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. KovachStephen 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

School of Medicine

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390 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 (US)
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

ASJC Scopus subject areas

General

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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

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

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

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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",

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doi = "10.1073/pnas.0912702107",

language = "English (US)",

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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

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U2 - 10.1073/pnas.0912702107

DO - 10.1073/pnas.0912702107

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SN - 0027-8424

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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

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ER -

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

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