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JAMA Ophthalmol. 2014 May;132(5):521-7.

VEGFA and VEGFR2 gene polymorphisms and response to anti-vascular endothelial growth factor therapy: comparison of age-related macular degeneration treatments trials (CATT).

Collaborators (886)

Williams DF, Beardsley S, Bennett S, Cantrill H, Chan-Tram C, Cheshier H, Damato K, Davies J, Dev S, Enloe J, Follano G, Gilbert P, Johnson J, Jones T, Mayleben L, Mittra R, Moos M, Neist R, Oestreich N, Quiram P, Ramsay R, Ryan E, Schindeldecker S, Snater J, Steele T, Selders D, Tonsfeldt J, Valardi S, Fish GE, Aquado HA, Arceneaux S, Arnwine J, Bell K, Bell T, Boleman B, Bradley P, Callanan D, Coors L, Creighton J, Crew T, Cummings K, Dock C, Duignan K, Fuller D, Gray K, Hendrix B, Hesse N, Jaramillo D, Jost B, Lash S, Lonsdale L, Mackens M, Mutz K, Potts M, Sanchez B, Snyder W, Solley W, Tarter C, Wang R, William P, Perkins SL, Anderson N, Arnold A, Blais P, Googe J, Higdon TT, Hunt C, Johnson M, Miller J, Morris CK, Oelrich S, Oliver K, Seitz V, Whetstone J, Doft BH, Bedel J, Bergren R, Borthwick A, Conrad P, Fec A, Fulwylie C, Ingram W, Latham S, Lester G, Liu J, Lobes L, Lucko NM, Mechling H, Merlotti L, McBroom K, Olsen K, Puskas D, Rath P, Schmucher M, Schueckler L, Schultz C, Shultz H, Steinberg D, Vyas A, Whale K, Yeckel K, Orth DH, Arredonde LS, Brown S, Ciscato BJ, Civantos JM, Figliulo C, Hasan S, Kosinski B, Muir D, Nelson K, Packo K, Pollack JS, Rezaei K, Shelton G, Townsend-Patrick S, Walsh M, McDonald HR, Ansari N, Bye A, Fu AD, Grout S, Indermill C, Johnson RN, Jumper JM, Linares S, Lujan BJ, Munden A, Persons M, Rodrigues R, Rose JM, Teske B, Urias Y, Young S, Dreyer RF, Daniel H, Connaughton M, Handelman I, Hobbs S, Hoerner C, Hudson D, Kopfer M, Lee M, Lemley C, Logan J, Ma C, Mallet C, Milliron A, Peters M, Wohlsein H, Pearlman JA, Andrews M, Bartlett M, Carlson N, Cox E, Equi R, Gonzalez M, Griffin S, Hogue F, Kennedy L, Kryuchkov L, Lopez C, Lopez D, Luevano B, McKenna E, Patel A, Reed B, Secor N, Sison IR, Tsai T, Varghis N, Waller B, Wendel R, Yebra R, Roth DB, Deinzer J, Fine H, Green F, Green S, Keyser B, Leff S, Leviton A, Martir A, Mosenthine K, Muscle S, Okoren L, Parker S, Prenner J, Price N, Rogers D, Rosas L, Schlosser A, Studenko L, Tantum T, Wheatley H, Trese MT, Aaberg T, Bell T, Bezaire D, Bridges C, Bryant D, Capone A, Coleman M, Consolo C, Cook C, DuLong C, Garretson B, Grooten T, Hammersley J, Hassan T, Jessick H, Jones N, Kinsman C, Krumlauf J, Lewis S, Locke H, Margherio A, Markus D, Marsh T, Neal S, Noffke A, Oh K, Pence C, Preston L, Raphaelian P, Regan VR, Roberts P, Ruby A, Sarrafizadeh R, Scherf M, Scott S, Sneed S, Staples L, Terry B, Trese MT, Videtich J, Williams G, Zajechowski M, Joseph DP, Blinder K, Boyd L, Buckley S, Crow M, Dinatale A, Engelbrecht N, Forke B, Gabel D, Grand G, Grillion-Cerone J, Holekamp N, Kelly C, Nobel G, Pepple K, Raeber M, Rao PK, Ressel T, Schremp S, Sgorlon M, Shears S, Thomas M, Timma C, Vaughn A, Walters C, Weeks R, Wehmeier J, Wright T, Berinstein DM, Ayyad A, Barazi MK, Bickhart E, Brady T, Byank L, Cronise A, Denny V, Dunn C, Flory M, Frantz R, Garfinkel RA, Gilbert W, Lai MM, Melamud A, Newgen