Evidence of association of APOE with age-related macular degeneration - a pooled analysis of 15 studies

Gareth J. Mckay; Chris C. Patterson; Usha Chakravarthy; Shilpa Dasari; Caroline C. Klaver; Johannes R. Vingerling; Lintje Ho; Paulus T.V.M. de Jong; Astrid E. Fletcher; Ian S. Young; Johan H. Seland; Mati Rahu; Gisele Soubrane; Laura Tomazzoli; Fotis Topouzis; Jesus Vioque; Aroon D. Hingorani; Reecha Sofat; Michael Dean; Julie Sawitzke; Johanna M. Seddon; Inga Peter; Andrew R. Webster; Anthony T. Moore; John R.W. Yates; Valentina Cipriani; Lars G. Fritsche; Bernhard H.F. Weber; Claudia N. Keilhauer; Andrew J. Lotery; Sarah Ennis; Michael L. Klein; Peter J. Francis; Dwight Stambolian; Anton Orlin; Michael B. Gorin; Daniel E. Weeks; Chia Ling Kuo; Anand Swaroop; Mohammad Othman; Atsuhiro Kanda; Wei Chen; Goncalo R. Abecasis; Alan F. Wright; Caroline Hayward; Paul N. Baird; Robyn H. Guymer; John Attia; Ammarin Thakkinstian; Giuliana Silvestri

doi:10.1002/humu.21577

Evidence of association of APOE with age-related macular degeneration - a pooled analysis of 15 studies

Gareth J. Mckay, Chris C. Patterson, Usha Chakravarthy, Shilpa Dasari, Caroline C. Klaver, Johannes R. Vingerling, Lintje Ho, Paulus T.V.M. de Jong, Astrid E. Fletcher, Ian S. Young, Johan H. Seland, Mati Rahu, Gisele Soubrane, Laura Tomazzoli, Fotis Topouzis, Jesus Vioque, Aroon D. Hingorani, Reecha Sofat, Michael Dean, Julie SawitzkeJohanna M. Seddon, Inga Peter, Andrew R. Webster, Anthony T. Moore, John R.W. Yates, Valentina Cipriani, Lars G. Fritsche, Bernhard H.F. Weber, Claudia N. Keilhauer, Andrew J. Lotery, Sarah Ennis, Michael L. Klein, Peter J. Francis, Dwight Stambolian, Anton Orlin, Michael B. Gorin, Daniel E. Weeks, Chia Ling Kuo, Anand Swaroop, Mohammad Othman, Atsuhiro Kanda, Wei Chen, Goncalo R. Abecasis, Alan F. Wright, Caroline Hayward, Paul N. Baird, Robyn H. Guymer, John Attia, Ammarin Thakkinstian, Giuliana Silvestri

Ophthalmology

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

124 Scopus citations

Abstract

Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status has been reported. We present a pooled analysis (n = 21,160) demonstrating associations between late AMD and APOε4 (odds ratio [OR] = 0.72 per haplotype; confidence interval [CI]: 0.65-0.74; P = 4.41×10 ^-11) and APOε2 (OR = 1.83 for homozygote carriers; CI: 1.04-3.23; P = 0.04), following adjustment for age group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR = 1.54; CI: 1.38-1.72; P = 2.8×10 ^-15) and atrophic (OR = 1.38; CI: 1.18-1.61; P = 3.37×10 ^-5) AMD but not early AMD (OR = 0.94; CI: 0.86-1.03; P = 0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyond ε2 and ε4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology.

