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

被引：415

作者：

Chen, Wei ^{[1
]}

Stambolian, Dwight

Edwards, Albert O. ^{[2
]}

Branham, Kari E. ^{[3
]}

Othman, Mohammad ^{[3
]}

Jakobsdottir, Johanna ^{[4
]}

Tosakulwong, Nirubol ^{[2
]}

Pericak-Vance, Margaret A. ^{[5
]}

Campochiaro, Peter A. ^{[6
]}

Klein, Michael L. ^{[7
]}

Tan, Perciliz L. ^{[6
]}

Conley, Yvette P. ^{[4
]}

Kanda, Atsuhiro ^{[8
]}

Kopplin, Laura ^{[9
]}

Li, Yanming ^{[1
]}

Augustaitis, Katherine J. ^{[3
]}

Karoukis, Athanasios J. ^{[3
]}

Scott, William K. ^{[5
]}

Agarwal, Anita ^{[10
]}

Kovach, Jaclyn L. ^{[5
]}

Schwartz, Stephen G. ^{[5
]}

Postel, Eric A. ^{[11
]}

Brooks, Matthew ^{[8
]}

Baratz, Keith H. ^{[2
]}

Brown, William L. ^{[2
]}

Brucker, Alexander J.

Orlin, Anton

Brown, Gary ^{[13
,14
]}

Ho, Allen ^{[13
,14
]}

Regillo, Carl ^{[13
,14
]}

Donoso, Larry ^{[15
]}

Tian, Lifeng

Kaderli, Brian

Hadley, Dexter

Hagstrom, Stephanie A. ^{[9
,16
]}

Peachey, Neal S. ^{[9
,16
,17
]}

Klein, Ronald ^{[18
]}

Klein, Barbara E. K. ^{[18
]}

Gotoh, Norimoto ^{[19
]}

Yamashiro, Kenji ^{[19
]}

Ferris, Frederick, III

Fagerness, Jesen A. ^{[20
,21
]}

Reynolds, Robyn ^{[22
]}

Farrer, Lindsay A. ^{[23
]}

Kim, Ivana K. ^{[24
]}

Miller, Joan W. ^{[24
]}

Corton, Marta ^{[25
,26
]}

Carracedo, Angel ^{[26
]}

Sanchez-Salorio, Manuel ^{[27
]}

Pugh, Elizabeth W. ^{[28
]}

机构：

[1] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[2] Mayo Clin, Rochester, MN 55906 USA

[3] Univ Michigan, Ann Arbor, MI 48105 USA

[4] Univ Pittsburgh, Pittsburgh, PA 15260 USA

[5] Univ Miami, Miller Sch Med, Miami, FL USA

[6] Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA

[7] Oregon Hlth & Sci Univ, Portland, OR 97239 USA

[8] NEI, Neurobiol Neurodegenerat & Repair Lab, Bethesda, MD 20892 USA

[9] Case Western Reserve Univ, Cleveland, OH 44106 USA

[10] Vanderbilt Univ, Med Ctr, Nashville, TN 37232 USA

[11] Duke Univ, Med Ctr, Durham, NC 27705 USA

[12] Univ Penn, CAPT Coordinating Ctr, Philadelphia, PA 19104 USA

[13] Mid Atlantic Retina, Cherry Hill, NJ 08002 USA

[14] Thomas Jefferson Univ, Philadelphia, PA 19107 USA

[15] Philadelphia Retina Endowment Fund, Philadelphia, PA 19107 USA

[16] Cleveland Clin Fdn, Cleveland, OH 44195 USA

[17] Vet Affairs Med Ctr, Louis Stokes Cleveland Dept, Cleveland, OH 44106 USA

[18] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI 53705 USA

[19] Kyoto Univ, Grad Sch Med, Kyoto 6068501, Japan

[20] Massachusetts Gen Hosp, Cambridge, MA 02114 USA

[21] Broad Inst, Cambridge, MA 02114 USA

[22] Tufts Med Ctr, Boston, MA 02111 USA

[23] Boston Univ, Boston, MA 02215 USA

[24] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA

[25] Complexo Hosp Univ Santiago, Santiago De Compostela 15706, Spain

[26] Univ Santiago de Compostela, Santiago De Compostela 15705, Spain

[27] Inst Gallego Oftalmol, Santiago De Compostela 15706, Spain

[28] Johns Hopkins Sch Med, Ctr Inherited Dis Res, Baltimore, MD 21287 USA

[29] Tufts Univ, Sch Med, Boston, MA 02111 USA

[30] Univ Calif Los Angeles, Los Angeles, CA 90095 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2010年 / 107卷 / 16期

基金：

美国国家卫生研究院;

关键词：

genome-wide association study; single nucleotide polymorphism; COMPLEMENT FACTOR-H; GENOME-WIDE ASSOCIATION; RISK-FACTORS; DISEASE; POLYMORPHISM; MACULOPATHY; COMMON; METAANALYSIS; DEPOSITS; DRUSEN;

D O I：

10.1073/pnas.0912702107

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：7401 / 7406

页数：6

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