Aged; D055316:Cystatin C / Q000097:blood / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D016896:Treatment Outcome
chemical_list: D055316:Cystatin C; D010975:Platelet Aggregation Inhibitors; D004247:DNA