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 & 30 others 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 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

Research output: Contribution to journalArticle

72 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1407-1416
Number of pages10
JournalHuman Mutation
Volume32
Issue number12
DOIs
StatePublished - Dec 2011

Fingerprint

Macular Degeneration
Apolipoproteins E
Odds Ratio
Confidence Intervals
Smoking
Haplotypes
Cholesterol
Vision Disorders
Homozygote
Disease Progression
Carrier Proteins
Age Groups
Lipids

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Mckay, G. J., Patterson, C. C., Chakravarthy, U., Dasari, S., Klaver, C. C., Vingerling, J. R., ... 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

Evidence of association of APOE with age-related macular degeneration - a pooled analysis of 15 studies. / Mckay, Gareth J.; Patterson, Chris C.; Chakravarthy, Usha; Dasari, Shilpa; Klaver, Caroline C.; Vingerling, Johannes R.; Ho, Lintje; de Jong, Paulus T V M; Fletcher, Astrid E.; Young, Ian S.; Seland, Johan H.; Rahu, Mati; Soubrane, Gisele; Tomazzoli, Laura; Topouzis, Fotis; Vioque, Jesus; Hingorani, Aroon D.; Sofat, Reecha; Dean, Michael; Sawitzke, Julie; Seddon, Johanna M.; Peter, Inga; Webster, Andrew R.; Moore, Anthony T.; Yates, John R W; Cipriani, Valentina; Fritsche, Lars G.; Weber, Bernhard H F; Keilhauer, Claudia N.; Lotery, Andrew J.; Ennis, Sarah; Klein, Michael; Francis, Peter J.; Stambolian, Dwight; Orlin, Anton; Gorin, Michael B.; Weeks, Daniel E.; Kuo, Chia Ling; Swaroop, Anand; Othman, Mohammad; Kanda, Atsuhiro; Chen, Wei; Abecasis, Goncalo R.; Wright, Alan F.; Hayward, Caroline; Baird, Paul N.; Guymer, Robyn H.; Attia, John; Thakkinstian, Ammarin; Silvestri, Giuliana.

In: Human Mutation, Vol. 32, No. 12, 12.2011, p. 1407-1416.

Research output: Contribution to journalArticle

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, M, 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
Mckay GJ, Patterson CC, Chakravarthy U, Dasari S, Klaver CC, Vingerling JR et al. Evidence of association of APOE with age-related macular degeneration - a pooled analysis of 15 studies. Human Mutation. 2011 Dec;32(12):1407-1416. https://doi.org/10.1002/humu.21577
Mckay, Gareth J. ; Patterson, Chris C. ; Chakravarthy, Usha ; Dasari, Shilpa ; Klaver, Caroline C. ; Vingerling, Johannes R. ; Ho, Lintje ; de Jong, Paulus T V M ; Fletcher, Astrid E. ; Young, Ian S. ; Seland, Johan H. ; Rahu, Mati ; Soubrane, Gisele ; Tomazzoli, Laura ; Topouzis, Fotis ; Vioque, Jesus ; Hingorani, Aroon D. ; Sofat, Reecha ; Dean, Michael ; Sawitzke, Julie ; Seddon, Johanna M. ; Peter, Inga ; Webster, Andrew R. ; Moore, Anthony T. ; Yates, John R W ; Cipriani, Valentina ; Fritsche, Lars G. ; Weber, Bernhard H F ; Keilhauer, Claudia N. ; Lotery, Andrew J. ; Ennis, Sarah ; Klein, Michael ; Francis, Peter J. ; Stambolian, Dwight ; Orlin, Anton ; Gorin, Michael B. ; Weeks, Daniel E. ; Kuo, Chia Ling ; Swaroop, Anand ; Othman, Mohammad ; Kanda, Atsuhiro ; Chen, Wei ; Abecasis, Goncalo R. ; Wright, Alan F. ; Hayward, Caroline ; Baird, Paul N. ; Guymer, Robyn H. ; Attia, John ; Thakkinstian, Ammarin ; Silvestri, Giuliana. / Evidence of association of APOE with age-related macular degeneration - a pooled analysis of 15 studies. In: Human Mutation. 2011 ; Vol. 32, No. 12. pp. 1407-1416.
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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

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AU - Vioque, Jesus

AU - Hingorani, Aroon D.

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AU - Sawitzke, Julie

AU - Seddon, Johanna M.

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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

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

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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 - Age-related macular degeneration

KW - AMD

KW - APOE

KW - Apolipoprotein E

KW - Case-control association study

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