Genetic variants in CETP increase risk of intracerebral hemorrhage

Christopher D. Anderson; Guido J. Falcone; Chia Ling Phuah; Farid Radmanesh; H. Bart Brouwers; Thomas W K Battey; Alessandro Biffi; Gina M. Peloso; Dajiang J. Liu; Alison M. Ayres; Joshua N. Goldstein; Anand Viswanathan; Steven M. Greenberg; Magdy Selim; James F. Meschia; Devin L. Brown; Bradford B. Worrall; Scott L. Silliman; David L. Tirschwell; Matthew L. Flaherty; Peter Kraft; Jeremiasz M. Jagiella; Helena Schmidt; Björn M. Hansen; Jordi Jimenez-Conde; Eva Giralt-Steinhauer; Roberto Elosua; Elisa Cuadrado-Godia; Carolina Soriano; Koen M. van Nieuwenhuizen; Catharina J M Klijn; Kristiina Rannikmae; Neshika Samarasekera; Rustam Al Shahi Salman; Catherine L. Sudlow; Ian J. Deary; Andrea Morotti; Alessandro Pezzini; Joanna Pera; Andrzej Urbanik; Alexander Pichler; Christian Enzinger; Bo Norrving; Joan Montaner; Israel Fernandez-Cadenas; Pilar Delgado; Jaume Roquer; Arne Lindgren; Agnieszka Slowik; Reinhold Schmidt; Chelsea S. Kidwell; Steven J. Kittner; Salina P. Waddy; Carl D. Langefeld; Goncalo Abecasis; Cristen J. Willer; Sekar Kathiresan; Daniel Woo; Jonathan Rosand

doi:10.1002/ana.24780

Genetic variants in CETP increase risk of intracerebral hemorrhage

Christopher D. Anderson^*, Guido J. Falcone, Chia Ling Phuah, Farid Radmanesh, H. Bart Brouwers, Thomas W K Battey, Alessandro Biffi, Gina M. Peloso, Dajiang J. Liu, Alison M. Ayres, Joshua N. Goldstein, Anand Viswanathan, Steven M. Greenberg, Magdy Selim, James F. Meschia, Devin L. Brown, Bradford B. Worrall, Scott L. Silliman, David L. Tirschwell, Matthew L. FlahertyPeter Kraft, Jeremiasz M. Jagiella, Helena Schmidt, Björn M. Hansen, Jordi Jimenez-Conde, Eva Giralt-Steinhauer, Roberto Elosua, Elisa Cuadrado-Godia, Carolina Soriano, Koen M. van Nieuwenhuizen, Catharina J M Klijn, Kristiina Rannikmae, Neshika Samarasekera, Rustam Al Shahi Salman, Catherine L. Sudlow, Ian J. Deary, Andrea Morotti, Alessandro Pezzini, Joanna Pera, Andrzej Urbanik, Alexander Pichler, Christian Enzinger, Bo Norrving, Joan Montaner, Israel Fernandez-Cadenas, Pilar Delgado, Jaume Roquer, Arne Lindgren, Agnieszka Slowik, Reinhold Schmidt, Chelsea S. Kidwell, Steven J. Kittner, Salina P. Waddy, Carl D. Langefeld, Goncalo Abecasis, Cristen J. Willer, Sekar Kathiresan, Daniel Woo, Jonathan Rosand

^*Corresponding author for this work

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

Abstract

Objective: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH. Methods: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk. Results: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR]=1.25, standard error [SE]=0.06, p=6.0×10^-4) with no heterogeneity across studies (I²=0%). This association was replicated in patients of European ancestry (p=0.03). A genetic score of CETP variants found to increase HDL-C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR=1.86, SE=0.13, p=1.39×10^-6). Interpretation: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted.

