Common genetic variation in the 3'-BCL11B gene desert is associated with carotid-femoral pulse wave velocity and excess cardiovascular disease risk: the AortaGen Consortium

Gary F Mitchell; Germaine C Verwoert; Kirill V Tarasov; Aaron Isaacs; Albert V Smith; null Yasmin; Ernst R Rietzschel; Toshiko Tanaka; Yongmei Liu; Afshin Parsa; Samer S Najjar; Kevin M O'Shaughnessy; Sigurdur Sigurdsson; Marc L De Buyzere; Martin G Larson; Mark P S Sie; Jeanette S Andrews; Wendy S Post; Francesco U S Mattace-Raso; Carmel M McEniery; Gudny Eiriksdottir; Patrick Segers; Ramachandran S Vasan; Marie Josee E van Rijn; Timothy D Howard; Patrick F McArdle; Abbas Dehghan; Elizabeth S Jewell; Stephen J Newhouse; Sofie Bekaert; Naomi M Hamburg; Anne B Newman; Albert Hofman; Angelo Scuteri; Dirk De Bacquer; Mohammad Arfan Ikram; Bruce M Psaty; Christian Fuchsberger; Matthias Olden; Louise V Wain; Paul Elliott; Nicholas L Smith; Janine F Felix; Jeanette Erdmann; Joseph A Vita; Kim Sutton-Tyrrell; Eric J G Sijbrands; Serena Sanna; Lenore J Launer; Tim De Meyer; Andrew D Johnson; Anna F C Schut; David M Herrington; Fernando Rivadeneira; Manuela Uda; Ian B Wilkinson; Thor Aspelund; Thierry C Gillebert; Luc Van Bortel; Emelia J Benjamin; Ben A Oostra; Jingzhong Ding; Quince Gibson; André G Uitterlinden; Gonçalo R Abecasis; John R Cockcroft; Vilmundur Gudnason; Guy G De Backer; Luigi Ferrucci; Tamara B Harris; Alan R Shuldiner; Cornelia M van Duijn; Daniel Levy; Edward G Lakatta; Jacqueline C M Witteman

doi:10.1161/CIRCGENETICS.111.959817

Common genetic variation in the 3'-BCL11B gene desert is associated with carotid-femoral pulse wave velocity and excess cardiovascular disease risk: the AortaGen Consortium

Gary F Mitchell^*, Germaine C Verwoert, Kirill V Tarasov, Aaron Isaacs, Albert V Smith, Yasmin, Ernst R Rietzschel, Toshiko Tanaka, Yongmei Liu, Afshin Parsa, Samer S Najjar, Kevin M O'Shaughnessy, Sigurdur Sigurdsson, Marc L De Buyzere, Martin G Larson, Mark P S Sie, Jeanette S Andrews, Wendy S Post, Francesco U S Mattace-Raso, Carmel M McEnieryGudny Eiriksdottir, Patrick Segers, Ramachandran S Vasan, Marie Josee E van Rijn, Timothy D Howard, Patrick F McArdle, Abbas Dehghan, Elizabeth S Jewell, Stephen J Newhouse, Sofie Bekaert, Naomi M Hamburg, Anne B Newman, Albert Hofman, Angelo Scuteri, Dirk De Bacquer, Mohammad Arfan Ikram, Bruce M Psaty, Christian Fuchsberger, Matthias Olden, Louise V Wain, Paul Elliott, Nicholas L Smith, Janine F Felix, Jeanette Erdmann, Joseph A Vita, Kim Sutton-Tyrrell, Eric J G Sijbrands, Serena Sanna, Lenore J Launer, Tim De Meyer, Andrew D Johnson, Anna F C Schut, David M Herrington, Fernando Rivadeneira, Manuela Uda, Ian B Wilkinson, Thor Aspelund, Thierry C Gillebert, Luc Van Bortel, Emelia J Benjamin, Ben A Oostra, Jingzhong Ding, Quince Gibson, André G Uitterlinden, Gonçalo R Abecasis, John R Cockcroft, Vilmundur Gudnason, Guy G De Backer, Luigi Ferrucci, Tamara B Harris, Alan R Shuldiner, Cornelia M van Duijn, Daniel Levy, Edward G Lakatta, Jacqueline C M Witteman

^*Corresponding author for this work

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

Abstract

BACKGROUND: Carotid-femoral pulse wave velocity (CFPWV) is a heritable measure of aortic stiffness that is strongly associated with increased risk for major cardiovascular disease events.

