Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study

Sander W van der Laan; Tove Fall; Aicha Soumaré; Alexander Teumer; Sanaz Sedaghat; Jens Baumert; Delilah Zabaneh; Jessica van Setten; Ivana Isgum; Tessel E Galesloot; Johannes Arpegård; Philippe Amouyel; Stella Trompet; Melanie Waldenberger; Marcus Dörr; Patrik K Magnusson; Vilmantas Giedraitis; Anders Larsson; Andrew P Morris; Janine F Felix; Alanna C Morrison; Nora Franceschini; Joshua C Bis; Maryam Kavousi; Christopher O'Donnell; Fotios Drenos; Vinicius Tragante; Patricia B Munroe; Rainer Malik; Martin Dichgans; Bradford B Worrall; Jeanette Erdmann; Christopher P Nelson; Nilesh J Samani; Heribert Schunkert; Jonathan Marchini; Riyaz S Patel; Aroon D Hingorani; Lars Lind; Nancy L Pedersen; Jacqueline de Graaf; Lambertus A L M Kiemeney; Sebastian E Baumeister; Oscar H Franco; Albert Hofman; André G Uitterlinden; Wolfgang Koenig; Christa Meisinger; Annette Peters; Barbara Thorand; J Wouter Jukema; Bjørn Odvar Eriksen; Ingrid Toft; Tom Wilsgaard; N Charlotte Onland-Moret; Yvonne T van der Schouw; Stéphanie Debette; Meena Kumari; Per Svensson; Pim van der Harst; Mika Kivimaki; Brendan J Keating; Naveed Sattar; Abbas Dehghan; Alex P Reiner; Erik Ingelsson; Hester M den Ruijter; Paul I W de Bakker; Gerard Pasterkamp; Johan Ärnlöv; Michael V Holmes; Folkert W Asselbergs

doi:10.1016/j.jacc.2016.05.092

Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study

Sander W van der Laan, Tove Fall, Aicha Soumaré, Alexander Teumer, Sanaz Sedaghat, Jens Baumert, Delilah Zabaneh, Jessica van Setten, Ivana Isgum, Tessel E Galesloot, Johannes Arpegård, Philippe Amouyel, Stella Trompet, Melanie Waldenberger, Marcus Dörr, Patrik K Magnusson, Vilmantas Giedraitis, Anders Larsson, Andrew P Morris, Janine F FelixAlanna C Morrison, Nora Franceschini, Joshua C Bis, Maryam Kavousi, Christopher O'Donnell, Fotios Drenos, Vinicius Tragante, Patricia B Munroe, Rainer Malik, Martin Dichgans, Bradford B Worrall, Jeanette Erdmann, Christopher P Nelson, Nilesh J Samani, Heribert Schunkert, Jonathan Marchini, Riyaz S Patel, Aroon D Hingorani, Lars Lind, Nancy L Pedersen, Jacqueline de Graaf, Lambertus A L M Kiemeney, Sebastian E Baumeister, Oscar H Franco, Albert Hofman, André G Uitterlinden, Wolfgang Koenig, Christa Meisinger, Annette Peters, Barbara Thorand, J Wouter Jukema, Bjørn Odvar Eriksen, Ingrid Toft, Tom Wilsgaard, N Charlotte Onland-Moret, Yvonne T van der Schouw, Stéphanie Debette, Meena Kumari, Per Svensson, Pim van der Harst, Mika Kivimaki, Brendan J Keating, Naveed Sattar, Abbas Dehghan, Alex P Reiner, Erik Ingelsson, Hester M den Ruijter, Paul I W de Bakker, Gerard Pasterkamp, Johan Ärnlöv, Michael V Holmes, Folkert W Asselbergs

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND: Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation.

OBJECTIVES: The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population.

METHODS: We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure.

RESULTS: Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 × 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 × 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0.994), which was statistically different from the observational estimate (p = 1.6 × 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD.

CONCLUSIONS: Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD.