J, Newton S, Oliver D, Osman M, Sanders R, von Fricken M, Dugel P, Arenas S, Balea G, Bartoli D, Bucci J, Cornelius JA, Dickens S, Doherty D, Dunlap H, Goldenberg D, Jamal K, Jimenez N, Kavanagh N, Kunimoto D, Martin J, Miner J, Mobley S, Park D, Quinlan E, Sipperley J, Slagle C, Smith D, Yafchak M, Yager R, Flaxel C, Bailey S, Francis P, Howell C, Hwang T, Ira S, Klein M, Lauer A, Liesegang T, Lundquist A, Nolte S, Nolte SK, Pickell S, Pope S, Rossi J, Schain M, Steinkamp P, Toomey MD, Vahrenwald D, West K, Hubbard B, Andelman S, Bergstrom C, Brower J, Cribbs B, Curtis L, Dobbs J, DuBois L, Gaultney J, Gibbs D, Jordan D, Leef D, Martin DF, Myles R, Olsen T, Schwent B, Srivastava S, Waldron R, Antoszyk AN, Balasubramaniam U, Brooks D, Brown J, Browning D, Clark L, Ennis S, Held S, Helms JV, Herby J, Karow A, Leotaud P, Massimino C, McClain D, McOwen M, Mindel J, Pereira C, Pierce R, Powers M, Price A, Rohrer J, Sanders J, Avery RL, Avery K, Basefsky J, Beckner L, Castellarin A, Couvillion S, Giust J, Giust M, Nasir M, Pieramici D, Rabena M, Risard S, See R, Smith J, Wan L, Bakri S, Abu-Yaghi N, Barkmeier A, Berg K, Burrington J, Edwards A, Goddard S, Howard S, Iezzi R, Lewison D, Link T, McCannel CA, Overend J, Pach J, Ruszczyk M, Shultz R, Stephan C, Vogen D, Bradford RH Jr, Bergman V, Burris R, Butt A, Daniels B, Dwiggins C, Fransen S, Guerrero T, Haivala D, Harris A, Icks S, Kingsley R, Redder L, Topping TM, Bennett S, Chong S, Ciotti M, Cleary T, Corey E, Donovan D, Frederick A, Freese L, Graham M, Gud N, Howard T, Jones M, Michael M, Moses K, Stone J, Ty R, Wiegand T, Williams L, Winder B, Awh CC, Amonette M, Arrindell E, Busbee B, Dilback A, Downs S, Guidry A, Gutow G, Hardin J, Hines S, Hutchins E, LaCivita K, Lester A, Malott L, McCain M, Miracle J, Moffat K, Palazzotta L, Robbinson K, Sonkin P, Travis A, Wallace RT, Winters KJ, Wray J, Harris AE, Bunnell M, Crooks K, Fitzgerald R, Javid C, Kew C, Kill E, Kline P, Kreienkamp J, Martinez M, Moore RA, Saavedra E, Taylor L, Walsh M, Wilson L, Ciulla TA, Coyle E, Harrington T, Harris C, Hood C, Kerr I, Maturi R, Moore D, Morrow S, Savage J, Sink B, Steele T, Thukral N, Wilburn J, Walker JP, Banks J, Ciampaglia D, Dyshanowitz D, Frederick J, Ghuman AT, Grodin R, Kiesel C, Knips E, McCue J, Ortiz M, Peters C, Raskauskas P, Schoeman E, Sharma A, Wing G, Youngblood R, Chandra SR, Altaweel M, Blodi B, Burke K, Dietzman KA, Gottlieb J, Knutson G, Krolnik D, Nork TM, Olson S, Peterson J, Reed S, Soderling B, Somers G, Stevens T, Wealti A, Bearelly S, Branchaud B, Bryant JW, Crowell S, Fekrat S, Merritt G, Harrison C, Jones S, McClain N, McCuen B, Mruthyunjaya P, Queen J, Sarin N, Skalak C, Skelly M, Suner I, Tomany R, Welch L, Park SS, Cassidy A, Chandra K, Good I, Imson K, Kaur S, Metzler H, Morse L, Redenbo E, Salvador M, Telander D, Thomas M, Cindy W, Barr CC, Battcher A, Bottorff M, Chasteen M, Clark K, Denning D, Schoen D, Schultz A, Tempel E, Wheeler L, Whittington GK, Stone TW, Blevins T, Buck M, Cruz L, Heath W, Holcomb D, Isernhagen R, Kidd T, Kitchens J, Sears C, Slade E, Van Arsdall J, VanHoose B, Wolfe J, Wood W, Zilis J, Crooks C, Disney L, Liu M, Petty S, Sall S, Folk JC, Aly T, Brotherton A, Critser