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 Kovach & 46 others Stephen 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

Research output: Contribution to journalArticle

359 Citations (Scopus)

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 languageEnglish
Pages (from-to)7401-7406
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number16
DOIs
StatePublished - Apr 20 2010

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Macular Degeneration
HDL Lipoproteins
Genome-Wide Association Study
HDL Cholesterol
Alleles
Metalloproteases
General Hospitals
Extracellular Matrix
Genotype

Keywords

  • Genome-wide association study
  • Single nucleotide polymorphism

ASJC Scopus subject areas

  • General

Cite this

Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. / Chen, Wei; Stambolian, Dwight; Edwards, Albert O.; Branham, Kari E.; Othman, Mohammad; Jakobsdottir, Johanna; Tosakulwong, Nirubol; Pericak-Vance, Margaret A; Campochiaro, Peter A.; Klein, Michael L.; Tan, Perciliz L.; Conley, Yvette P.; Kanda, Atsuhiro; Kopplin, Laura; Li, Yanming; Augustaitis, Katherine J.; Karoukis, Athanasios J.; Scott, William K; Agarwal, Anita; Kovach, Jaclyn; Schwartz, Stephen; Postel, Eric A.; Brooks, Matthew; Baratz, Keith H.; Brown, William L.; Brucker, Alexander J.; Orlin, Anton; Brown, Gary; Ho, Allen; Regillo, Carl; Donoso, Larry; Tian, Lifeng; Kaderli, Brian; Hadley, Dexter; Hagstrom, Stephanie A.; Peachey, Neal S.; Klein, Ronald; Klein, Barbara E K; Gotoh, Norimoto; Yamashiro, Kenji; Ferris, Frederick; Fagerness, Jesen A.; Reynolds, Robyn; Farrer, Lindsay A.; Kim, Ivana K.; Miller, Joan W.; Cortón, Marta; Carracedo, Angel; Sanchez-Salorio, Manuel; Pugh, Elizabeth W.; Doheny, Kimberly F.; Brion, Maria; DeAngelis, Margaret M.; Weeks, Daniel E.; Zack, Donald J.; Chew, Emily Y.; Heckenlively, John R.; Yoshimura, Nagahisa; Iyengar, Sudha K.; Francis, Peter J.; Katsanis, Nicholas; Seddon, Johanna M.; Haines, Jonathan L.; Gorin, Michael B.; Abecasis, Gonçalo R.; Swaroop, Anand.

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 journalArticle

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, J, Schwartz, S, 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
Chen, Wei ; Stambolian, Dwight ; Edwards, Albert O. ; Branham, Kari E. ; Othman, Mohammad ; Jakobsdottir, Johanna ; Tosakulwong, Nirubol ; Pericak-Vance, Margaret A ; Campochiaro, Peter A. ; Klein, Michael L. ; Tan, Perciliz L. ; Conley, Yvette P. ; Kanda, Atsuhiro ; Kopplin, Laura ; Li, Yanming ; Augustaitis, Katherine J. ; Karoukis, Athanasios J. ; Scott, William K ; Agarwal, Anita ; Kovach, Jaclyn ; Schwartz, Stephen ; Postel, Eric A. ; Brooks, Matthew ; Baratz, Keith H. ; Brown, William L. ; Brucker, Alexander J. ; Orlin, Anton ; Brown, Gary ; Ho, Allen ; Regillo, Carl ; Donoso, Larry ; Tian, Lifeng ; Kaderli, Brian ; Hadley, Dexter ; Hagstrom, Stephanie A. ; Peachey, Neal S. ; Klein, Ronald ; Klein, Barbara E K ; Gotoh, Norimoto ; Yamashiro, Kenji ; Ferris, Frederick ; Fagerness, Jesen A. ; Reynolds, Robyn ; Farrer, Lindsay A. ; Kim, Ivana K. ; Miller, Joan W. ; Cortón, Marta ; Carracedo, Angel ; Sanchez-Salorio, Manuel ; Pugh, Elizabeth W. ; Doheny, Kimberly F. ; Brion, Maria ; DeAngelis, Margaret M. ; Weeks, Daniel E. ; Zack, Donald J. ; Chew, Emily Y. ; Heckenlively, John R. ; Yoshimura, Nagahisa ; Iyengar, Sudha K. ; Francis, Peter J. ; Katsanis, Nicholas ; Seddon, Johanna M. ; Haines, Jonathan L. ; Gorin, Michael B. ; Abecasis, Gonçalo R. ; Swaroop, Anand. / Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 16. pp. 7401-7406.
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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.",
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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

AU - Schwartz, Stephen

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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