Cumulative Effect of Risk Alleles in CFH , ARMS2 , and VEGFA on the Response to Ranibizumab Treatment in Age-related Macular Degeneration
Purpose Intravitreal ranibizumab injections currently are the standard treatment for neovascular age-related macular degeneration (AMD). However, a broad range of response rates have been observed, the reasons for which are poorly understood. This pharmacogenetic study evaluated the impact of high-r...
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| Veröffentlicht in: | Ophthalmology (Rochester, Minn.) Minn.), 2012-11, Vol.119 (11), p.2304-2311 |
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| creator | Smailhodzic, Dzenita, MD Muether, Philipp S., MD Chen, John, MD Kwestro, Angela, MD Zhang, Alice Yang, MD Omar, Amer, MD Van de Ven, Johannes P.H., MD Keunen, Jan E.E., MD, PhD Kirchhof, Bernd, MD, PhD Hoyng, Carel B., MD, PhD Klevering, B. Jeroen, MD, PhD Koenekoop, Robert K., MD, PhD Fauser, Sascha, MD, PhD den Hollander, Anneke I., PhD |
| description | Purpose Intravitreal ranibizumab injections currently are the standard treatment for neovascular age-related macular degeneration (AMD). However, a broad range of response rates have been observed, the reasons for which are poorly understood. This pharmacogenetic study evaluated the impact of high-risk alleles in CFH , ARMS2 , VEGFA , vascular endothelial growth factor (VEGF) receptor KDR , and genes involved in angiogenesis ( LRP5 , FZD4 ) on the response to ranibizumab treatment and on the age of treatment onset. In contrast to previous studies, the data were stratified according to the number of high-risk alleles to enable the study of the combined effects of these genotypes on the treatment response. Design Case series study. Participants A cohort of 420 eyes of 397 neovascular AMD patients. Methods The change in visual acuity (VA) between baseline and after 3 ranibizumab injections was calculated. Genotyping of single nucleotide polymorphisms in the CFH , ARMS2 , VEGFA , KDR , LPR5 , and FZD4 genes was performed. Associations were assessed using linear mixed models. Main Outcome Measures The VA change after 3 ranibizumab injections and the age of neovascular disease onset. Results After ranibizumab treatment, AMD patients without risk alleles in the CFH and ARMS2 genes (4.8%) demonstrated a mean VA improvement of 10 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, whereas no VA improvement was observed in AMD patients with 4 CFH and ARMS2 risk alleles (6.9%; P = 0.014). Patients with 4 high-risk alleles in CFH and ARMS2 were 5.2 years younger than patients with 1 or 2 risk alleles, respectively (63.5%; P |
| doi_str_mv | 10.1016/j.ophtha.2012.05.040 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1139620167</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0161642012005015</els_id><sourcerecordid>1139620167</sourcerecordid><originalsourceid>FETCH-LOGICAL-c513t-800fdd4cebb56e28682f8630e4419b69ffef45874cadee20e156e1666e1ce6cc3</originalsourceid><addsrcrecordid>eNqFksFu1DAQhiMEokvhDRDyBYkDCWPHcbIXpGjZbZFaIW0LV8txJl1vE3uxk0rlDXhrHO0CEhcunss383v-f5LkNYWMAhUf9pk77MadyhhQlkGRAYcnyYIWfJnykuZPk0XEaCo4g7PkRQh7ABAi58-TM8YqDpzli-TnahqmXo3mAcm661CPxHVka8I9qfseewzEWLLaXJL3pN5e37BYlW3Jt_XFpibOknGHZIvh4GxAMjqyVdY05sc0qIbcelTjgHacZ9R3mHqMUtiSa6WjqCef8A4t-ijv7MvkWaf6gK9O9Tz5ulnfri7Tqy8Xn1f1VaoLmo9pBdC1LdfYNIVAVomKdZXIATmny0Ys4w4dL6qSa9UiMkAaMSpEfDQKrfPz5N1x7sG77xOGUQ4maOx7ZdFNQVKaL0X0VJQR5UdUexeCx04evBmUf5QU5ByC3MtjCHIOQUIhYwix7c1JYWoGbP80_XY9Am9PgApa9Z1XVpvwlxNlWbJi1v945DD68WDQy6ANWo2t8TEp2Trzv5_8O0D3xpqoeY-PGPZu8jZ6LakMsUfezAcz3wtlAAXQIv8FOkW6iA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1139620167</pqid></control><display><type>article</type><title>Cumulative Effect of Risk Alleles in CFH , ARMS2 , and VEGFA on the Response to Ranibizumab Treatment in Age-related Macular Degeneration</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Smailhodzic, Dzenita, MD ; Muether, Philipp S., MD ; Chen, John, MD ; Kwestro, Angela, MD ; Zhang, Alice Yang, MD ; Omar, Amer, MD ; Van de Ven, Johannes P.H., MD ; Keunen, Jan E.E., MD, PhD ; Kirchhof, Bernd, MD, PhD ; Hoyng, Carel B., MD, PhD ; Klevering, B. Jeroen, MD, PhD ; Koenekoop, Robert K., MD, PhD ; Fauser, Sascha, MD, PhD ; den Hollander, Anneke I., PhD</creator><creatorcontrib>Smailhodzic, Dzenita, MD ; Muether, Philipp S., MD ; Chen, John, MD ; Kwestro, Angela, MD ; Zhang, Alice Yang, MD ; Omar, Amer, MD ; Van de Ven, Johannes P.H., MD ; Keunen, Jan E.E., MD, PhD ; Kirchhof, Bernd, MD, PhD ; Hoyng, Carel B., MD, PhD ; Klevering, B. Jeroen, MD, PhD ; Koenekoop, Robert K., MD, PhD ; Fauser, Sascha, MD, PhD ; den Hollander, Anneke I., PhD</creatorcontrib><description>Purpose Intravitreal ranibizumab injections currently are the standard treatment for neovascular age-related macular degeneration (AMD). However, a broad range of response rates have been observed, the reasons for which are poorly understood. This pharmacogenetic study evaluated the impact of high-risk alleles in CFH , ARMS2 , VEGFA , vascular endothelial growth factor (VEGF) receptor KDR , and genes involved in angiogenesis ( LRP5 , FZD4 ) on the response to ranibizumab treatment and on the age of treatment onset. In contrast to previous studies, the data were stratified according to the number of high-risk alleles to enable the study of the combined effects of these genotypes on the treatment response. Design Case series study. Participants A cohort of 420 eyes of 397 neovascular AMD patients. Methods The change in visual acuity (VA) between baseline and after 3 ranibizumab injections was calculated. Genotyping of single nucleotide polymorphisms in the CFH , ARMS2 , VEGFA , KDR , LPR5 , and FZD4 genes was performed. Associations were assessed using linear mixed models. Main Outcome Measures The VA change after 3 ranibizumab injections and the age of neovascular disease onset. Results After ranibizumab treatment, AMD patients without risk alleles in the CFH and ARMS2 genes (4.8%) demonstrated a mean VA improvement of 10 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, whereas no VA improvement was observed in AMD patients with 4 CFH and ARMS2 risk alleles (6.9%; P = 0.014). Patients with 4 high-risk alleles in CFH and ARMS2 were 5.2 years younger than patients with 1 or 2 risk alleles, respectively (63.5%; P <0.0001). The mean age at which the first ranibizumab treatment was carried out among AMD patients with all 6 risk alleles in CFH , ARMS2 , and VEGFA was 65.9 years (2%) versus 75.3 years in patients with 0 or 1 high-risk allele (8.8%; P = 0.001). After ranibizumab treatment, patients with 6 high-risk alleles demonstrated a mean VA loss of 10 ETDRS letters ( P <0.0001). Conclusions This study evaluated the largest pharmacogenetic AMD cohort reported to date. A cumulative effect of high-risk alleles in CFH , ARMS2 , and VEGFA seems to be associated with a younger age of onset in combination with poor response rates to ranibizumab treatment. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.</description><identifier>ISSN: 0161-6420</identifier><identifier>EISSN: 1549-4713</identifier><identifier>DOI: 10.1016/j.ophtha.2012.05.040</identifier><identifier>PMID: 22840423</identifier><identifier>CODEN: OPHTDG</identifier><language>eng</language><publisher>New York, NY: Elsevier Inc</publisher><subject>Age of Onset ; Aged ; Aged, 80 and over ; Alleles ; Angiogenesis Inhibitors - therapeutic use ; Antibodies, Monoclonal, Humanized - therapeutic use ; Biological and medical sciences ; Cohort Studies ; Complement Factor H - genetics ; Female ; Fluorescein Angiography ; Frizzled Receptors - genetics ; Genotype ; Humans ; Intravitreal Injections ; Low Density Lipoprotein Receptor-Related Protein-5 - genetics ; Male ; Medical sciences ; Middle Aged ; Miscellaneous ; Ophthalmology ; Pharmacogenetics ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide ; Proteins - genetics ; Ranibizumab ; Retinopathies ; Risk Factors ; Tomography, Optical Coherence ; Vascular Endothelial Growth Factor A - genetics ; Vascular Endothelial Growth Factor Receptor-2 - genetics ; Visual Acuity - physiology ; Wet Macular Degeneration - drug therapy ; Wet Macular Degeneration - genetics ; Wet Macular Degeneration - physiopathology</subject><ispartof>Ophthalmology (Rochester, Minn.), 2012-11, Vol.119 (11), p.2304-2311</ispartof><rights>American Academy of Ophthalmology</rights><rights>2012 American Academy of Ophthalmology</rights><rights>2014 INIST-CNRS</rights><rights>Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c513t-800fdd4cebb56e28682f8630e4419b69ffef45874cadee20e156e1666e1ce6cc3</citedby><cites>FETCH-LOGICAL-c513t-800fdd4cebb56e28682f8630e4419b69ffef45874cadee20e156e1666e1ce6cc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0161642012005015$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27903,27904,65309</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26777257$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22840423$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Smailhodzic, Dzenita, MD</creatorcontrib><creatorcontrib>Muether, Philipp S., MD</creatorcontrib><creatorcontrib>Chen, John, MD</creatorcontrib><creatorcontrib>Kwestro, Angela, MD</creatorcontrib><creatorcontrib>Zhang, Alice Yang, MD</creatorcontrib><creatorcontrib>Omar, Amer, MD</creatorcontrib><creatorcontrib>Van de Ven, Johannes P.H., MD</creatorcontrib><creatorcontrib>Keunen, Jan E.E., MD, PhD</creatorcontrib><creatorcontrib>Kirchhof, Bernd, MD, PhD</creatorcontrib><creatorcontrib>Hoyng, Carel B., MD, PhD</creatorcontrib><creatorcontrib>Klevering, B. Jeroen, MD, PhD</creatorcontrib><creatorcontrib>Koenekoop, Robert K., MD, PhD</creatorcontrib><creatorcontrib>Fauser, Sascha, MD, PhD</creatorcontrib><creatorcontrib>den Hollander, Anneke I., PhD</creatorcontrib><title>Cumulative Effect of Risk Alleles in CFH , ARMS2 , and VEGFA on the Response to Ranibizumab Treatment in Age-related Macular Degeneration</title><title>Ophthalmology (Rochester, Minn.)</title><addtitle>Ophthalmology</addtitle><description>Purpose Intravitreal ranibizumab injections currently are the standard treatment for neovascular age-related macular degeneration (AMD). However, a broad range of response rates have been observed, the reasons for which are poorly understood. This pharmacogenetic study evaluated the impact of high-risk alleles in CFH , ARMS2 , VEGFA , vascular endothelial growth factor (VEGF) receptor KDR , and genes involved in angiogenesis ( LRP5 , FZD4 ) on the response to ranibizumab treatment and on the age of treatment onset. In contrast to previous studies, the data were stratified according to the number of high-risk alleles to enable the study of the combined effects of these genotypes on the treatment response. Design Case series study. Participants A cohort of 420 eyes of 397 neovascular AMD patients. Methods The change in visual acuity (VA) between baseline and after 3 ranibizumab injections was calculated. Genotyping of single nucleotide polymorphisms in the CFH , ARMS2 , VEGFA , KDR , LPR5 , and FZD4 genes was performed. Associations were assessed using linear mixed models. Main Outcome Measures The VA change after 3 ranibizumab injections and the age of neovascular disease onset. Results After ranibizumab treatment, AMD patients without risk alleles in the CFH and ARMS2 genes (4.8%) demonstrated a mean VA improvement of 10 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, whereas no VA improvement was observed in AMD patients with 4 CFH and ARMS2 risk alleles (6.9%; P = 0.014). Patients with 4 high-risk alleles in CFH and ARMS2 were 5.2 years younger than patients with 1 or 2 risk alleles, respectively (63.5%; P <0.0001). The mean age at which the first ranibizumab treatment was carried out among AMD patients with all 6 risk alleles in CFH , ARMS2 , and VEGFA was 65.9 years (2%) versus 75.3 years in patients with 0 or 1 high-risk allele (8.8%; P = 0.001). After ranibizumab treatment, patients with 6 high-risk alleles demonstrated a mean VA loss of 10 ETDRS letters ( P <0.0001). Conclusions This study evaluated the largest pharmacogenetic AMD cohort reported to date. A cumulative effect of high-risk alleles in CFH , ARMS2 , and VEGFA seems to be associated with a younger age of onset in combination with poor response rates to ranibizumab treatment. