Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration

Wei Chen; Dwight Stambolian; Albert O. Edwards; Kari E. Branham; Mohammad Othman; Johanna Jakobsdottir; Nirubol Tosakulwong; Margaret A. Pericak-Vance; Peter A. Campochiaro; Michael L. Klein; Perciliz L. Tan; Yvette P. Conley; Atsuhiro Kanda; Laura Kopplin; Yanming Li; Katherine J. Augustaitis; Athanasios J. Karoukis; William K. Scott; Anita Agarwal; Jaclyn L. Kovach; Stephen G. Schwartz; Eric A. Postel; Matthew Brooks; Keith H. Baratz; William L. Brown; Alexander J. Brucker; Anton Orlin; Gary Brown; Allen Ho; Carl Regillo; Larry Donoso; Lifeng Tian; Brian Kaderli; Dexter Hadley; Stephanie A. Hagstrom; Neal S. Peachey; Ronald Klein; Barbara E.K. Klein; Norimoto Gotoh; Kenji Yamashiro; Frederick Ferris; Jesen A. Fagerness; Robyn Reynolds; Lindsay A. Farrer; Ivana K. Kim; Joan W. Miller; Marta Cortón; Angel Carracedo; Manuel Sanchez-Salorio; Elizabeth W. Pugh; Kimberly F. Doheny; Maria Brion; Margaret M. DeAngelis; Daniel E. Weeks; Donald J. Zack; Emily Y. Chew; John R. Heckenlively; Nagahisa Yoshimura; Sudha K. Iyengar; Peter J. Francis; Nicholas Katsanis; Johanna M. Seddon; Jonathan L. Haines; Michael B. Gorin; Gonçalo R. Abecasis; Anand Swaroop

doi:10.1073/pnas.0912702107

Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration

Wei Chen
, Dwight Stambolian
, Albert O. Edwards
, Kari E. Branham
, Mohammad Othman
, Johanna Jakobsdottir
, Nirubol Tosakulwong
, Margaret A. Pericak-Vance
, Peter A. Campochiaro
, Michael L. Klein
, Perciliz L. Tan
, Yvette P. Conley
, Atsuhiro Kanda
, Laura Kopplin
, Yanming Li
, Katherine J. Augustaitis
, Athanasios J. Karoukis
, William K. Scott
, Anita Agarwal
, Jaclyn L. Kovach

Stephen G. Schwartz, Eric A. Postel, Matthew Brooks, Keith H. Baratz, William L. Brown, Alexander J. Brucker, Anton Orlin, Gary Brown, Allen Ho, Carl Regillo, Larry Donoso, Lifeng Tian, Brian Kaderli, Dexter Hadley, Stephanie A. Hagstrom, Neal S. Peachey, Ronald Klein, Barbara E.K. Klein, Norimoto Gotoh, Kenji Yamashiro, Frederick Ferris, Jesen A. Fagerness, Robyn Reynolds, Lindsay A. Farrer, Ivana K. Kim, Joan W. Miller, Marta Cortón, Angel Carracedo, Manuel Sanchez-Salorio, Elizabeth W. Pugh, Kimberly F. Doheny, Maria Brion, Margaret M. DeAngelis, Daniel E. Weeks, Donald J. Zack, Emily Y. Chew, John R. Heckenlively, Nagahisa Yoshimura, Sudha K. Iyengar, Peter J. Francis, Nicholas Katsanis, Johanna M. Seddon, Jonathan L. Haines, Michael B. Gorin, Gonçalo R. Abecasis, Anand Swaroop

Department of Ophthalmology

University of Michigan, Ann Arbor
University of Pennsylvania
Mayo Clinic Rochester, MN
University of Pittsburgh
University of Miami
Johns Hopkins University
Oregon Health and Science University
National Institutes of Health
Case Western Reserve University
Vanderbilt University
Duke University
Mid-Atlantic Retina
Thomas Jefferson University
Philadelphia Retina Endowment Fund
Cleveland Clinic Foundation
Louis Stokes Cleveland VA Medical Center
University of Wisconsin-Madison
Kyoto University
Massachusetts General Hospital
Tufts-New England Medical Center
Boston University
Harvard University
Complejo Hospitalario Universitario de Santiago
University of Santiago de Compostela
Instituto Gallego de Oftalmología
Tufts University
University of California at Los Angeles

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

468 Scopus citations

Abstract

We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10^-75), ARMS2 (P < 10 ^-59), C2/CFB (P < 10^-20), C3 (P < 10^-9), and CFI (P < 10^-6). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 x 10 ^-11), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 x 10^-7; CETP, P = 7.4 x 10^-7) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c - associated alleles near LPL (P = 3.0 x 10^-3) and ABCA1 (P = 5.6 x 10 ^-4). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.

