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

Authors
Wei Chen,Dwight Stambolian
Albert Edwards,Kari Branham,Mohammad Othman,Jóhanna Jakobsdóttir,Nirubol Tosakulwong,Margaret Pericak‐Vance,Peter Campochiaro,Michael Klein,Perciliz Tan,Yvette Conley,Atsuhiro Kanda,Laura Kopplin,Yanming Li,Katherine Augustaitis,Athanasios Karoukis,William Scott,Anita Agarwal,Jaclyn Kovach,Stephen Schwartz,Eric Postel,Matthew Brooks,Keith Baratz,William Brown,Alexander Brucker,Anton Orlin,Gary Brown,Allen Ho,Carl Regillo,Larry Donoso,Lifeng Tian,Brian Kaderli,Dexter Hadley,Stephanie Hagstrom,Neal Peachey,Ronald Klein,Barbara Klein,Norimoto Gotoh,Kenji Yamashiro,Frederick Ferris,Jesen Fagerness,Robyn Reynolds,Lindsay Farrer,Ivana Kim,Joan Miller,Marta Cortón,Ángel Carracedo,Manuel Sánchez‐Salorio,Vittorio Perduca,Kimberly Doheny,Marı́a Brión,Margaret DeAngelis,Daniel Weeks,Donald Zack,Emily Chew,John Heckenlively,Nagahisa Yoshimura,Sudha Iyengar,Peter Francis,Nicholas Katsanis,Johanna Seddon,Jonathan Haines,Michael Gorin,Gonçalo Abecasis,Anand Swaroop,Robert Johnson,Everett Ai,H. McDonald,Margaret Stolarczuk,Peter Pavan,Karina Billiris,Mohan Iyer,Matthew Menosky,Scott Pautler,Sharon Millard,G. Hubbard,Thomas Aaberg,Laura Dubois,Alice Lyon,Susan Anderson-Nelson,Lee Jampol,David Weinberg,Annie Muñana,Zuzanna Rozenbajgier,David Orth,Jack Cohen,Matthew MacCumber,Celeste Figliulo,Liz Porcz,James Folk,H. Boldt,Stephen Russell,Rachel Ivins,Connie Hinz,Charles Barr,Steve Bloom,Ken Jaegers,Brian Kritchman,Greg Whittington,Jeffrey Heier,Albert Frederick,Ted Maddess,Trexler Topping,Heather Davis,Susan Bressler,Neil Bressler,W Doll,Michael Trese,A. Capone,Bruce Garretson,T. Hassan,Alan Ruby,Tammy Osentoski,Colin McCannel,Margaret Ruszczyk,G. Grand,Kevin Blinder,Nancy Holekamp,Daniel Joseph,Gaurav Shah,Ginny Nobel,Andrew Antoszyk,David Brown,Amy Stallings,Lawrence Singerman,David Miller,Michael Novák,Scott Pendergast,Hernando Zegarra,Stephanie Schura,Sheila Smith-Brewer,Frederick Davidorf,Robert Chambers,Louis Chorich,Jill Salerno,Richard Dreyer,Colin Ma,Marcia Kopfer,David Wilson,Susan Nolte,Juan Grunwald,Joshua Dunaief,Stuart Fine,Albert Maguire,Robert Stoltz,Monique McRay,Gary Fish,Rajiv Anand,Rand Spencer,Jean Arnwine,Suresh Chandra,Michael Altaweel,Barbara Blodi,Justin Gottlieb,Michael Ip,T. Nork,Jennie Perry-Raymond,Maureen Maguire,Mary Brightwell-Arnold,Sandra Harkins,Ellen Peskin,Gui‐Shuang Ying,Natalie Kurinij,Ángel Carracedo
+163 authors
,Elizabeth Pugh
Published
Apr 12, 2010
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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 × 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.

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