METHODS AND RESULTS: We conducted a meta-analysis of genome-wide association data in 9 community-based European ancestry cohorts consisting of 20 634 participants. Results were replicated in 2 additional European ancestry cohorts involving 5306 participants. Based on a preliminary analysis of 6 cohorts, we identified a locus on chromosome 14 in the 3'-BCL11B gene desert that is associated with CFPWV (rs7152623, minor allele frequency=0.42, β=-0.075±0.012 SD/allele, P=2.8×10(-10); replication β=-0.086±0.020 SD/allele, P=1.4×10(-6)). Combined results for rs7152623 from 11 cohorts gave β=-0.076±0.010 SD/allele, P=3.1×10(-15). The association persisted when adjusted for mean arterial pressure (β=-0.060±0.009 SD/allele, P=1.0×10(-11)). Results were consistent in younger (<55 years, 6 cohorts, n=13 914, β=-0.081±0.014 SD/allele, P=2.3×10(-9)) and older (9 cohorts, n=12 026, β=-0.061±0.014 SD/allele, P=9.4×10(-6)) participants. In separate meta-analyses, the locus was associated with increased risk for coronary artery disease (hazard ratio=1.05; confidence interval=1.02-1.08; P=0.0013) and heart failure (hazard ratio=1.10, CI=1.03-1.16, P=0.004).

CONCLUSIONS: Common genetic variation in a locus in the BCL11B gene desert that is thought to harbor 1 or more gene enhancers is associated with higher CFPWV and increased risk for cardiovascular disease. Elucidation of the role this novel locus plays in aortic stiffness may facilitate development of therapeutic interventions that limit aortic stiffening and related cardiovascular disease events.

Original language	English
Pages (from-to)	81-90
Number of pages	10
Journal	Circulation : Cardiovascular Genetics
Volume	5
Issue number	1
DOIs	https://doi.org/10.1161/CIRCGENETICS.111.959817
Publication status	Published - 1 Feb 2012
Externally published	Yes

Keywords

Adolescent
Adult
Aged
Aged, 80 and over
Alleles
Cardiovascular Diseases/genetics
Cohort Studies
Female
Gene Frequency
Genetic Loci
Genetic Variation
Genome-Wide Association Study
Genotype
Humans
Male
Middle Aged
Phenotype
Proportional Hazards Models
Repressor Proteins/genetics
Risk Factors
Tumor Suppressor Proteins/genetics
Vascular Stiffness/physiology
Young Adult

Access to Document

10.1161/CIRCGENETICS.111.959817

Cite this

Mitchell, G. F., Verwoert, G. C., Tarasov, K. V., Isaacs, A., Smith, A. V., Yasmin, Rietzschel, E. R., Tanaka, T., Liu, Y., Parsa, A., Najjar, S. S., O'Shaughnessy, K. M., Sigurdsson, S., De Buyzere, M. L., Larson, M. G., Sie, M. P. S., Andrews, J. S., Post, W. S., Mattace-Raso, F. U. S., ... Witteman, J. C. M. (2012). Common genetic variation in the 3'-BCL11B gene desert is associated with carotid-femoral pulse wave velocity and excess cardiovascular disease risk: the AortaGen Consortium. Circulation : Cardiovascular Genetics, 5(1), 81-90. https://doi.org/10.1161/CIRCGENETICS.111.959817

@article{aa88ed087e594cc7b2fb4bc6196059ef,

title = "Common genetic variation in the 3'-BCL11B gene desert is associated with carotid-femoral pulse wave velocity and excess cardiovascular disease risk: the AortaGen Consortium",

abstract = "BACKGROUND: Carotid-femoral pulse wave velocity (CFPWV) is a heritable measure of aortic stiffness that is strongly associated with increased risk for major cardiovascular disease events.METHODS AND RESULTS: We conducted a meta-analysis of genome-wide association data in 9 community-based European ancestry cohorts consisting of 20 634 participants. Results were replicated in 2 additional European ancestry cohorts involving 5306 participants. Based on a preliminary analysis of 6 cohorts, we identified a locus on chromosome 14 in the 3'-BCL11B gene desert that is associated with CFPWV (rs7152623, minor allele frequency=0.42, β=-0.075±0.012 SD/allele, P=2.8×10(-10); replication β=-0.086±0.020 SD/allele, P=1.4×10(-6)). Combined results for rs7152623 from 11 cohorts gave β=-0.076±0.010 SD/allele, P=3.1×10(-15). The association persisted when adjusted for mean arterial pressure (β=-0.060±0.009 SD/allele, P=1.0×10(-11)). Results were consistent in younger (<55 years, 6 cohorts, n=13 914, β=-0.081±0.014 SD/allele, P=2.3×10(-9)) and older (9 cohorts, n=12 026, β=-0.061±0.014 SD/allele, P=9.4×10(-6)) participants. In separate meta-analyses, the locus was associated with increased risk for coronary artery disease (hazard ratio=1.05; confidence interval=1.02-1.08; P=0.0013) and heart failure (hazard ratio=1.10, CI=1.03-1.16, P=0.004).CONCLUSIONS: Common genetic variation in a locus in the BCL11B gene desert that is thought to harbor 1 or more gene enhancers is associated with higher CFPWV and increased risk for cardiovascular disease. Elucidation of the role this novel locus plays in aortic stiffness may facilitate development of therapeutic interventions that limit aortic stiffening and related cardiovascular disease events.",