Original language	English (US)
Pages (from-to)	1407-1416
Number of pages	10
Journal	Human mutation
Volume	32
Issue number	12
DOIs	https://doi.org/10.1002/humu.21577
State	Published - Dec 2011

Keywords

AMD
APOE
Age-related macular degeneration
Apolipoprotein E
Case-control association study

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1002/humu.21577

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Mckay, G. J., Patterson, C. C., Chakravarthy, U., Dasari, S., Klaver, C. C., Vingerling, J. R., Ho, L., de Jong, P. T. V. M., Fletcher, A. E., Young, I. S., Seland, J. H., Rahu, M., Soubrane, G., Tomazzoli, L., Topouzis, F., Vioque, J., Hingorani, A. D., Sofat, R., Dean, M., ... Silvestri, G. (2011). Evidence of association of APOE with age-related macular degeneration - a pooled analysis of 15 studies. Human mutation, 32(12), 1407-1416. https://doi.org/10.1002/humu.21577

Mckay, GJ, Patterson, CC, Chakravarthy, U, Dasari, S, Klaver, CC, Vingerling, JR, Ho, L, de Jong, PTVM, Fletcher, AE, Young, IS, Seland, JH, Rahu, M, Soubrane, G, Tomazzoli, L, Topouzis, F, Vioque, J, Hingorani, AD, Sofat, R, Dean, M, Sawitzke, J, Seddon, JM, Peter, I, Webster, AR, Moore, AT, Yates, JRW, Cipriani, V, Fritsche, LG, Weber, BHF, Keilhauer, CN, Lotery, AJ, Ennis, S, Klein, ML, Francis, PJ, Stambolian, D, Orlin, A, Gorin, MB, Weeks, DE, Kuo, CL, Swaroop, A, Othman, M, Kanda, A, Chen, W, Abecasis, GR, Wright, AF, Hayward, C, Baird, PN, Guymer, RH, Attia, J, Thakkinstian, A & Silvestri, G 2011, 'Evidence of association of APOE with age-related macular degeneration - a pooled analysis of 15 studies', Human mutation, vol. 32, no. 12, pp. 1407-1416. https://doi.org/10.1002/humu.21577

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title = "Evidence of association of APOE with age-related macular degeneration - a pooled analysis of 15 studies",

abstract = "Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status has been reported. We present a pooled analysis (n = 21,160) demonstrating associations between late AMD and APOε4 (odds ratio [OR] = 0.72 per haplotype; confidence interval [CI]: 0.65-0.74; P = 4.41×10 -11) and APOε2 (OR = 1.83 for homozygote carriers; CI: 1.04-3.23; P = 0.04), following adjustment for age group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR = 1.54; CI: 1.38-1.72; P = 2.8×10 -15) and atrophic (OR = 1.38; CI: 1.18-1.61; P = 3.37×10 -5) AMD but not early AMD (OR = 0.94; CI: 0.86-1.03; P = 0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyond ε2 and ε4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology.",

keywords = "AMD, APOE, Age-related macular degeneration, Apolipoprotein E, Case-control association study",

author = "Mckay, {Gareth J.} and Patterson, {Chris C.} and Usha Chakravarthy and Shilpa Dasari and Klaver, {Caroline C.} and Vingerling, {Johannes R.} and Lintje Ho and {de Jong}, {Paulus T.V.M.} and Fletcher, {Astrid E.} and Young, {Ian S.} and Seland, {Johan H.} and Mati Rahu and Gisele Soubrane and Laura Tomazzoli and Fotis Topouzis and Jesus Vioque and Hingorani, {Aroon D.} and Reecha Sofat and Michael Dean and Julie Sawitzke and Seddon, {Johanna M.} and Inga Peter and Webster, {Andrew R.} and Moore, {Anthony T.} and Yates, {John R.W.} and Valentina Cipriani and Fritsche, {Lars G.} and Weber, {Bernhard H.F.} and Keilhauer, {Claudia N.} and Lotery, {Andrew J.} and Sarah Ennis and Klein, {Michael L.} and Francis, {Peter J.} and Dwight Stambolian and Anton Orlin and Gorin, {Michael B.} and Weeks, {Daniel E.} and Kuo, {Chia Ling} and Anand Swaroop and Mohammad Othman and Atsuhiro Kanda and Wei Chen and Abecasis, {Goncalo R.} and Wright, {Alan F.} and Caroline Hayward and Baird, {Paul N.} and Guymer, {Robyn H.} and John Attia and Ammarin Thakkinstian and Giuliana Silvestri",

year = "2011",

month = dec,

doi = "10.1002/humu.21577",

language = "English (US)",

volume = "32",

pages = "1407--1416",

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T1 - Evidence of association of APOE with age-related macular degeneration - a pooled analysis of 15 studies

AU - Mckay, Gareth J.

