Portal de Periódicos da CAPES

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

2010; National Academy of Sciences; Volume: 107; Issue: 16 Linguagem: Inglês

10.1073/pnas.0912702107

1091-6490

Wei Chen, Dwight Stambolian, Albert O. Edwards, Kari Branham, Mohammad Othman, Jóhanna Jakobsdóttir, Nirubol Tosakulwong, Margaret A. Pericak‐Vance, Peter A. Campochiaro, Michael L. Klein, Perciliz L. Tan, Yvette P. Conley, Atsuhiro Kanda, Laura J. 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 C. Brown, Allen C. Ho, Carl D. Regillo, Larry A. Donoso, Lifeng Tian, Brian Kaderli, Dexter Hadley, Stephanie A. Hagstrom, Neal S. Peachey, Ronald Klein, Barbara E.K. Klein, Norimoto Gotoh, Kenji Yamashiro, Frederick L. Ferris, Jesen Fagerness, Robyn Reynolds, Lindsay A. Farrer, Ivana K. Kim, Joan W. Miller, Marta Cortón, Ángel Carracedo, Manuel Sánchez‐Salorio, Elizabeth Pugh, Kimberly F. Doheny, Marı́a Brión, 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, Robert N. Johnson, Everett Ai, H. Richard McDonald, Margaret Stolarczuk, Peter R. Pavan, Karina K. Billiris, Mohan Iyer, Matthew M. Menosky, Scott E. Pautler, Sharon M. Millard, G. Baker Hubbard, Thomas Aaberg, Lindy DuBois, Alice T. Lyon, Susan Anderson-Nelson, Lee M. Jampol, David V. Weinberg, Annie Muñana, Zuzanna Rozenbajgier, David H. Orth, Jack Cohen, Matthew MacCumber, Matthew MacCumber, Celeste Figliulo, Liz Porcz, James C. Folk, H. Culver Boldt, Stephen R. Russell, Rachel Ivins, Connie J. Hinz, Charles C. Barr, Steve Bloom, Ken Jaegers, Brian Kritchman, Greg K. Whittington, Jeffrey S. Heier, Albert R. Frederick, Michael G. Morley, Trexler M. Topping, Heather L. Davis, Susan B. Bressler, Neil M. Bressler, W T Jr Doll, Michael T. Trese, A. Capone, Bruce R. Garretson, T. Hassan, Alan Ruby, Tammy Osentoski, Colin A. McCannel, Margaret Ruszczyk, G. Grand, Kevin J. Blinder, Nancy M. Holekamp, Daniel P. Joseph, Gaurav K. Shah, Ginny Nobel, Andrew N. Antoszyk, David J. Browning, Alison H Stallings, Lawrence J. Singerman, David T. Miller, Michael Novák, Scott Pendergast, Hernando Zegarra, Stephanie A. Schura, Sheila Smith-Brewer, Frederick H. Davidorf, Robert Chambers, Louis J. Chorich, Jill Salerno, Richard F. Dreyer, Colin Ma, Marcia Kopfer, Michael L. Klein, David J. Wilson, Susan K. Nolte, Juan E. Grunwald, Alexander J. Brucker, Josh Dunaief, Stuart L. Fine, Albert M. Maguire, Robert A. Stoltz, Monique McRay, Gary E. Fish, Rajiv Anand, Rand Spencer, Jean Arnwine, Suresh R. Chandra, Michael M. Altaweel, Barbara Blodi, Justin L. Gottlieb, Michael S. Ip, T. Michael Nork, Jennie Perry-Raymond, Stuart L. Fine, Maureen G. Maguire, Mary Brightwell-Arnold, Sandra Harkins, Ellen Peskin, Gui‐Shuang Ying, Natalie Kurinij,

Lipid metabolism and disorders

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 × 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 × 10 −7 ; CETP , P = 7.4 × 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 × 10 −3 ) and ABCA1 ( P = 5.6 × 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.