keywords = "Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Cardiovascular Diseases/genetics, Cohort Studies, Female, Gene Frequency, Genetic Loci, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Phenotype, Proportional Hazards Models, Repressor Proteins/genetics, Risk Factors, Tumor Suppressor Proteins/genetics, Vascular Stiffness/physiology, Young Adult",

author = "Mitchell, {Gary F} and Verwoert, {Germaine C} and Tarasov, {Kirill V} and Aaron Isaacs and Smith, {Albert V} and Yasmin and Rietzschel, {Ernst R} and Toshiko Tanaka and Yongmei Liu and Afshin Parsa and Najjar, {Samer S} and O'Shaughnessy, {Kevin M} and Sigurdur Sigurdsson and {De Buyzere}, {Marc L} and Larson, {Martin G} and Sie, {Mark P S} and Andrews, {Jeanette S} and Post, {Wendy S} and Mattace-Raso, {Francesco U S} and McEniery, {Carmel M} and Gudny Eiriksdottir and Patrick Segers and Vasan, {Ramachandran S} and {van Rijn}, {Marie Josee E} and Howard, {Timothy D} and McArdle, {Patrick F} and Abbas Dehghan and Jewell, {Elizabeth S} and Newhouse, {Stephen J} and Sofie Bekaert and Hamburg, {Naomi M} and Newman, {Anne B} and Albert Hofman and Angelo Scuteri and {De Bacquer}, Dirk and Ikram, {Mohammad Arfan} and Psaty, {Bruce M} and Christian Fuchsberger and Matthias Olden and Wain, {Louise V} and Paul Elliott and Smith, {Nicholas L} and Felix, {Janine F} and Jeanette Erdmann and Vita, {Joseph A} and Kim Sutton-Tyrrell and Sijbrands, {Eric J G} and Serena Sanna and Launer, {Lenore J} and {De Meyer}, Tim and Johnson, {Andrew D} and Schut, {Anna F C} and Herrington, {David M} and Fernando Rivadeneira and Manuela Uda and Wilkinson, {Ian B} and Thor Aspelund and Gillebert, {Thierry C} and {Van Bortel}, Luc and Benjamin, {Emelia J} and Oostra, {Ben A} and Jingzhong Ding and Quince Gibson and Uitterlinden, {Andr{\'e} G} and Abecasis, {Gon{\c c}alo R} and Cockcroft, {John R} and Vilmundur Gudnason and {De Backer}, {Guy G} and Luigi Ferrucci and Harris, {Tamara B} and Shuldiner, {Alan R} and {van Duijn}, {Cornelia M} and Daniel Levy and Lakatta, {Edward G} and Witteman, {Jacqueline C M}",