D, Hinz CJ, Karakas S, Kirschner V, Lester C, Mondague C, Russell S, Stockman H, Taylor B, Verdick R, Walshire J, Thompson JT, Connell B, Constantine M, Davis JL Jr, Holsapple G, Hunter L, Lenane CN, Mitchell R, Russel L, Sjaarda R, Brown DM, Benz M, Burns L, Garranza JG, Fish R, Goates D, Hay S, Jeffers T, Kegley E, Kubecka D, McGilvra S, Richter B, Sneed V, Stoever C, Tellez I, Wong T, Kim I, Andreoli C, Barresi L, Brett S, Callahan C, Capaccioli K, Carli W, Coppola M, Emmanuel N, Evans C, Fagan A, Grillo M, Head J, Kieser T, Lee E, Lord U, Miretsky E, Palitsch K, Petrin T, Reader L, Reznichenko S, Robertson M, Smith J, Vavvas D, Wells J, Cahill C, Clark WL, Henry K, Johnson D, Miller P, Oliver L, Spivey R, Swinford T, Taylor M, Lambert M, Chase K, Fredrickson D, Khawly J, Lazarte V, Lowd D, Miller P, Willis A, Ferrone PJ, Almonte M, Arnott R, Aviles I, Carbon S, Chitjian M, DAmore K, Elliott C, Fastenberg D, Golub B, Graham K, Lavorna A, Murphy L, Palomo A, Puglisi C, Rhee D, Romero J, Rosenblatt B, Ssalcedo G, Schlameuss M, Shakin E, Sookhai V, Kaiser R, Affel E, Brown G, Centinaro C, Fine D, Fineman M, Formoso M, Garg S, Grande L, Herbert C, Ho A, Hsu J, Jay M, Lavetsky L, Liebenbaum E, Maguire J, Monsonego J, O'Connor L, Pierce L, Regillo C, Rosari M, Spirn M, Vander J, Walsh J, Davidorf FH, Barnett A, Chang S, Christoforidis J, Elliott J, Justice H, Letson A, McKinney K, Perry J, Salerno JA, Ssavage S, Shelley S, Singerman LJ, Coney J, DuBois J, DuBois K, Greanoff G, Himmelman D, Llc M, Mcnamara E, Novak M, Pendergast S, Rath S, Smith-Brewer S, Tanner V, Weiss DE, Zegarra H, Halperin L, Aramayo P, Dhalla M, Fernandez B, Fernandez C, Lopez J, Lopez M, Mariano J, Murphy K, Sherley C, Veksler R, Rahhal F, Babikian R, Boyer D, Hami S, kessinger J, Kurokouch J, Mukarram S, Pachman S, Protacio E, Sierra J, Tabandeh H, Zamboni A, Belz J, Butcher T, Cain T, Coffey T, Firestone D, Gore N, Singletary P, Sotirakos P, Starr J, Meredith TA, Barnhart CJ, Cantrell D, Esquejo-Leon R, Houghton O, Kaur H, NDure F, Glatzer R, Joffe L, Schindler R, Martin DF, Fine SL, Katz M, Maguire MG, Brightwell-Arnold M, Glaser R, Hall J, Harkins S, Huang J, Khvatov A, McWilliams K, Nolte SK, Peskin E, Pistilli M, Ryan S, Schnader A, Ying GS, Jaffe G, Afrani-Sakyi J, Balsley B, Bennett LS, Brooks A, Brower-Lingsch A, Bruce L, Burns R, Busian D, Choong J, Cloaninger L, DeCroos FC, DuBois E, El-Dairi M, Gach S, Hall K, Hawks T, Huang C, Heydary C, Ho A, Kini S, McCall M, Muhammad D, Nicholson J, Queen J, Rieves P, Shields K, Skalak C, Specker A, Stinnett S, Subramaniam S, Tenbrink P, Toth C, Towe A, Welch K, Williamas N, Winter K, Young E, Grunwald JE, Alexander J, Daniel E, Flannagan E, Martin ER, Parker C, Sepielli K, Shannon T, Whearry C, Redford M, Martin DF, Avery RL, Bakri SJ, Daniel E, Fine SL, Grunwald JE, Jaffe G, Kopfer MR, Maguire MG, Meredith TA, Peskin E, Redford M, Williams DF, Martin DF, Bennett LS, Daniel E, Ferris FL 3rd, Fine SL, Grunwald JE, Faffe G, Maguire MG, Peskin E, Redford M, Toth C, Peskin E, Brightwell-Arnold M, DuPont J, Maguire MG, McWilliams K, Nolte SK, Friedman LM, Bressler SB, DeMets DL, Friedlander M, Johnson MW, Lindblad A, Losordo DW, Miller FG.

