Citations 2
Genetic variants near TIMP3 and high-density lipoprotein–associated loci influence susceptibility to age-related macular degeneration
Stambolian, Dwight, Edwards, Albert O., Branham, Kari , Othman, Mohammad , Jakobsdóttir, Jóhanna , Tosakulwong, Nirubol , Pericak‐Vance, Margaret A. , Klein, Michael L. , Tan, Perciliz L. , Kanda, Atsuhiro , Kopplin, Laura J. , Li, Yanming , Augustaitis, Katherine J., Karoukis, Athanasios J., Scott, William K. , Agarwal, Anita , Kovach, Jaclyn L. , Postel, Eric A. , Brooks, Matthew, Baratz, Keith H. , Brown, William L. , Brucker, Alexander J., Orlin, Anton, Brown, Gary C. , Ho, Allen C. , Regillo, Carl D. , Donoso, Larry A., Tian, Lifeng , Kaderli, Brian, Hadley, Dexter , Hagstrom, Stephanie A. , Peachey, Neal S. , Klein, Ronald , Klein, Barbara E.K. , Gotoh, Norimoto, Yamashiro, Kenji , Ferris, Frederick L. , Fagerness, Jesen, Reynolds, Robyn, Farrer, Lindsay A. , Kim, Ivana K. , Miller, Joan W. , Cortón, Marta , Carracedo, Ãngel , Sánchez‐Salorio, Manuel, Pugh, Elizabeth, Doheny, Kimberly F. , Brión, Marı́a , Weeks, Daniel E. , Zack, Donald J. , Heckenlively, John R., Yoshimura, Nagahisa , Iyengar, Sudha K. , Francis, Peter J. , Katsanis, Nicholas , Seddon, Johanna M. , Haines, Jonathan L. , Abecasis, Gonçalo R. , Swaroop, Anand , Johnson, Robert N., Ai, Everett, McDonald, H. Richard , Stolarczuk, Margaret, Pavan, Peter R., Billiris, Karina K., Iyer, Mohan , Menosky, Matthew M., Pautler, Scott E. , Millard, Sharon M., Hubbard, G. Baker , Aaberg, Thomas , DuBois, Lindy, Lyon, Alice T., Anderson-Nelson, Susan, Jampol, Lee M. , Muñana, Annie, Rozenbajgier, Zuzanna, Orth, David H., Cohen, Jack, MacCumber, Matthew, Figliulo, Celeste, Porcz, Liz, Folk, James C. , Boldt, H. Culver , Russell, Stephen R. , Ivins, Rachel, Hinz, Connie J., Bloom, Steve, Jaegers, Ken, Kritchman, Brian, Whittington, Greg K., Frederick, Albert R., Morley, Michael G., Topping, Trexler M., Davis, Heather L., Bressler, Susan B., Bressler, Neil M. , Doll, W T Jr, Trese, Michael T. , Garretson, Bruce R., Ruby, Alan, Osentoski, Tammy, Ruszczyk, Margaret, Grand, G., Joseph, Daniel P., Shah, Gaurav K. , Nobel, Ginny, Antoszyk, Andrew N., Stallings, Alison H, Singerman, Lawrence J. , Miller, David T. , Novák, Michael, Pendergast, Scott, Zegarra, Hernando, Schura, Stephanie A., Smith-Brewer, Sheila, Davidorf, Frederick H., Chorich, Louis J., Salerno, Jill, Dreyer, Richard F., Ma, Colin, Kopfer, Marcia, Wilson, David J. , Nolte, Susan K., Grunwald, Juan E. , Dunaief, Josh, Fine, Stuart L., Maguire, Albert M. , Stoltz, Robert A., McRay, Monique, Fish, Gary E., Anand, Rajiv, Spencer, Rand , Arnwine, Jean, Chandra, Suresh R., Blodi, Barbara, Gottlieb, Justin L., Ip, Michael S. , Nork, T. Michael , Perry-Raymond, Jennie, Brightwell-Arnold, Mary, Harkins, Sandra, Peskin, Ellen, Ying, Gui‐Shuang , Kurinij, Natalie, Chen, Wei , Campochiaro, Peter A. , Conley, Yvette P. , Schwartz, Stephen G. , DeAngelis, Margaret M. , Chew, Emily Y. , Gorin, Michael B. , Menosky, Matthew M., Weinberg, David V. , Barr, Charles C. , Heier, Jeffrey S. , Capone, A. , Hassan, T. , McCannel, Colin A. , Blinder, Kevin J. , Holekamp, Nancy M. , Browning, David J. , Chambers, Robert , Altaweel, Michael M. , Maguire, Maureen G. , Weeks, Daniel E , Brion, María , Abecasis, Gonçalo
Proceedings of the National Academy of Sciences | April 12, 2010 | Volume: 107 | Issue: 16 | Pages: 7401-7406
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.
Spectrum and Frequency of Cardiac Channel Defects in Swimming-Triggered Arrhythmia Syndromes
Choi, Grace R., Kopplin, Laura J. , Tester, David J. , Will, Melissa L., Haglund, Carla M., Ackerman, Michael J.
Circulation | October 5, 2004 | Volume: 110 | Issue: 15 | Pages: 2119-2124
10.1161/01.cir.0000144471.98080.ca
Background— Swimming is a relatively genotype-specific arrhythmogenic trigger for type 1 long-QT syndrome (LQT1). We hypothesize that mimickers of concealed LQT1, namely catecholaminergic polymorphic ventricular tachycardia (CPVT), may also underlie swimming-triggered cardiac events. Methods and Results— Between August 1997 and May 2003, 388 consecutive, unrelated patients were referred specifically for LQTS genetic testing. The presence of a personal and/or family history of a near-drowning or drowning was determined by review of the medical records and/or phone interviews and was blinded to genetic test results. Comprehensive mutational analysis of the 5 LQTS-causing channel genes, KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6), along with KCNJ2 (Andersen-Tawil syndrome) and targeted analysis of 18 CPVT1-associated exons in RyR2 , was performed with the use of denaturing high-performance liquid chromatography and direct DNA sequencing. Approximately 11% (43 of 388) of the index cases had a positive swimming phenotype. Thirty-three of these 43 index cases had a “Schwartz” score (≥4) suggesting high clinical probability of LQTS. Among this subset, 28 patients (85%) were LQT1, 2 patients (6%) were LQT2, and 3 were genotype negative. Among the 10 cases with low clinical probability for LQTS, 9 had novel, putative CPVT1-causing RyR2 mutations. Conclusions— In contrast to previous studies that suggested universal LQT1 specificity, genetic heterogeneity underlies channelopathies that are suspected chiefly because of a near-drowning or drowning. CPVT1 and strategic genotyping of RyR2 should be considered when LQT1 is excluded in the pathogenesis of a swimming-triggered arrhythmia syndrome.