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Association of a cystatin C gene variant with cystatin C levels, CKD, and risk of incident cardiovascular disease and mortality.

TitleAssociation of a cystatin C gene variant with cystatin C levels, CKD, and risk of incident cardiovascular disease and mortality.
Publication TypeJournal Article
Year of Publication2014
AuthorsO'Seaghdha CM, Tin A, Yang Q, Katz R, Liu Y, Harris T, Astor B, Coresh JJ, Fox CS, Kao LWH
Secondary AuthorsShlipak MG
JournalAm J Kidney Dis
Volume63
Issue1
Pagination16-22
Date Published2014 Jan
ISSN1523-6838
KeywordsAged, Bias, Biomarkers, Cardiovascular Diseases, Creatinine, Cystatin C, Female, Genetic Variation, Glomerular Filtration Rate, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic, Risk Assessment, Risk Factors, Severity of Illness Index, Statistics as Topic, Survival Rate
Abstract

BACKGROUND: Carriers of the T allele of the single-nucleotide polymorphism rs13038305 tend to have lower cystatin C levels and higher cystatin C-based estimated glomerular filtration rate (eGFRcys). Adjusting for this genetic effect on cystatin C concentrations may improve GFR estimation, reclassify cases of chronic kidney disease (CKD), and strengthen risk estimates for cardiovascular disease (CVD) and mortality.

STUDY DESIGN: Observational.

SETTING & POPULATION: 4 population-based cohorts: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health (CHS), Framingham Heart (FHS), and Health, Aging, and Body Composition (Health ABC) studies.

PREDICTORS: We estimated the association of rs13038305 with eGFRcys and serum creatinine-based eGFR (eGFRcr) and performed longitudinal analyses of the associations of eGFRcys with mortality and cardiovascular events following adjustment for rs13038305.

OUTCOMES: We assessed reclassification by genotype-adjusted eGFRcys across CKD categories:

RESULTS: In 14,645 participants, each copy of the T allele of rs13038305 (frequency, 21%) was associated with a 6.4% lower cystatin C concentration, 5.5-mL/min/1.73 m(2) higher eGFRcys, and 36% [95% CI, 29%-41%] lower odds of CKD. Associations with CVD (HR, 1.17; 95% CI, 1.14-1.20) and mortality (HR, 1.22; 95% CI, 1.19-1.24) per 10-mL/min/1.73 m(2) lower eGFRcys were similar with or without rs13038305 adjustment. 1,134 (7.7%) participants were reclassified to a worse CKD category following rs13038305 adjustment, and rates of CVD and mortality were higher in individuals who were reclassified. However, the overall net reclassification index was not significant for either outcome, at 0.009 (95% CI, -0.003 to 0.022) for mortality and 0.014 (95% CI, 0.0 to 0.028) for CVD.

LIMITATIONS: rs13038305 explains only a small proportion of cystatin C variation.

CONCLUSIONS: Statistical adjustment can correct a genetic bias in GFR estimates based on cystatin C in carriers of the T allele of rs13038305 and result in changes in disease classification. However, on a population level, the effects on overall reclassification of CKD status are modest.

DOI10.1053/j.ajkd.2013.06.015
Alternate JournalAm J Kidney Dis
PubMed ID23932088
PubMed Central IDPMC3872167
Grant ListUL1 TR001079 / TR / NCATS NIH HHS / United States
N01AG62101 / AG / NIA NIH HHS / United States
R01 AG034853 / AG / NIA NIH HHS / United States
T32 HL007024 / HL / NHLBI NIH HHS / United States
1R01AG032098-01A1 / AG / NIA NIH HHS / United States
K23 DK082793 / DK / NIDDK NIH HHS / United States
/ / Intramural NIH HHS / United States
R01 AG027002 / AG / NIA NIH HHS / United States
N01AG62103 / AG / NIA NIH HHS / United States
HHSN268200782096C / / PHS HHS / United States
N01AG62106 / AG / NIA NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States