AU - Patterson, Chris C.

AU - Chakravarthy, Usha

AU - Dasari, Shilpa

AU - Klaver, Caroline C.

AU - Vingerling, Johannes R.

AU - Ho, Lintje

AU - de Jong, Paulus T.V.M.

AU - Fletcher, Astrid E.

AU - Young, Ian S.

AU - Seland, Johan H.

AU - Rahu, Mati

AU - Soubrane, Gisele

AU - Tomazzoli, Laura

AU - Topouzis, Fotis

AU - Vioque, Jesus

AU - Hingorani, Aroon D.

AU - Sofat, Reecha

AU - Dean, Michael

AU - Sawitzke, Julie

AU - Seddon, Johanna M.

AU - Peter, Inga

AU - Webster, Andrew R.

AU - Moore, Anthony T.

AU - Yates, John R.W.

AU - Cipriani, Valentina

AU - Fritsche, Lars G.

AU - Weber, Bernhard H.F.

AU - Keilhauer, Claudia N.

AU - Lotery, Andrew J.

AU - Ennis, Sarah

AU - Klein, Michael L.

AU - Francis, Peter J.

AU - Stambolian, Dwight

AU - Orlin, Anton

AU - Gorin, Michael B.

AU - Weeks, Daniel E.

AU - Kuo, Chia Ling

AU - Swaroop, Anand

AU - Othman, Mohammad

AU - Kanda, Atsuhiro

AU - Chen, Wei

AU - Abecasis, Goncalo R.

AU - Wright, Alan F.

AU - Hayward, Caroline

AU - Baird, Paul N.

AU - Guymer, Robyn H.

AU - Attia, John

AU - Thakkinstian, Ammarin

AU - Silvestri, Giuliana

PY - 2011/12

Y1 - 2011/12

N2 - Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status has been reported. We present a pooled analysis (n = 21,160) demonstrating associations between late AMD and APOε4 (odds ratio [OR] = 0.72 per haplotype; confidence interval [CI]: 0.65-0.74; P = 4.41×10 -11) and APOε2 (OR = 1.83 for homozygote carriers; CI: 1.04-3.23; P = 0.04), following adjustment for age group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR = 1.54; CI: 1.38-1.72; P = 2.8×10 -15) and atrophic (OR = 1.38; CI: 1.18-1.61; P = 3.37×10 -5) AMD but not early AMD (OR = 0.94; CI: 0.86-1.03; P = 0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyond ε2 and ε4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology.

AB - Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status has been reported. We present a pooled analysis (n = 21,160) demonstrating associations between late AMD and APOε4 (odds ratio [OR] = 0.72 per haplotype; confidence interval [CI]: 0.65-0.74; P = 4.41×10 -11) and APOε2 (OR = 1.83 for homozygote carriers; CI: 1.04-3.23; P = 0.04), following adjustment for age group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR = 1.54; CI: 1.38-1.72; P = 2.8×10 -15) and atrophic (OR = 1.38; CI: 1.18-1.61; P = 3.37×10 -5) AMD but not early AMD (OR = 0.94; CI: 0.86-1.03; P = 0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyond ε2 and ε4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology.

KW - AMD

KW - APOE

KW - Age-related macular degeneration

KW - Apolipoprotein E

KW - Case-control association study

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JO - Human mutation

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Evidence of association of APOE with age-related macular degeneration - a pooled analysis of 15 studies

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