A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration

Zhenglin Yang; Nicola J. Camp; Hui Sun; Zongzhong Tong; Daniel Gibbs; D. Joshua Cameron; Haoyu Chen; Yu Zhao; Erik Pearson; Xi Li; Jeremy Chien; Andrew DeWan; Jennifer Harmon; Paul S. Bernstein; Viji Shridhar; Norman A. Zabriskie; Josephine Hoh; Kimberly Howes; Kang Zhang

doi:10.1126/science.1133811

A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration

Zhenglin Yang, Nicola J. Camp, Hui Sun, Zongzhong Tong, Daniel Gibbs, D. Joshua Cameron, Haoyu Chen, Yu Zhao, Erik Pearson, Xi Li, Jeremy Chien, Andrew DeWan, Jennifer Harmon, Paul S. Bernstein, Viji Shridhar, Norman A. Zabriskie, Josephine Hoh, Kimberly Howes, Kang Zhang

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

615 Scopus citations

Abstract

Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the developed world and has a strong genetic predisposition. A locus at human chromosome 10q26 affects the risk of AMD, but the precise gene(s) have not been identified. We genotyped 581 AMD cases and 309 normal controls in a Caucasian cohort in Utah. We demonstrate that a single-nucleotide polymorphism, rs11200638, in the promoter region of HTRA1 is the most likely causal variant for AMD at 10q26 and is estimated to confer a population attributable risk of 49.3%. The HTRA1 gene encodes a secreted serine protease. Preliminary analysis of lymphocytes and retinal pigment epithelium from four AMD patients revealed that the risk allele was associated with elevated expression levels of HTRA1 mRNA and protein. We also found that drusen in the eyes of AMD patients were strongly immunolabeled with HTRA1 antibody. Together, these findings support a key role for HTRA1 in AMD susceptibility and identify a potential new pathway for AMD pathogenesis.

Original language	English (US)
Pages (from-to)	992-993
Number of pages	2
Journal	Science
Volume	314
Issue number	5801
DOIs	https://doi.org/10.1126/science.1133811
State	Published - Nov 10 2006

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Yang, Z., Camp, N. J., Sun, H., Tong, Z., Gibbs, D., Cameron, D. J., Chen, H., Zhao, Y., Pearson, E., Li, X., Chien, J., DeWan, A., Harmon, J., Bernstein, P. S., Shridhar, V., Zabriskie, N. A., Hoh, J., Howes, K., & Zhang, K. (2006). A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science, 314(5801), 992-993. https://doi.org/10.1126/science.1133811

Yang, Z, Camp, NJ, Sun, H, Tong, Z, Gibbs, D, Cameron, DJ, Chen, H, Zhao, Y, Pearson, E, Li, X, Chien, J, DeWan, A, Harmon, J, Bernstein, PS, Shridhar, V, Zabriskie, NA, Hoh, J, Howes, K & Zhang, K 2006, 'A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration', Science, vol. 314, no. 5801, pp. 992-993. https://doi.org/10.1126/science.1133811

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title = "A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration",

abstract = "Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the developed world and has a strong genetic predisposition. A locus at human chromosome 10q26 affects the risk of AMD, but the precise gene(s) have not been identified. We genotyped 581 AMD cases and 309 normal controls in a Caucasian cohort in Utah. We demonstrate that a single-nucleotide polymorphism, rs11200638, in the promoter region of HTRA1 is the most likely causal variant for AMD at 10q26 and is estimated to confer a population attributable risk of 49.3%. The HTRA1 gene encodes a secreted serine protease. Preliminary analysis of lymphocytes and retinal pigment epithelium from four AMD patients revealed that the risk allele was associated with elevated expression levels of HTRA1 mRNA and protein. We also found that drusen in the eyes of AMD patients were strongly immunolabeled with HTRA1 antibody. Together, these findings support a key role for HTRA1 in AMD susceptibility and identify a potential new pathway for AMD pathogenesis.",

author = "Zhenglin Yang and Camp, {Nicola J.} and Hui Sun and Zongzhong Tong and Daniel Gibbs and Cameron, {D. Joshua} and Haoyu Chen and Yu Zhao and Erik Pearson and Xi Li and Jeremy Chien and Andrew DeWan and Jennifer Harmon and Bernstein, {Paul S.} and Viji Shridhar and Zabriskie, {Norman A.} and Josephine Hoh and Kimberly Howes and Kang Zhang",

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doi = "10.1126/science.1133811",

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T1 - A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration

AU - Yang, Zhenglin

AU - Camp, Nicola J.

AU - Sun, Hui

AU - Tong, Zongzhong

AU - Gibbs, Daniel

AU - Cameron, D. Joshua

AU - Chen, Haoyu

AU - Zhao, Yu

AU - Pearson, Erik

AU - Li, Xi

AU - Chien, Jeremy

AU - DeWan, Andrew

AU - Harmon, Jennifer

AU - Bernstein, Paul S.

AU - Shridhar, Viji

AU - Zabriskie, Norman A.

AU - Hoh, Josephine

AU - Howes, Kimberly

AU - Zhang, Kang

PY - 2006/11/10

Y1 - 2006/11/10

N2 - Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the developed world and has a strong genetic predisposition. A locus at human chromosome 10q26 affects the risk of AMD, but the precise gene(s) have not been identified. We genotyped 581 AMD cases and 309 normal controls in a Caucasian cohort in Utah. We demonstrate that a single-nucleotide polymorphism, rs11200638, in the promoter region of HTRA1 is the most likely causal variant for AMD at 10q26 and is estimated to confer a population attributable risk of 49.3%. The HTRA1 gene encodes a secreted serine protease. Preliminary analysis of lymphocytes and retinal pigment epithelium from four AMD patients revealed that the risk allele was associated with elevated expression levels of HTRA1 mRNA and protein. We also found that drusen in the eyes of AMD patients were strongly immunolabeled with HTRA1 antibody. Together, these findings support a key role for HTRA1 in AMD susceptibility and identify a potential new pathway for AMD pathogenesis.

AB - Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the developed world and has a strong genetic predisposition. A locus at human chromosome 10q26 affects the risk of AMD, but the precise gene(s) have not been identified. We genotyped 581 AMD cases and 309 normal controls in a Caucasian cohort in Utah. We demonstrate that a single-nucleotide polymorphism, rs11200638, in the promoter region of HTRA1 is the most likely causal variant for AMD at 10q26 and is estimated to confer a population attributable risk of 49.3%. The HTRA1 gene encodes a secreted serine protease. Preliminary analysis of lymphocytes and retinal pigment epithelium from four AMD patients revealed that the risk allele was associated with elevated expression levels of HTRA1 mRNA and protein. We also found that drusen in the eyes of AMD patients were strongly immunolabeled with HTRA1 antibody. Together, these findings support a key role for HTRA1 in AMD susceptibility and identify a potential new pathway for AMD pathogenesis.

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A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration

Abstract

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