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.</description><subject>Age of Onset</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Alleles</subject><subject>Angiogenesis Inhibitors - therapeutic use</subject><subject>Antibodies, Monoclonal, Humanized - therapeutic use</subject><subject>Biological and medical sciences</subject><subject>Cohort Studies</subject><subject>Complement Factor H - genetics</subject><subject>Female</subject><subject>Fluorescein Angiography</subject><subject>Frizzled Receptors - genetics</subject><subject>Genotype</subject><subject>Humans</subject><subject>Intravitreal Injections</subject><subject>Low Density Lipoprotein Receptor-Related Protein-5 - genetics</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Miscellaneous</subject><subject>Ophthalmology</subject><subject>Pharmacogenetics</subject><subject>Polymerase Chain Reaction</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Proteins - genetics</subject><subject>Ranibizumab</subject><subject>Retinopathies</subject><subject>Risk Factors</subject><subject>Tomography, Optical Coherence</subject><subject>Vascular Endothelial Growth Factor A - genetics</subject><subject>Vascular Endothelial Growth Factor Receptor-2 - genetics</subject><subject>Visual Acuity - physiology</subject><subject>Wet Macular Degeneration - drug therapy</subject><subject>Wet Macular Degeneration - genetics</subject><subject>Wet Macular Degeneration - physiopathology</subject><issn>0161-6420</issn><issn>1549-4713</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFksFu1DAQhiMEokvhDRDyBYkDCWPHcbIXpGjZbZFaIW0LV8txJl1vE3uxk0rlDXhrHO0CEhcunss383v-f5LkNYWMAhUf9pk77MadyhhQlkGRAYcnyYIWfJnykuZPk0XEaCo4g7PkRQh7ABAi58-TM8YqDpzli-TnahqmXo3mAcm661CPxHVka8I9qfseewzEWLLaXJL3pN5e37BYlW3Jt_XFpibOknGHZIvh4GxAMjqyVdY05sc0qIbcelTjgHacZ9R3mHqMUtiSa6WjqCef8A4t-ijv7MvkWaf6gK9O9Tz5ulnfri7Tqy8Xn1f1VaoLmo9pBdC1LdfYNIVAVomKdZXIATmny0Ys4w4dL6qSa9UiMkAaMSpEfDQKrfPz5N1x7sG77xOGUQ4maOx7ZdFNQVKaL0X0VJQR5UdUexeCx04evBmUf5QU5ByC3MtjCHIOQUIhYwix7c1JYWoGbP80_XY9Am9PgApa9Z1XVpvwlxNlWbJi1v945DD68WDQy6ANWo2t8TEp2Trzv5_8O0D3xpqoeY-PGPZu8jZ6LakMsUfezAcz3wtlAAXQIv8FOkW6iA</recordid><startdate>20121101</startdate><enddate>20121101</enddate><creator>Smailhodzic, Dzenita, MD</creator><creator>Muether, Philipp S., MD</creator><creator>Chen, John, MD</creator><creator>Kwestro, Angela, MD</creator><creator>Zhang, Alice Yang, MD</creator><creator>Omar, Amer, MD</creator><creator>Van de Ven, Johannes P.H., MD</creator><creator>Keunen, Jan E.E., MD, PhD</creator><creator>Kirchhof, Bernd, MD, PhD</creator><creator>Hoyng, Carel B., MD, PhD</creator><creator>Klevering, B. Jeroen, MD, PhD</creator><creator>Koenekoop, Robert K., MD, PhD</creator><creator>Fauser, Sascha, MD, PhD</creator><creator>den Hollander, Anneke I., PhD</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20121101</creationdate><title>Cumulative Effect of Risk Alleles in CFH , ARMS2 , and VEGFA on the Response to Ranibizumab Treatment in Age-related Macular Degeneration</title><author>Smailhodzic, Dzenita, MD ; Muether, Philipp S., MD ; Chen, John, MD ; Kwestro, Angela, MD ; Zhang, Alice Yang, MD ; Omar, Amer, MD ; Van de Ven, Johannes P.H., MD ; Keunen, Jan E.E., MD, PhD ; Kirchhof, Bernd, MD, PhD ; Hoyng, Carel B., MD, PhD ; Klevering, B. Jeroen, MD, PhD ; Koenekoop, Robert K., MD, PhD ; Fauser, Sascha, MD, PhD ; den Hollander, Anneke