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

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 ch...

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Published in:American journal of kidney diseases Vol. 63; no. 1; p. 16
Main Authors: O'Seaghdha, Conall M, Tin, Adrienne, Yang, Qiong, Katz, Ronit, Liu, Yongmei, Harris, Tamara, Astor, Brad, Coresh, Josef, Fox, Caroline S, Kao, W H Linda, Shlipak, Michael G
Format: Journal Article
Language:English
Published: United States 01.01.2014
Subjects:
Aged
Bias
Biomarkers - blood
Cardiovascular Diseases - blood
Cardiovascular Diseases - genetics
Cardiovascular Diseases - mortality
Creatinine - blood
Cystatin C - blood
Cystatin C - genetics
Female
Genetic Variation
Glomerular Filtration Rate - genetics
Humans
Male
Middle Aged
Polymorphism, Single Nucleotide
Renal Insufficiency, Chronic - blood
Renal Insufficiency, Chronic - classification
Renal Insufficiency, Chronic - epidemiology
Renal Insufficiency, Chronic - genetics
Renal Insufficiency, Chronic - physiopathology
Risk Assessment
Risk Factors
Severity of Illness Index
Statistics as Topic
Survival Rate
net reclassification improvement
chronic kidney disease
genetics
single-nucleotide polymorphism
Cystatin C
ISSN:1523-6838, 1523-6838
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Summary: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. Observational. 4 population-based cohorts: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health (CHS), Framingham Heart (FHS), and Health, Aging, and Body Composition (Health ABC) studies. 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. We assessed reclassification by genotype-adjusted eGFRcys across CKD categories: <45, 45-59, 60-89, and ≥ 90 mL/min/1.73 m(2). We compared mortality and CVD outcomes in those reclassified to a worse eGFRcys category with those unaffected. Results were combined using fixed-effect inverse-variance meta-analysis. 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. rs13038305 explains only a small proportion of cystatin C variation. 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.
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ISSN:1523-6838
1523-6838
DOI:10.1053/j.ajkd.2013.06.015