Abstract

IMPORTANCE:

Individual variation in response and duration of anti-vascular endothelial growth factor (VEGF) therapy is seen among patients with neovascular age-related macular degeneration. Identification of genetic markers that affect clinical response may result in optimization of anti-VEGF therapy.

OBJECTIVE:

To evaluate the pharmacogenetic relationship between genotypes of single-nucleotide polymorphisms (SNPs) in the VEGF signaling pathway and response to treatment with ranibizumab or bevacizumab for neovascular age-related macular degeneration.

DESIGN, SETTING, AND PARTICIPANTS:

In total, 835 of 1149 patients (72.7%) participating in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) at 43 CATT clinical centers.

INTERVENTION:

Each patient was genotyped for 7 SNPs in VEGFA (rs699946, rs699947, rs833069, rs833070, rs1413711, rs2010963, and rs2146323) and 1 SNP in VEGFR2 (rs2071559) using TaqMan SNP genotyping assays.

MAIN OUTCOMES AND MEASURES:

Genotypic frequencies were compared with clinical measures of response to therapy at 1 year, including the mean visual acuity, mean change in visual acuity, at least a 15-letter increase, retinal thickness, mean change in total foveal thickness, presence of fluid on optical coherence tomography, presence of leakage on fluorescein angiography, mean change in lesion size, and mean number of injections administered. Differences in response by genotype were evaluated with tests of linear trend calculated from logistic regression models for categorical outcomes and linear regression models for continuous outcomes. The method of controlling the false discovery rate was used to adjust for multiple comparisons.

RESULTS:

For each of the measures of visual acuity evaluated, no association was observed with any of the genotypes or with the number of risk alleles. Four VEGFA SNPs demonstrated an association with retinal thickness: rs699947 (P = .03), rs833070 (P = .04), rs1413711 (P = .045), and rs2146323 (P = .006). However, adjusted P values for these associations were all statistically nonsignificant (range, P = .24 to P = .45). Among the participants in 2 as-needed groups, no association was found in the number of injections among the different genotypes or for the total number of risk alleles. The effect of risk alleles on each clinical measure did not differ by treatment group, drug, or dosing regimen (P > .01 for all).

CONCLUSIONS AND RELEVANCE:

This study provides evidence that no pharmacogenetic associations exist between the studied VEGFA and VEGFR2 SNPs and response to anti-VEGF therapy.

TRIAL REGISTRATION:

clinicaltrials.gov Identifier: NCT00593450.

PMID:
24652518
PMCID:
PMC4162123
DOI:
10.1001/jamaophthalmol.2014.109
[Indexed for MEDLINE]
Free PMC Article
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