I., PhD</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c513t-800fdd4cebb56e28682f8630e4419b69ffef45874cadee20e156e1666e1ce6cc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Age of Onset</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Alleles</topic><topic>Angiogenesis Inhibitors - therapeutic use</topic><topic>Antibodies, Monoclonal, Humanized - therapeutic use</topic><topic>Biological and medical sciences</topic><topic>Cohort Studies</topic><topic>Complement Factor H - genetics</topic><topic>Female</topic><topic>Fluorescein Angiography</topic><topic>Frizzled Receptors - genetics</topic><topic>Genotype</topic><topic>Humans</topic><topic>Intravitreal Injections</topic><topic>Low Density Lipoprotein Receptor-Related Protein-5 - genetics</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Miscellaneous</topic><topic>Ophthalmology</topic><topic>Pharmacogenetics</topic><topic>Polymerase Chain Reaction</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Proteins - genetics</topic><topic>Ranibizumab</topic><topic>Retinopathies</topic><topic>Risk Factors</topic><topic>Tomography, Optical Coherence</topic><topic>Vascular Endothelial Growth Factor A - genetics</topic><topic>Vascular Endothelial Growth Factor Receptor-2 - genetics</topic><topic>Visual Acuity - physiology</topic><topic>Wet Macular Degeneration - drug therapy</topic><topic>Wet Macular Degeneration - genetics</topic><topic>Wet Macular Degeneration - physiopathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Smailhodzic, Dzenita, MD</creatorcontrib><creatorcontrib>Muether, Philipp S., MD</creatorcontrib><creatorcontrib>Chen, John, MD</creatorcontrib><creatorcontrib>Kwestro, Angela, MD</creatorcontrib><creatorcontrib>Zhang, Alice Yang, MD</creatorcontrib><creatorcontrib>Omar, Amer, MD</creatorcontrib><creatorcontrib>Van de Ven, Johannes P.H., MD</creatorcontrib><creatorcontrib>Keunen, Jan E.E., MD, PhD</creatorcontrib><creatorcontrib>Kirchhof, Bernd, MD, PhD</creatorcontrib><creatorcontrib>Hoyng, Carel B., MD, PhD</creatorcontrib><creatorcontrib>Klevering, B. Jeroen, MD, PhD</creatorcontrib><creatorcontrib>Koenekoop, Robert K., MD, PhD</creatorcontrib><creatorcontrib>Fauser, Sascha, MD, PhD</creatorcontrib><creatorcontrib>den Hollander, Anneke I., PhD</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Ophthalmology (Rochester, Minn.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Smailhodzic, Dzenita, MD</au><au>Muether, Philipp S., MD</au><au>Chen, John, MD</au><au>Kwestro, Angela, MD</au><au>Zhang, Alice Yang, MD</au><au>Omar, Amer, MD</au><au>Van de Ven, Johannes P.H., MD</au><au>Keunen, Jan E.E., MD, PhD</au><au>Kirchhof, Bernd, MD, PhD</au><au>Hoyng, Carel B., MD, PhD</au><au>Klevering, B. Jeroen, MD, PhD</au><au>Koenekoop, Robert K., MD, PhD</au><au>Fauser, Sascha, MD, PhD</au><au>den Hollander, Anneke I., PhD</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cumulative Effect of Risk Alleles in CFH , ARMS2 , and VEGFA on the Response to Ranibizumab Treatment in Age-related Macular Degeneration</atitle><jtitle>Ophthalmology (Rochester, Minn.)</jtitle><addtitle>Ophthalmology</addtitle><date>2012-11-01</date><risdate>2012</risdate><volume>119</volume><issue>11</issue><spage>2304</spage><epage>2311</epage><pages>2304-2311</pages><issn>0161-6420</issn><eissn>1549-4713</eissn><coden>OPHTDG</coden><abstract>Purpose Intravitreal ranibizumab injections currently are the standard treatment for neovascular age-related macular degeneration (AMD). However, a broad range of response rates have been observed, the reasons for which are poorly understood. This pharmacogenetic study evaluated the impact of high-risk alleles in CFH , ARMS2 , VEGFA , vascular endothelial growth factor (VEGF) receptor KDR , and genes involved in angiogenesis ( LRP5 , FZD4 ) on the response to ranibizumab treatment and on the age of treatment onset. In contrast to previous studies, the data were stratified