Original language	English
Pages (from-to)	7401-7406
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	107
Issue number	16
DOIs	https://doi.org/10.1073/pnas.0912702107
State	Published - Apr 20 2010

Keywords

Genome-wide association study
Single nucleotide polymorphism

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10.1073/pnas.0912702107

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Chen, W., Stambolian, D., Edwards, A. O., Branham, K. E., Othman, M., Jakobsdottir, J., Tosakulwong, N., Pericak-Vance, M. A., Campochiaro, P. A., Klein, M. L., Tan, P. L., Conley, Y. P., Kanda, A., Kopplin, L., Li, Y., Augustaitis, K. J., Karoukis, A. J., Scott, W. K., Agarwal, A., ... Swaroop, A. (2010). Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proceedings of the National Academy of Sciences of the United States of America, 107(16), 7401-7406. https://doi.org/10.1073/pnas.0912702107

@article{002f6f8e0aeb452b9f94b8b8ee91c08d,

title = "Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration",

abstract = "We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10-75), ARMS2 (P < 10 -59), C2/CFB (P < 10-20), C3 (P < 10-9), and CFI (P < 10-6). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 x 10 -11), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 x 10-7; CETP, P = 7.4 x 10-7) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c - associated alleles near LPL (P = 3.0 x 10-3) and ABCA1 (P = 5.6 x 10 -4). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99\%) with the highest-risk genotypes were cases, and 85\% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.",

keywords = "Genome-wide association study, Single nucleotide polymorphism",

author = "Wei Chen and Dwight Stambolian and Edwards, \{Albert O.\} and Branham, \{Kari E.\} and Mohammad Othman and Johanna Jakobsdottir and Nirubol Tosakulwong and Pericak-Vance, \{Margaret A.\} and Campochiaro, \{Peter A.\} and Klein, \{Michael L.\} and Tan, \{Perciliz L.\} and Conley, \{Yvette P.\} and Atsuhiro Kanda and Laura Kopplin and Yanming Li and Augustaitis, \{Katherine J.\} and Karoukis, \{Athanasios J.\} and Scott, \{William K.\} and Anita Agarwal and Kovach, \{Jaclyn L.\} and Schwartz, \{Stephen G.\} and Postel, \{Eric A.\} and Matthew Brooks and Baratz, \{Keith H.\} and Brown, \{William L.\} and Brucker, \{Alexander J.\} and Anton Orlin and Gary Brown and Allen Ho and Carl Regillo and Larry Donoso and Lifeng Tian and Brian Kaderli and Dexter Hadley and Hagstrom, \{Stephanie A.\} and Peachey, \{Neal S.\} and Ronald Klein and Klein, \{Barbara E.K.\} and Norimoto Gotoh and Kenji Yamashiro and Frederick Ferris and Fagerness, \{Jesen A.\} and Robyn Reynolds and Farrer, \{Lindsay A.\} and Kim, \{Ivana K.\} and Miller, \{Joan W.\} and Marta Cort{\'o}n and Angel Carracedo and Manuel Sanchez-Salorio and Pugh, \{Elizabeth W.\} and Doheny, \{Kimberly F.\} and Maria Brion and DeAngelis, \{Margaret M.\} and Weeks, \{Daniel E.\} and Zack, \{Donald J.\} and Chew, \{Emily Y.\} and Heckenlively, \{John R.\} and Nagahisa Yoshimura and Iyengar, \{Sudha K.\} and Francis, \{Peter J.\} and Nicholas Katsanis and Seddon, \{Johanna M.\} and Haines, \{Jonathan L.\} and Gorin, \{Michael B.\} and Abecasis, \{Gon{\c c}alo R.\} and Anand Swaroop",