Original language	English
Pages (from-to)	934-945
Number of pages	12
Journal	Journal of the American College of Cardiology
Volume	68
Issue number	9
DOIs	https://doi.org/10.1016/j.jacc.2016.05.092
Publication status	Published - 30 Aug 2016

Keywords

coronary heart disease
genetics
heart failure
ischemic stroke

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10.1016/j.jacc.2016.05.092

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van der Laan, S. W., Fall, T., Soumaré, A., Teumer, A., Sedaghat, S., Baumert, J., Zabaneh, D., van Setten, J., Isgum, I., Galesloot, T. E., Arpegård, J., Amouyel, P., Trompet, S., Waldenberger, M., Dörr, M., Magnusson, P. K., Giedraitis, V., Larsson, A., Morris, A. P., ... Asselbergs, F. W. (2016). Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study. Journal of the American College of Cardiology, 68(9), 934-945. https://doi.org/10.1016/j.jacc.2016.05.092

@article{cf3979dcdb2f4064a496943a56fbfdf3,

title = "Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study",

abstract = "BACKGROUND: Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation.OBJECTIVES: The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population.METHODS: We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure.RESULTS: Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 × 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 × 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0.994), which was statistically different from the observational estimate (p = 1.6 × 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD.CONCLUSIONS: Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD.",

keywords = "coronary heart disease, genetics, heart failure, ischemic stroke",

author = "{van der Laan}, {Sander W} and Tove Fall and Aicha Soumar{\'e} and Alexander Teumer and Sanaz Sedaghat and Jens Baumert and Delilah Zabaneh and {van Setten}, Jessica and Ivana Isgum and Galesloot, {Tessel E} and Johannes Arpeg{\aa}rd and Philippe Amouyel and Stella Trompet and Melanie Waldenberger and Marcus D{\"o}rr and Magnusson, {Patrik K} and Vilmantas Giedraitis and Anders Larsson and Morris, {Andrew P} and Felix, {Janine F} and Morrison, {Alanna C} and Nora Franceschini and Bis, {Joshua C} and Maryam Kavousi and Christopher O'Donnell and Fotios Drenos and Vinicius Tragante and Munroe, {Patricia B} and Rainer Malik and Martin Dichgans and Worrall, {Bradford B} and Jeanette Erdmann and Nelson, {Christopher P} and Samani, {Nilesh J} and Heribert Schunkert and Jonathan Marchini and Patel, {Riyaz S} and Hingorani, {Aroon D} and Lars Lind and Pedersen, {Nancy L} and {de Graaf}, Jacqueline and Kiemeney, {Lambertus A L M} and Baumeister, {Sebastian E} and Franco, {Oscar H} and Albert Hofman and Uitterlinden, {Andr{\'e} G} and Wolfgang Koenig and Christa Meisinger and Annette Peters and Barbara Thorand and Jukema, {J Wouter} and Eriksen, {Bj{\o}rn Odvar} and Ingrid Toft and Tom Wilsgaard and Onland-Moret, {N Charlotte} and {van der Schouw}, {Yvonne T} and St{\'e}phanie Debette and Meena Kumari and Per Svensson and {van der Harst}, Pim and Mika Kivimaki and Keating, {Brendan J} and Naveed Sattar and Abbas Dehghan and Reiner, {Alex P} and Erik Ingelsson and {den Ruijter}, {Hester M} and {de Bakker}, {Paul I W} and Gerard Pasterkamp and Johan {\"A}rnl{\"o}v and Holmes, {Michael V} and Asselbergs, {Folkert W}",

year = "2016",

month = aug,

day = "30",

doi = "10.1016/j.jacc.2016.05.092",

language = "English",

volume = "68",

pages = "934--945",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

publisher = "Elsevier",

number = "9",

}

van der Laan, SW, Fall, T, Soumaré, A, Teumer, A, Sedaghat, S, Baumert, J, Zabaneh, D, van Setten, J, Isgum, I, Galesloot, TE, Arpegård, J, Amouyel, P, Trompet, S, Waldenberger, M, Dörr, M, Magnusson, PK, Giedraitis, V, Larsson, A, Morris, AP, Felix, JF, Morrison, AC, Franceschini, N, Bis, JC, Kavousi, M, O'Donnell, C, Drenos, F, Tragante, V, Munroe, PB, Malik, R, Dichgans, M, Worrall, BB, Erdmann, J, Nelson, CP, Samani, NJ, Schunkert, H, Marchini, J, Patel, RS, Hingorani, AD, Lind, L, Pedersen, NL, de Graaf, J, Kiemeney, LALM, Baumeister, SE, Franco, OH, Hofman, A, Uitterlinden, AG, Koenig, W, Meisinger, C, Peters, A, Thorand, B, Jukema, JW, Eriksen, BO, Toft, I, Wilsgaard, T, Onland-Moret, NC , van der Schouw, YT, Debette, S, Kumari, M, Svensson, P, van der Harst, P, Kivimaki, M, Keating, BJ, Sattar, N, Dehghan, A, Reiner, AP, Ingelsson, E, den Ruijter, HM, de Bakker, PIW, Pasterkamp, G, Ärnlöv, J, Holmes, MV & Asselbergs, FW 2016, 'Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study', Journal of the American College of Cardiology, vol. 68, no. 9, pp. 934-945. https://doi.org/10.1016/j.jacc.2016.05.092