according to the number of high-risk alleles to enable the study of the combined effects of these genotypes on the treatment response. Design Case series study. Participants A cohort of 420 eyes of 397 neovascular AMD patients. Methods The change in visual acuity (VA) between baseline and after 3 ranibizumab injections was calculated. Genotyping of single nucleotide polymorphisms in the CFH , ARMS2 , VEGFA , KDR , LPR5 , and FZD4 genes was performed. Associations were assessed using linear mixed models. Main Outcome Measures The VA change after 3 ranibizumab injections and the age of neovascular disease onset. Results After ranibizumab treatment, AMD patients without risk alleles in the CFH and ARMS2 genes (4.8%) demonstrated a mean VA improvement of 10 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, whereas no VA improvement was observed in AMD patients with 4 CFH and ARMS2 risk alleles (6.9%; P = 0.014). Patients with 4 high-risk alleles in CFH and ARMS2 were 5.2 years younger than patients with 1 or 2 risk alleles, respectively (63.5%; P <0.0001). The mean age at which the first ranibizumab treatment was carried out among AMD patients with all 6 risk alleles in CFH , ARMS2 , and VEGFA was 65.9 years (2%) versus 75.3 years in patients with 0 or 1 high-risk allele (8.8%; P = 0.001). After ranibizumab treatment, patients with 6 high-risk alleles demonstrated a mean VA loss of 10 ETDRS letters ( P <0.0001). Conclusions This study evaluated the largest pharmacogenetic AMD cohort reported to date. A cumulative effect of high-risk alleles in CFH , ARMS2 , and VEGFA seems to be associated with a younger age of onset in combination with poor response rates to ranibizumab treatment. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.</abstract><cop>New York, NY</cop><pub>Elsevier Inc</pub><pmid>22840423</pmid><doi>10.1016/j.ophtha.2012.05.040</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0161-6420 |
| ispartof | Ophthalmology (Rochester, Minn.), 2012-11, Vol.119 (11), p.2304-2311 |
| issn | 0161-6420 1549-4713 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1139620167 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Age of Onset Aged Aged, 80 and over Alleles Angiogenesis Inhibitors - therapeutic use Antibodies, Monoclonal, Humanized - therapeutic use Biological and medical sciences Cohort Studies Complement Factor H - genetics Female Fluorescein Angiography Frizzled Receptors - genetics Genotype Humans Intravitreal Injections Low Density Lipoprotein Receptor-Related Protein-5 - genetics Male Medical sciences Middle Aged Miscellaneous Ophthalmology Pharmacogenetics Polymerase Chain Reaction Polymorphism, Single Nucleotide Proteins - genetics Ranibizumab Retinopathies Risk Factors Tomography, Optical Coherence Vascular Endothelial Growth Factor A - genetics Vascular Endothelial Growth Factor Receptor-2 - genetics Visual Acuity - physiology Wet Macular Degeneration - drug therapy Wet Macular Degeneration - genetics Wet Macular Degeneration - physiopathology |
| title | Cumulative Effect of Risk Alleles in CFH , ARMS2 , and VEGFA on the Response to Ranibizumab Treatment in Age-related Macular Degeneration |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T15%3A55%3A01IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Cumulative%20Effect%20of%20Risk%20Alleles%20in%20CFH%20,%20ARMS2%20,%20and%20VEGFA%20on%20the%20Response%20to%20Ranibizumab%20Treatment%20in%20Age-related%20Macular%20Degeneration&rft.jtitle=Ophthalmology%20(Rochester,%20Minn.)&rft.au=Smailhodzic,%20Dzenita,%20MD&rft.date=2012-11-01&rft.volume=119&rft.issue=11&rft.spage=2304&rft.epage=2311&rft.pages=2304-2311&rft.issn=0161-6420&rft.eissn=1549-4713&rft.coden=OPHTDG&rft_id=info:doi/10.1016/j.ophtha.2012.05.040&rft_dat=%3Cproquest_cross%3E1139620167%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1139620167&rft_id=info:pmid/22840423&rft_els_id=S0161642012005015&rfr_iscdi=true |