year = "2012",

month = feb,

day = "1",

doi = "10.1161/CIRCGENETICS.111.959817",

language = "English",

volume = "5",

pages = "81--90",

journal = "Circulation : Cardiovascular Genetics",

issn = "1942-3268",

publisher = "LIPPINCOTT WILLIAMS & WILKINS",

number = "1",

}

Mitchell, GF, Verwoert, GC, Tarasov, KV, Isaacs, A, Smith, AV, Yasmin, Rietzschel, ER, Tanaka, T, Liu, Y, Parsa, A, Najjar, SS, O'Shaughnessy, KM, Sigurdsson, S, De Buyzere, ML, Larson, MG, Sie, MPS, Andrews, JS, Post, WS, Mattace-Raso, FUS, McEniery, CM, Eiriksdottir, G, Segers, P, Vasan, RS, van Rijn, MJE, Howard, TD, McArdle, PF, Dehghan, A, Jewell, ES, Newhouse, SJ, Bekaert, S, Hamburg, NM, Newman, AB, Hofman, A, Scuteri, A, De Bacquer, D, Ikram, MA, Psaty, BM, Fuchsberger, C, Olden, M, Wain, LV, Elliott, P, Smith, NL, Felix, JF, Erdmann, J, Vita, JA, Sutton-Tyrrell, K, Sijbrands, EJG, Sanna, S, Launer, LJ, De Meyer, T, Johnson, AD, Schut, AFC, Herrington, DM, Rivadeneira, F, Uda, M, Wilkinson, IB, Aspelund, T, Gillebert, TC, Van Bortel, L, Benjamin, EJ, Oostra, BA, Ding, J, Gibson, Q, Uitterlinden, AG, Abecasis, GR, Cockcroft, JR, Gudnason, V, De Backer, GG, Ferrucci, L, Harris, TB, Shuldiner, AR, van Duijn, CM, Levy, D, Lakatta, EG & Witteman, JCM 2012, 'Common genetic variation in the 3'-BCL11B gene desert is associated with carotid-femoral pulse wave velocity and excess cardiovascular disease risk: the AortaGen Consortium', Circulation : Cardiovascular Genetics, vol. 5, no. 1, pp. 81-90. https://doi.org/10.1161/CIRCGENETICS.111.959817

Common genetic variation in the 3'-BCL11B gene desert is associated with carotid-femoral pulse wave velocity and excess cardiovascular disease risk: the AortaGen Consortium. / Mitchell, Gary F; Verwoert, Germaine C; Tarasov, Kirill V et al.
In: Circulation : Cardiovascular Genetics, Vol. 5, No. 1, 01.02.2012, p. 81-90.

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

TY - JOUR

T1 - Common genetic variation in the 3'-BCL11B gene desert is associated with carotid-femoral pulse wave velocity and excess cardiovascular disease risk

