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


METHODS
Observational.


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


METHODS
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.


RESULTS
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.


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.


CONCLUSIONS
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.
National Heart, Lung and Blood Institute's Framingham Heart Study and the Center for Population Studies, Framingham, MA; Renal Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Conall M
CM
O'Seaghdha
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
Adrienne
A
Tin
Department of Biostatistics, Boston University School of Public Health, Boston, MA.
Qiong
Q
Yang
San Francisco VA Medical Center; Departments of Medicine, Epidemiology & Biostatistics, University of California, San Francisco, CA.
Ronit
R
Katz
Department of Epidemiology & Prevention, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC.
Yongmei
Y
Liu
Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, MD.
Tamara
T
Harris
Department of Population Health Sciences, The University of Wisconsin, School of Medicine and Public Health, Madison, WI.
Brad
B
Astor
Welch Center for Prevention, Epidemiology and Clinical Research, The Johns Hopkins University, Baltimore, MD.
Josef
J
Coresh
National Heart, Lung and Blood Institute's Framingham Heart Study and the Center for Population Studies, Framingham, MA; Division of Endocrinology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Caroline S
CS
Fox
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
W H Linda
WH
Kao
San Francisco VA Medical Center; Departments of Medicine, Epidemiology & Biostatistics, University of California, San Francisco, CA. Electronic address: michael.shlipak@ucsf.edu.
Michael G
MG
Shlipak
D000368:Aged; D015982:Bias; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics / Q000401:mortality; D003404:Creatinine / Q000097:blood; D055316:Cystatin C / Q000097:blood / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005919:Glomerular Filtration Rate / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000145:classification / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D013223:Statistics as Topic; D015996:Survival Rate
D015415:Biomarkers; C525030:CST3 protein, human; D055316:Cystatin C; D003404:Creatinine
Cystatin C; chronic kidney disease; genetics; net reclassification improvement; single-nucleotide polymorphism