Original language	English
Pages (from-to)	730–740
Journal	Annals of Neurology
Volume	80
Issue number	5
DOIs	https://doi.org/10.1002/ana.24780
Publication status	Published - Nov 2016

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Anderson, C. D., Falcone, G. J., Phuah, C. L., Radmanesh, F., Brouwers, H. B., Battey, T. W. K., Biffi, A., Peloso, G. M., Liu, D. J., Ayres, A. M., Goldstein, J. N., Viswanathan, A., Greenberg, S. M., Selim, M., Meschia, J. F., Brown, D. L., Worrall, B. B., Silliman, S. L., Tirschwell, D. L., ... Rosand, J. (2016). Genetic variants in CETP increase risk of intracerebral hemorrhage. Annals of Neurology, 80(5), 730–740 . https://doi.org/10.1002/ana.24780

@article{944ef53c8f504c04af08c2b0bd5d9493,

title = "Genetic variants in CETP increase risk of intracerebral hemorrhage",

abstract = "Objective: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH. Methods: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk. Results: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR]=1.25, standard error [SE]=0.06, p=6.0×10-4) with no heterogeneity across studies (I2=0%). This association was replicated in patients of European ancestry (p=0.03). A genetic score of CETP variants found to increase HDL-C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR=1.86, SE=0.13, p=1.39×10-6). Interpretation: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted.",

author = "Anderson, {Christopher D.} and Falcone, {Guido J.} and Phuah, {Chia Ling} and Farid Radmanesh and Brouwers, {H. Bart} and Battey, {Thomas W K} and Alessandro Biffi and Peloso, {Gina M.} and Liu, {Dajiang J.} and Ayres, {Alison M.} and Goldstein, {Joshua N.} and Anand Viswanathan and Greenberg, {Steven M.} and Magdy Selim and Meschia, {James F.} and Brown, {Devin L.} and Worrall, {Bradford B.} and Silliman, {Scott L.} and Tirschwell, {David L.} and Flaherty, {Matthew L.} and Peter Kraft and Jagiella, {Jeremiasz M.} and Helena Schmidt and Hansen, {Bj{\"o}rn M.} and Jordi Jimenez-Conde and Eva Giralt-Steinhauer and Roberto Elosua and Elisa Cuadrado-Godia and Carolina Soriano and {van Nieuwenhuizen}, {Koen M.} and Klijn, {Catharina J M} and Kristiina Rannikmae and Neshika Samarasekera and Salman, {Rustam Al Shahi} and Sudlow, {Catherine L.} and Deary, {Ian J.} and Andrea Morotti and Alessandro Pezzini and Joanna Pera and Andrzej Urbanik and Alexander Pichler and Christian Enzinger and Bo Norrving and Joan Montaner and Israel Fernandez-Cadenas and Pilar Delgado and Jaume Roquer and Arne Lindgren and Agnieszka Slowik and Reinhold Schmidt and Kidwell, {Chelsea S.} and Kittner, {Steven J.} and Waddy, {Salina P.} and Langefeld, {Carl D.} and Goncalo Abecasis and Willer, {Cristen J.} and Sekar Kathiresan and Daniel Woo and Jonathan Rosand",

year = "2016",

month = nov,

doi = "10.1002/ana.24780",

language = "English",

volume = "80",

pages = "730–740 ",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "John Wiley & Sons Inc.",

number = "5",

}

Anderson, CD, Falcone, GJ, Phuah, CL, Radmanesh, F, Brouwers, HB, Battey, TWK, Biffi, A, Peloso, GM, Liu, DJ, Ayres, AM, Goldstein, JN, Viswanathan, A, Greenberg, SM, Selim, M, Meschia, JF, Brown, DL, Worrall, BB, Silliman, SL, Tirschwell, DL, Flaherty, ML, Kraft, P, Jagiella, JM, Schmidt, H, Hansen, BM, Jimenez-Conde, J, Giralt-Steinhauer, E, Elosua, R, Cuadrado-Godia, E, Soriano, C, van Nieuwenhuizen, KM, Klijn, CJM, Rannikmae, K, Samarasekera, N, Salman, RAS, Sudlow, CL, Deary, IJ, Morotti, A, Pezzini, A, Pera, J, Urbanik, A, Pichler, A, Enzinger, C, Norrving, B, Montaner, J, Fernandez-Cadenas, I, Delgado, P, Roquer, J, Lindgren, A, Slowik, A, Schmidt, R, Kidwell, CS, Kittner, SJ, Waddy, SP, Langefeld, CD, Abecasis, G, Willer, CJ, Kathiresan, S, Woo, D & Rosand, J 2016, 'Genetic variants in CETP increase risk of intracerebral hemorrhage', Annals of Neurology, vol. 80, no. 5, pp. 730–740 . https://doi.org/10.1002/ana.24780

