Genetic associations with valvular calcification and aortic stenosis

George Thanassoulis; Catherine Y Campbell; David S Owens; J Gustav Smith; Albert V Smith; Gina M Peloso; Kathleen F Kerr; Sonali Pechlivanis; Matthew J Budoff; Tamara B Harris; Rajeev Malhotra; Kevin D O'Brien; Pia R Kamstrup; Børge G Nordestgaard; Anne Tybjaerg-Hansen; Matthew A Allison; Thor Aspelund; Michael H Criqui; Susan R Heckbert; Shih-Jen Hwang; Yongmei Liu; Marketa Sjogren; Jesper van der Pals; Hagen Kälsch; Thomas W Mühleisen; Markus M Nöthen; L Adrienne Cupples; Muriel Caslake; Emanuele Di Angelantonio; John Danesh; Jerome I Rotter; Sigurdur Sigurdsson; Quenna Wong; Raimund Erbel; Sekar Kathiresan; Olle Melander; Vilmundur Gudnason; Christopher J O'Donnell; Wendy S Post; CHARGE Extracoronary Calcium Working Group

doi:10.1056/NEJMoa1109034

Genetic associations with valvular calcification and aortic stenosis

George Thanassoulis, Catherine Y Campbell, David S Owens, J Gustav Smith, Albert V Smith, Gina M Peloso, Kathleen F Kerr, Sonali Pechlivanis, Matthew J Budoff, Tamara B Harris, Rajeev Malhotra, Kevin D O'Brien, Pia R Kamstrup, Børge G Nordestgaard, Anne Tybjaerg-Hansen, Matthew A Allison, Thor Aspelund, Michael H Criqui, Susan R Heckbert, Shih-Jen HwangYongmei Liu, Marketa Sjogren, Jesper van der Pals, Hagen Kälsch, Thomas W Mühleisen, Markus M Nöthen, L Adrienne Cupples, Muriel Caslake, Emanuele Di Angelantonio, John Danesh, Jerome I Rotter, Sigurdur Sigurdsson, Quenna Wong, Raimund Erbel, Sekar Kathiresan, Olle Melander, Vilmundur Gudnason, Christopher J O'Donnell, Wendy S Post, CHARGE Extracoronary Calcium Working Group

499 Citations (Scopus)

Abstract

BACKGROUND: Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. METHODS: We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. RESULTS: One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P = 9.0×10^-10), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P = 1.5×10^-8 and P = 1.8×10 ^-8, respectively), but the findings were not replicated consistently. CONCLUSIONS: Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aorticvalve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)

Original language	English
Journal	New England Journal of Medicine
Volume	368
Issue number	6
Pages (from-to)	503-12
Number of pages	10
ISSN	0028-4793
DOIs	https://doi.org/10.1056/NEJMoa1109034
Publication status	Published - 7 Feb 2013

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Thanassoulis, G., Campbell, C. Y., Owens, D. S., Smith, J. G., Smith, A. V., Peloso, G. M., Kerr, K. F., Pechlivanis, S., Budoff, M. J., Harris, T. B., Malhotra, R., O'Brien, K. D., Kamstrup, P. R., Nordestgaard, B. G., Tybjaerg-Hansen, A., Allison, M. A., Aspelund, T., Criqui, M. H., Heckbert, S. R., ... CHARGE Extracoronary Calcium Working Group (2013). Genetic associations with valvular calcification and aortic stenosis. New England Journal of Medicine, 368(6), 503-12. https://doi.org/10.1056/NEJMoa1109034

Thanassoulis, G, Campbell, CY, Owens, DS, Smith, JG, Smith, AV, Peloso, GM, Kerr, KF, Pechlivanis, S, Budoff, MJ, Harris, TB, Malhotra, R, O'Brien, KD, Kamstrup, PR, Nordestgaard, BG , Tybjaerg-Hansen, A, Allison, MA, Aspelund, T, Criqui, MH, Heckbert, SR, Hwang, S-J, Liu, Y, Sjogren, M, van der Pals, J, Kälsch, H, Mühleisen, TW, Nöthen, MM, Cupples, LA, Caslake, M, Di Angelantonio, E, Danesh, J, Rotter, JI, Sigurdsson, S, Wong, Q, Erbel, R, Kathiresan, S, Melander, O, Gudnason, V, O'Donnell, CJ, Post, WS & CHARGE Extracoronary Calcium Working Group 2013, 'Genetic associations with valvular calcification and aortic stenosis', New England Journal of Medicine, vol. 368, no. 6, pp. 503-12. https://doi.org/10.1056/NEJMoa1109034