TY - JOUR

T1 - Cystatin C and Cardiovascular Disease

T2 - A Mendelian Randomization Study

AU - van der Laan, Sander W

AU - Fall, Tove

AU - Soumaré, Aicha

AU - Teumer, Alexander

AU - Sedaghat, Sanaz

AU - Baumert, Jens

AU - Zabaneh, Delilah

AU - van Setten, Jessica

AU - Isgum, Ivana

AU - Galesloot, Tessel E

AU - Arpegård, Johannes

AU - Amouyel, Philippe

AU - Trompet, Stella

AU - Waldenberger, Melanie

AU - Dörr, Marcus

AU - Magnusson, Patrik K

AU - Giedraitis, Vilmantas

AU - Larsson, Anders

AU - Morris, Andrew P

AU - Felix, Janine F

AU - Morrison, Alanna C

AU - Franceschini, Nora

AU - Bis, Joshua C

AU - Kavousi, Maryam

AU - O'Donnell, Christopher

AU - Drenos, Fotios

AU - Tragante, Vinicius

AU - Munroe, Patricia B

AU - Malik, Rainer

AU - Dichgans, Martin

AU - Worrall, Bradford B

AU - Erdmann, Jeanette

AU - Nelson, Christopher P

AU - Samani, Nilesh J

AU - Schunkert, Heribert

AU - Marchini, Jonathan

AU - Patel, Riyaz S

AU - Hingorani, Aroon D

AU - Lind, Lars

AU - Pedersen, Nancy L

AU - de Graaf, Jacqueline

AU - Kiemeney, Lambertus A L M

AU - Baumeister, Sebastian E

AU - Franco, Oscar H

AU - Hofman, Albert

AU - Uitterlinden, André G

AU - Koenig, Wolfgang

AU - Meisinger, Christa

AU - Peters, Annette

AU - Thorand, Barbara

AU - Jukema, J Wouter

AU - Eriksen, Bjørn Odvar

AU - Toft, Ingrid

AU - Wilsgaard, Tom

AU - Onland-Moret, N Charlotte

AU - van der Schouw, Yvonne T

AU - Debette, Stéphanie

AU - Kumari, Meena

AU - Svensson, Per

AU - van der Harst, Pim

AU - Kivimaki, Mika

AU - Keating, Brendan J

AU - Sattar, Naveed

AU - Dehghan, Abbas

AU - Reiner, Alex P

AU - Ingelsson, Erik

AU - den Ruijter, Hester M

AU - de Bakker, Paul I W

AU - Pasterkamp, Gerard

AU - Ärnlöv, Johan

AU - Holmes, Michael V

AU - Asselbergs, Folkert W

PY - 2016/8/30

Y1 - 2016/8/30

N2 - BACKGROUND: Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation.OBJECTIVES: The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population.METHODS: We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure.RESULTS: Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 × 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 × 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0.994), which was statistically different from the observational estimate (p = 1.6 × 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD.CONCLUSIONS: Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD.

AB - BACKGROUND: Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation.OBJECTIVES: The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population.METHODS: We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure.RESULTS: Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 × 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 × 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0.994), which was statistically different from the observational estimate (p = 1.6 × 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD.CONCLUSIONS: Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD.

KW - coronary heart disease

KW - genetics

KW - heart failure

KW - ischemic stroke

U2 - 10.1016/j.jacc.2016.05.092

DO - 10.1016/j.jacc.2016.05.092

M3 - Article

C2 - 27561768

SN - 0735-1097

VL - 68

SP - 934

EP - 945

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 9

ER -

Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study

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