Comparison of Heritability of Cystatin C- and Creatinine-based Estimates of Kidney Function and Their Relation to Heritability of Cardiovascular Disease

Overview

Journal J Am Heart Assoc

Specialty Cardiology & Vascular Diseases

Date 2015 Jan 16

PMID 25589536

Citations 31

Authors

Johannes Arpegard

Alexander Viktorin

Zheng Chang

Ulf de Faire

Patrik K E Magnusson

Per Svensson

Affiliations

Soon will be listed here.

Abstract

Background: Decreased renal function is an established risk factor for cardiovascular disease (CVD). Causal mechanisms between estimates of renal function and CVD are intricate and investigation of the relative importance of genetic and environmental factors for the variability of these phenotypes could provide new knowledge.

Methods And Results: Cystatin C and creatinine levels in 12 313 twins were analyzed. Uni- and bivariate heritability for these traits and CVD was estimated through structured equation modelling and genome-wide complex trait analysis (GCTA) in order to independently confirm additive genetic effects. Twin model-estimated heritability of Cystatin C was 0.55 (95% confidence interval [CI], 0.49 to 0.60) in men, 0.63 (0.59 to 0.66) in women, and 0.60 (0.56 to 0.63) in both sexes combined. For creatinine, heritability estimates were in the same range. Heritability of CVD was 0.39 (0.02 to 0.67) in men and 0.20 (0.00 to 0.61) in women. The phenotypic correlation between Cystatin C and CVD correlation was 0.16 (0.12 to 0.20) in men and 0.17 (0.13 to 0.21) in women, whereas the genetic correlation in males was 0.41 (0.21 to 0.62) while it was non-significant in females. Trough GCTA, the heritability of Cystatin C and creatinine in both sexes combined was estimated to 0.40 (SE 0.07, P=8E(-9)) and 0.19 (SE 0.07, P=0.003), respectively.

Conclusions: Twin model-based heritability of Cystatin C was higher compared to previous studies. Co-variation between Cystatin C and CVD in males was partly explained by additive genetic components, indicating that Cystatin C and CVD share genetic influences. The GCTA provided independent evidence for significant contribution of additive genetics to trait variance of Cystatin C.

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References

Ferraro S, Marano G, Biganzoli E, Boracchi P, Bongo A . Prognostic value of cystatin C in acute coronary syndromes: enhancer of atherosclerosis and promising therapeutic target. Clin Chem Lab Med. 2011; 49(9):1397-404. DOI: 10.1515/CCLM.2011.607. View

Ludvigsson J, Andersson E, Ekbom A, Feychting M, Kim J, Reuterwall C . External review and validation of the Swedish national inpatient register. BMC Public Health. 2011; 11:450. PMC: 3142234. DOI: 10.1186/1471-2458-11-450. View

Zuk O, Hechter E, Sunyaev S, Lander E . The mystery of missing heritability: Genetic interactions create phantom heritability. Proc Natl Acad Sci U S A. 2012; 109(4):1193-8. PMC: 3268279. DOI: 10.1073/pnas.1119675109. View

Silva D, Cortez-Dias N, Jorge C, Marques J, Carrilho-Ferreira P, Magalhaes A . Cystatin C as prognostic biomarker in ST-segment elevation acute myocardial infarction. Am J Cardiol. 2012; 109(10):1431-8. DOI: 10.1016/j.amjcard.2012.01.356. View

Benjamin D, Cesarini D, van der Loos M, Dawes C, Koellinger P, Magnusson P . The genetic architecture of economic and political preferences. Proc Natl Acad Sci U S A. 2012; 109(21):8026-31. PMC: 3361436. DOI: 10.1073/pnas.1120666109. View

Inker L, Schmid C, Tighiouart H, Eckfeldt J, Feldman H, Greene T . Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med. 2012; 367(1):20-9. PMC: 4398023. DOI: 10.1056/NEJMoa1114248. View

Magnusson P, Almqvist C, Rahman I, Ganna A, Viktorin A, Walum H . The Swedish Twin Registry: establishment of a biobank and other recent developments. Twin Res Hum Genet. 2012; 16(1):317-29. DOI: 10.1017/thg.2012.104. View

Kahn M, Robbins M, Kim M, Fuster V . Management of cardiovascular disease in patients with kidney disease. Nat Rev Cardiol. 2013; 10(5):261-73. DOI: 10.1038/nrcardio.2013.15. View

van Holten T, Waanders L, de Groot P, Vissers J, Hoefer I, Pasterkamp G . Circulating biomarkers for predicting cardiovascular disease risk; a systematic review and comprehensive overview of meta-analyses. PLoS One. 2013; 8(4):e62080. PMC: 3632595. DOI: 10.1371/journal.pone.0062080. View

10.

Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B . Chronic kidney disease: global dimension and perspectives. Lancet. 2013; 382(9888):260-72. DOI: 10.1016/S0140-6736(13)60687-X. View

11.

Shlipak M, Mattes M, Peralta C . Update on cystatin C: incorporation into clinical practice. Am J Kidney Dis. 2013; 62(3):595-603. PMC: 3755100. DOI: 10.1053/j.ajkd.2013.03.027. View

12.

Shlipak M, Matsushita K, Arnlov J, Inker L, Katz R, Polkinghorne K . Cystatin C versus creatinine in determining risk based on kidney function. N Engl J Med. 2013; 369(10):932-43. PMC: 3993094. DOI: 10.1056/NEJMoa1214234. View

13.

Svensson-Farbom P, Ohlson Andersson M, Almgren P, Hedblad B, Engstrom G, Persson M . Cystatin C identifies cardiovascular risk better than creatinine-based estimates of glomerular filtration in middle-aged individuals without a history of cardiovascular disease. J Intern Med. 2013; 275(5):506-21. DOI: 10.1111/joim.12169. View

14.

Plomin R, Deary I . Genetics and intelligence differences: five special findings. Mol Psychiatry. 2014; 20(1):98-108. PMC: 4270739. DOI: 10.1038/mp.2014.105. View

15.

Langefeld C, Beck S, Bowden D, Rich S, Wagenknecht L, Freedman B . Heritability of GFR and albuminuria in Caucasians with type 2 diabetes mellitus. Am J Kidney Dis. 2004; 43(5):796-800. DOI: 10.1053/j.ajkd.2003.12.043. View

16.

Fox C, Yang Q, Cupples L, Guo C, Larson M, Leip E . Genomewide linkage analysis to serum creatinine, GFR, and creatinine clearance in a community-based population: the Framingham Heart Study. J Am Soc Nephrol. 2004; 15(9):2457-61. DOI: 10.1097/01.ASN.0000135972.13396.6F. View

17.

Go A, Chertow G, Fan D, McCulloch C, Hsu C . Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004; 351(13):1296-305. DOI: 10.1056/NEJMoa041031. View

18.

Bathum L, Fagnani C, Christiansen L, Christensen K . Heritability of biochemical kidney markers and relation to survival in the elderly--results from a Danish population-based twin study. Clin Chim Acta. 2004; 349(1-2):143-50. DOI: 10.1016/j.cccn.2004.06.017. View

19.

Feldman M, Lewontin R . The heritability hang-up. Science. 1975; 190(4220):1163-8. DOI: 10.1126/science.1198102. View

20.

Lander E, Schork N . Genetic dissection of complex traits. Science. 1994; 265(5181):2037-48. DOI: 10.1126/science.8091226. View