TY - JOUR

T1 - Genetic variants in CETP increase risk of intracerebral hemorrhage

AU - Anderson, Christopher D.

AU - Falcone, Guido J.

AU - Phuah, Chia Ling

AU - Radmanesh, Farid

AU - Brouwers, H. Bart

AU - Battey, Thomas W K

AU - Biffi, Alessandro

AU - Peloso, Gina M.

AU - Liu, Dajiang J.

AU - Ayres, Alison M.

AU - Goldstein, Joshua N.

AU - Viswanathan, Anand

AU - Greenberg, Steven M.

AU - Selim, Magdy

AU - Meschia, James F.

AU - Brown, Devin L.

AU - Worrall, Bradford B.

AU - Silliman, Scott L.

AU - Tirschwell, David L.

AU - Flaherty, Matthew L.

AU - Kraft, Peter

AU - Jagiella, Jeremiasz M.

AU - Schmidt, Helena

AU - Hansen, Björn M.

AU - Jimenez-Conde, Jordi

AU - Giralt-Steinhauer, Eva

AU - Elosua, Roberto

AU - Cuadrado-Godia, Elisa

AU - Soriano, Carolina

AU - van Nieuwenhuizen, Koen M.

AU - Klijn, Catharina J M

AU - Rannikmae, Kristiina

AU - Samarasekera, Neshika

AU - Salman, Rustam Al Shahi

AU - Sudlow, Catherine L.

AU - Deary, Ian J.

AU - Morotti, Andrea

AU - Pezzini, Alessandro

AU - Pera, Joanna

AU - Urbanik, Andrzej

AU - Pichler, Alexander

AU - Enzinger, Christian

AU - Norrving, Bo

AU - Montaner, Joan

AU - Fernandez-Cadenas, Israel

AU - Delgado, Pilar

AU - Roquer, Jaume

AU - Lindgren, Arne

AU - Slowik, Agnieszka

AU - Schmidt, Reinhold

AU - Kidwell, Chelsea S.

AU - Kittner, Steven J.

AU - Waddy, Salina P.

AU - Langefeld, Carl D.

AU - Abecasis, Goncalo

AU - Willer, Cristen J.

AU - Kathiresan, Sekar

AU - Woo, Daniel

AU - Rosand, Jonathan

PY - 2016/11

Y1 - 2016/11

N2 - Objective: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH. Methods: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk. Results: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR]=1.25, standard error [SE]=0.06, p=6.0×10-4) with no heterogeneity across studies (I2=0%). This association was replicated in patients of European ancestry (p=0.03). A genetic score of CETP variants found to increase HDL-C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR=1.86, SE=0.13, p=1.39×10-6). Interpretation: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted.

AB - Objective: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH. Methods: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk. Results: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR]=1.25, standard error [SE]=0.06, p=6.0×10-4) with no heterogeneity across studies (I2=0%). This association was replicated in patients of European ancestry (p=0.03). A genetic score of CETP variants found to increase HDL-C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR=1.86, SE=0.13, p=1.39×10-6). Interpretation: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted.

UR - http://www.scopus.com/inward/record.url?scp=84991736574&partnerID=8YFLogxK

U2 - 10.1002/ana.24780

DO - 10.1002/ana.24780

M3 - Article

C2 - 27717122

AN - SCOPUS:84991736574

SN - 0364-5134

VL - 80

SP - 730

EP - 740

JO - Annals of Neurology

JF - Annals of Neurology

IS - 5

ER -

Genetic variants in CETP increase risk of intracerebral hemorrhage

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