year = "2010",

month = apr,

day = "20",

doi = "10.1073/pnas.0912702107",

language = "English",

volume = "107",

pages = "7401--7406",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "16",

}

Chen, W, Stambolian, D, Edwards, AO, Branham, KE, Othman, M, Jakobsdottir, J, Tosakulwong, N, Pericak-Vance, MA, Campochiaro, PA, Klein, ML, Tan, PL, Conley, YP, Kanda, A, Kopplin, L, Li, Y, Augustaitis, KJ, Karoukis, AJ, Scott, WK, Agarwal, A, Kovach, JL, Schwartz, SG, Postel, EA, Brooks, M, Baratz, KH, Brown, WL, Brucker, AJ, Orlin, A, Brown, G, Ho, A, Regillo, C, Donoso, L, Tian, L, Kaderli, B, Hadley, D, Hagstrom, SA, Peachey, NS, Klein, R, Klein, BEK, Gotoh, N, Yamashiro, K, Ferris, F, Fagerness, JA, Reynolds, R, Farrer, LA, Kim, IK, Miller, JW, Cortón, M, Carracedo, A, Sanchez-Salorio, M, Pugh, EW, Doheny, KF, Brion, M, DeAngelis, MM, Weeks, DE, Zack, DJ, Chew, EY, Heckenlively, JR, Yoshimura, N, Iyengar, SK, Francis, PJ, Katsanis, N, Seddon, JM, Haines, JL, Gorin, MB, Abecasis, GR & Swaroop, A 2010, 'Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 16, pp. 7401-7406. https://doi.org/10.1073/pnas.0912702107

Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. / Chen, Wei; Stambolian, Dwight; Edwards, Albert O. et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 16, 20.04.2010, p. 7401-7406.

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

TY - JOUR

T1 - Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration

AU - Chen, Wei

AU - Stambolian, Dwight

AU - Edwards, Albert O.

AU - Branham, Kari E.

AU - Othman, Mohammad

AU - Jakobsdottir, Johanna

AU - Tosakulwong, Nirubol

AU - Pericak-Vance, Margaret A.

AU - Campochiaro, Peter A.

AU - Klein, Michael L.

AU - Tan, Perciliz L.

AU - Conley, Yvette P.

AU - Kanda, Atsuhiro

AU - Kopplin, Laura

AU - Li, Yanming

AU - Augustaitis, Katherine J.

AU - Karoukis, Athanasios J.

AU - Scott, William K.

AU - Agarwal, Anita

AU - Kovach, Jaclyn L.

AU - Schwartz, Stephen G.

AU - Postel, Eric A.

AU - Brooks, Matthew

AU - Baratz, Keith H.

AU - Brown, William L.

AU - Brucker, Alexander J.

AU - Orlin, Anton

AU - Brown, Gary

AU - Ho, Allen

AU - Regillo, Carl

AU - Donoso, Larry

AU - Tian, Lifeng

AU - Kaderli, Brian

AU - Hadley, Dexter

AU - Hagstrom, Stephanie A.

AU - Peachey, Neal S.

AU - Klein, Ronald

AU - Klein, Barbara E.K.

AU - Gotoh, Norimoto

AU - Yamashiro, Kenji

AU - Ferris, Frederick

AU - Fagerness, Jesen A.

AU - Reynolds, Robyn

AU - Farrer, Lindsay A.

AU - Kim, Ivana K.

AU - Miller, Joan W.

AU - Cortón, Marta

AU - Carracedo, Angel

AU - Sanchez-Salorio, Manuel

AU - Pugh, Elizabeth W.

AU - Doheny, Kimberly F.

AU - Brion, Maria

AU - DeAngelis, Margaret M.

AU - Weeks, Daniel E.

AU - Zack, Donald J.

AU - Chew, Emily Y.

AU - Heckenlively, John R.

AU - Yoshimura, Nagahisa

AU - Iyengar, Sudha K.

AU - Francis, Peter J.

AU - Katsanis, Nicholas

AU - Seddon, Johanna M.

AU - Haines, Jonathan L.

AU - Gorin, Michael B.

AU - Abecasis, Gonçalo R.

AU - Swaroop, Anand

PY - 2010/4/20

Y1 - 2010/4/20

N2 - We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10-75), ARMS2 (P < 10 -59), C2/CFB (P < 10-20), C3 (P < 10-9), and CFI (P < 10-6). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 x 10 -11), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 x 10-7; CETP, P = 7.4 x 10-7) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c - associated alleles near LPL (P = 3.0 x 10-3) and ABCA1 (P = 5.6 x 10 -4). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.

AB - We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10-75), ARMS2 (P < 10 -59), C2/CFB (P < 10-20), C3 (P < 10-9), and CFI (P < 10-6). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 x 10 -11), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 x 10-7; CETP, P = 7.4 x 10-7) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c - associated alleles near LPL (P = 3.0 x 10-3) and ABCA1 (P = 5.6 x 10 -4). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.

KW - Genome-wide association study

KW - Single nucleotide polymorphism

UR - https://www.scopus.com/pages/publications/77952147434

U2 - 10.1073/pnas.0912702107

DO - 10.1073/pnas.0912702107

M3 - Article

C2 - 20385819

AN - SCOPUS:77952147434

SN - 0027-8424

VL - 107

SP - 7401

EP - 7406

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 16

ER -

Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration

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Keywords

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