@article{8ee5d2d9208a421c89434d4b22f96b48,

title = "Genetic associations with valvular calcification and aortic stenosis",

abstract = "BACKGROUND: Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. METHODS: We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. RESULTS: One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P = 9.0×10-10), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P = 1.5×10-8 and P = 1.8×10 -8, respectively), but the findings were not replicated consistently. CONCLUSIONS: Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aorticvalve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)",

author = "George Thanassoulis and Campbell, {Catherine Y} and Owens, {David S} and Smith, {J Gustav} and Smith, {Albert V} and Peloso, {Gina M} and Kerr, {Kathleen F} and Sonali Pechlivanis and Budoff, {Matthew J} and Harris, {Tamara B} and Rajeev Malhotra and O'Brien, {Kevin D} and Kamstrup, {Pia R} and Nordestgaard, {B{\o}rge G} and Anne Tybjaerg-Hansen and Allison, {Matthew A} and Thor Aspelund and Criqui, {Michael H} and Heckbert, {Susan R} and Shih-Jen Hwang and Yongmei Liu and Marketa Sjogren and {van der Pals}, Jesper and Hagen K{\"a}lsch and M{\"u}hleisen, {Thomas W} and N{\"o}then, {Markus M} and Cupples, {L Adrienne} and Muriel Caslake and {Di Angelantonio}, Emanuele and John Danesh and Rotter, {Jerome I} and Sigurdur Sigurdsson and Quenna Wong and Raimund Erbel and Sekar Kathiresan and Olle Melander and Vilmundur Gudnason and O'Donnell, {Christopher J} and Post, {Wendy S} and Anne Tybj{\ae}rg-Hansen",

year = "2013",

month = feb,

day = "7",

doi = "10.1056/NEJMoa1109034",

language = "English",

volume = "368",

pages = "503--12",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachusetts Medical Society",

number = "6",

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TY - JOUR

T1 - Genetic associations with valvular calcification and aortic stenosis

AU - Thanassoulis, George

AU - Campbell, Catherine Y

AU - Owens, David S

AU - Smith, J Gustav

AU - Smith, Albert V

AU - Peloso, Gina M

AU - Kerr, Kathleen F

AU - Pechlivanis, Sonali

AU - Budoff, Matthew J

AU - Harris, Tamara B

AU - Malhotra, Rajeev

AU - O'Brien, Kevin D

AU - Kamstrup, Pia R

AU - Nordestgaard, Børge G

AU - Tybjaerg-Hansen, Anne

AU - Allison, Matthew A

AU - Aspelund, Thor

AU - Criqui, Michael H

AU - Heckbert, Susan R

AU - Hwang, Shih-Jen

AU - Liu, Yongmei

AU - Sjogren, Marketa

AU - van der Pals, Jesper

AU - Kälsch, Hagen

AU - Mühleisen, Thomas W

AU - Nöthen, Markus M

AU - Cupples, L Adrienne

AU - Caslake, Muriel

AU - Di Angelantonio, Emanuele

AU - Danesh, John

AU - Rotter, Jerome I

AU - Sigurdsson, Sigurdur

AU - Wong, Quenna

AU - Erbel, Raimund

AU - Kathiresan, Sekar

AU - Melander, Olle

AU - Gudnason, Vilmundur

AU - O'Donnell, Christopher J

AU - Post, Wendy S

AU - CHARGE Extracoronary Calcium Working Group

PY - 2013/2/7

Y1 - 2013/2/7

N2 - BACKGROUND: Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. METHODS: We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. RESULTS: One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P = 9.0×10-10), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P = 1.5×10-8 and P = 1.8×10 -8, respectively), but the findings were not replicated consistently. CONCLUSIONS: Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aorticvalve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)

AB - BACKGROUND: Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. METHODS: We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. RESULTS: One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P = 9.0×10-10), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P = 1.5×10-8 and P = 1.8×10 -8, respectively), but the findings were not replicated consistently. CONCLUSIONS: Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aorticvalve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)

U2 - 10.1056/NEJMoa1109034

DO - 10.1056/NEJMoa1109034

M3 - Journal article

C2 - 23388002

SN - 0028-4793

VL - 368

SP - 503

EP - 512

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 6

ER -

Genetic associations with valvular calcification and aortic stenosis

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