T2 - the AortaGen Consortium

AU - Mitchell, Gary F

AU - Verwoert, Germaine C

AU - Tarasov, Kirill V

AU - Isaacs, Aaron

AU - Smith, Albert V

AU - Yasmin, null

AU - Rietzschel, Ernst R

AU - Tanaka, Toshiko

AU - Liu, Yongmei

AU - Parsa, Afshin

AU - Najjar, Samer S

AU - O'Shaughnessy, Kevin M

AU - Sigurdsson, Sigurdur

AU - De Buyzere, Marc L

AU - Larson, Martin G

AU - Sie, Mark P S

AU - Andrews, Jeanette S

AU - Post, Wendy S

AU - Mattace-Raso, Francesco U S

AU - McEniery, Carmel M

AU - Eiriksdottir, Gudny

AU - Segers, Patrick

AU - Vasan, Ramachandran S

AU - van Rijn, Marie Josee E

AU - Howard, Timothy D

AU - McArdle, Patrick F

AU - Dehghan, Abbas

AU - Jewell, Elizabeth S

AU - Newhouse, Stephen J

AU - Bekaert, Sofie

AU - Hamburg, Naomi M

AU - Newman, Anne B

AU - Hofman, Albert

AU - Scuteri, Angelo

AU - De Bacquer, Dirk

AU - Ikram, Mohammad Arfan

AU - Psaty, Bruce M

AU - Fuchsberger, Christian

AU - Olden, Matthias

AU - Wain, Louise V

AU - Elliott, Paul

AU - Smith, Nicholas L

AU - Felix, Janine F

AU - Erdmann, Jeanette

AU - Vita, Joseph A

AU - Sutton-Tyrrell, Kim

AU - Sijbrands, Eric J G

AU - Sanna, Serena

AU - Launer, Lenore J

AU - De Meyer, Tim

AU - Johnson, Andrew D

AU - Schut, Anna F C

AU - Herrington, David M

AU - Rivadeneira, Fernando

AU - Uda, Manuela

AU - Wilkinson, Ian B

AU - Aspelund, Thor

AU - Gillebert, Thierry C

AU - Van Bortel, Luc

AU - Benjamin, Emelia J

AU - Oostra, Ben A

AU - Ding, Jingzhong

AU - Gibson, Quince

AU - Uitterlinden, André G

AU - Abecasis, Gonçalo R

AU - Cockcroft, John R

AU - Gudnason, Vilmundur

AU - De Backer, Guy G

AU - Ferrucci, Luigi

AU - Harris, Tamara B

AU - Shuldiner, Alan R

AU - van Duijn, Cornelia M

AU - Levy, Daniel

AU - Lakatta, Edward G

AU - Witteman, Jacqueline C M

PY - 2012/2/1

Y1 - 2012/2/1

N2 - BACKGROUND: Carotid-femoral pulse wave velocity (CFPWV) is a heritable measure of aortic stiffness that is strongly associated with increased risk for major cardiovascular disease events.METHODS AND RESULTS: We conducted a meta-analysis of genome-wide association data in 9 community-based European ancestry cohorts consisting of 20 634 participants. Results were replicated in 2 additional European ancestry cohorts involving 5306 participants. Based on a preliminary analysis of 6 cohorts, we identified a locus on chromosome 14 in the 3'-BCL11B gene desert that is associated with CFPWV (rs7152623, minor allele frequency=0.42, β=-0.075±0.012 SD/allele, P=2.8×10(-10); replication β=-0.086±0.020 SD/allele, P=1.4×10(-6)). Combined results for rs7152623 from 11 cohorts gave β=-0.076±0.010 SD/allele, P=3.1×10(-15). The association persisted when adjusted for mean arterial pressure (β=-0.060±0.009 SD/allele, P=1.0×10(-11)). Results were consistent in younger (<55 years, 6 cohorts, n=13 914, β=-0.081±0.014 SD/allele, P=2.3×10(-9)) and older (9 cohorts, n=12 026, β=-0.061±0.014 SD/allele, P=9.4×10(-6)) participants. In separate meta-analyses, the locus was associated with increased risk for coronary artery disease (hazard ratio=1.05; confidence interval=1.02-1.08; P=0.0013) and heart failure (hazard ratio=1.10, CI=1.03-1.16, P=0.004).CONCLUSIONS: Common genetic variation in a locus in the BCL11B gene desert that is thought to harbor 1 or more gene enhancers is associated with higher CFPWV and increased risk for cardiovascular disease. Elucidation of the role this novel locus plays in aortic stiffness may facilitate development of therapeutic interventions that limit aortic stiffening and related cardiovascular disease events.

AB - BACKGROUND: Carotid-femoral pulse wave velocity (CFPWV) is a heritable measure of aortic stiffness that is strongly associated with increased risk for major cardiovascular disease events.METHODS AND RESULTS: We conducted a meta-analysis of genome-wide association data in 9 community-based European ancestry cohorts consisting of 20 634 participants. Results were replicated in 2 additional European ancestry cohorts involving 5306 participants. Based on a preliminary analysis of 6 cohorts, we identified a locus on chromosome 14 in the 3'-BCL11B gene desert that is associated with CFPWV (rs7152623, minor allele frequency=0.42, β=-0.075±0.012 SD/allele, P=2.8×10(-10); replication β=-0.086±0.020 SD/allele, P=1.4×10(-6)). Combined results for rs7152623 from 11 cohorts gave β=-0.076±0.010 SD/allele, P=3.1×10(-15). The association persisted when adjusted for mean arterial pressure (β=-0.060±0.009 SD/allele, P=1.0×10(-11)). Results were consistent in younger (<55 years, 6 cohorts, n=13 914, β=-0.081±0.014 SD/allele, P=2.3×10(-9)) and older (9 cohorts, n=12 026, β=-0.061±0.014 SD/allele, P=9.4×10(-6)) participants. In separate meta-analyses, the locus was associated with increased risk for coronary artery disease (hazard ratio=1.05; confidence interval=1.02-1.08; P=0.0013) and heart failure (hazard ratio=1.10, CI=1.03-1.16, P=0.004).CONCLUSIONS: Common genetic variation in a locus in the BCL11B gene desert that is thought to harbor 1 or more gene enhancers is associated with higher CFPWV and increased risk for cardiovascular disease. Elucidation of the role this novel locus plays in aortic stiffness may facilitate development of therapeutic interventions that limit aortic stiffening and related cardiovascular disease events.

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Alleles

KW - Cardiovascular Diseases/genetics

KW - Cohort Studies

KW - Female

KW - Gene Frequency

KW - Genetic Loci

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Male

KW - Middle Aged

KW - Phenotype

KW - Proportional Hazards Models

KW - Repressor Proteins/genetics

KW - Risk Factors

KW - Tumor Suppressor Proteins/genetics

KW - Vascular Stiffness/physiology

KW - Young Adult

U2 - 10.1161/CIRCGENETICS.111.959817

DO - 10.1161/CIRCGENETICS.111.959817

M3 - Article

C2 - 22068335

SN - 1942-3268

VL - 5

SP - 81

EP - 90

JO - Circulation : Cardiovascular Genetics

JF - Circulation : Cardiovascular Genetics

IS - 1

ER -