Increased High-Density Lipoprotein Levels Associated with Age-Related Macular Degeneration Evidence from the EYE-RISK and European Eye Epidemiology Consortia

Johanna M. Colijn; Anneke den Hollander; Ayse Demirkan; Audrey Cougnard-Gregoire; Timo Verzijden; Eveline Kersten; Magda A. Meester-Smoor; Benedicte M. J. Merle; Grigorios Papageorgiou; Shahzad Ahmad; Monique T. Mulder; Miguel Angelo Costa; Pascale Benlian; Geir Bertelsen; Alain M. Bron; Birte Claes; Catherine Creuzot-Garcher; Maja Gran Erke; Sascha Fauser; Paul J. Foster; Christopher J. Hammond; Hans-Werner Hense; Carel B. Hoyng; Anthony P. Khawaja; Jean-Francois Korobelnik; Stefano Piermarocchi; Tatiana Segato; Rufino Silva; Eric H. Souied; Katie M. Williams; Cornelia M. van Duijn; Cecile Delcourt; Caroline Klaver; Niyazi Acar; Lebriz Altay; Eleftherios Anastosopoulos; Augusto Azuara-Blanco; Tos Berendschot; Arthur Bergen; Christine Binquet; Alan Bird; Martin Bobak; Morten Bogelund Larsen; Camiel Boon; Rupert Bourne; Lionel Bretillon; Rebecca Broe; Alain Bron; Gabrielle Buitendijk; Theo Gorgels; European Eye Epidemiology Consortium

doi:10.1016/j.ophtha.2018.09.045

Increased High-Density Lipoprotein Levels Associated with Age-Related Macular Degeneration Evidence from the EYE-RISK and European Eye Epidemiology Consortia

Johanna M. Colijn, Anneke den Hollander, Ayse Demirkan, Audrey Cougnard-Gregoire, Timo Verzijden, Eveline Kersten, Magda A. Meester-Smoor, Benedicte M. J. Merle, Grigorios Papageorgiou, Shahzad Ahmad, Monique T. Mulder, Miguel Angelo Costa, Pascale Benlian, Geir Bertelsen, Alain M. Bron, Birte Claes, Catherine Creuzot-Garcher, Maja Gran Erke, Sascha Fauser, Paul J. FosterChristopher J. Hammond, Hans-Werner Hense, Carel B. Hoyng, Anthony P. Khawaja, Jean-Francois Korobelnik, Stefano Piermarocchi, Tatiana Segato, Rufino Silva, Eric H. Souied, Katie M. Williams, Cornelia M. van Duijn, Cecile Delcourt, Caroline Klaver^*, Niyazi Acar, Lebriz Altay, Eleftherios Anastosopoulos, Augusto Azuara-Blanco, Tos Berendschot, Arthur Bergen, Christine Binquet, Alan Bird, Martin Bobak, Morten Bogelund Larsen, Camiel Boon, Rupert Bourne, Lionel Bretillon, Rebecca Broe, Alain Bron, Gabrielle Buitendijk, Theo Gorgels, European Eye Epidemiology Consortium

^*Corresponding author for this work

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

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Abstract

Purpose: Genetic and epidemiologic studies have shown that lipid genes and high-density lipoproteins (HDLs) are implicated in age-related macular degeneration (AMD). We studied circulating lipid levels in relationship to AMD in a large European dataset.

Design: Pooled analysis of cross-sectional data.

Participants: Individuals (N = 30 953) aged 50 years or older participating in the European Eye Epidemiology (E3) consortium and 1530 individuals from the Rotterdam Study with lipid subfraction data.

Methods: AMD features were graded on fundus photographs using the Rotterdam classification. Routine blood lipid measurements, genetics, medication, and potential confounders were extracted from the E3 database. In a subgroup of the Rotterdam Study, lipid subfractions were identified by the Nightingale biomarker platform. Random-intercepts mixed-effects models incorporating confounders and study site as a random effect were used to estimate associations.

Main Outcome Measures: AMD features and stage; lipid measurements.

Results: HDL was associated with an increased risk of AMD (odds ratio [OR], 1.21 per 1-mmol/l increase; 95% confidence interval [CI], 1.14-1.29), whereas triglycerides were associated with a decreased risk (OR, 0.94 per 1-mmol/l increase; 95% CI, 0.91-0.97). Both were associated with drusen size. Higher HDL raised the odds of larger drusen, whereas higher triglycerides decreases the odds. LDL cholesterol reached statistical significance only in the association with early AMD (P = 0.045). Regarding lipid subfractions, the concentration of extra-large HDL particles showed the most prominent association with AMD (OR, 1.24; 95% CI, 1.10-1.40). The cholesteryl ester transfer protein risk variant (rs17231506) for AMD was in line with increased HDL levels (P = 7.7 x 10(-7)), but lipase C risk variants (rs2043085, rs2070895) were associated in an opposite way (P = 1.0 x 10(-6) and P = 1.6 x 10(-4)).

Conclusions: Our study suggested that HDL cholesterol is associated with increased risk of AMD and that triglycerides are negatively associated. Both show the strongest association with early AMD and drusen. Extra-large HDL subfractions seem to be drivers in the relationship with AMD, and variants in lipid genes play a more ambiguous role in this association. Whether systemic lipids directly influence AMD or represent lipid metabolism in the retina remains to be answered. (C) 2018 by the American Academy of Ophthalmology

Original language	English
Pages (from-to)	393-406
Number of pages	14
Journal	Ophthalmology
Volume	126
Issue number	3
DOIs	https://doi.org/10.1016/j.ophtha.2018.09.045
Publication status	Published - Mar 2019

Keywords

ACTIVATION
CHOLESTEROL
DRUSEN
GENOME-WIDE ASSOCIATION
HEPATIC LIPASE
MACULOPATHY
PLASMA
PROGRESSION
PROTEINS
STATIN USE

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Colijn, J. M., den Hollander, A., Demirkan, A., Cougnard-Gregoire, A., Verzijden, T., Kersten, E., Meester-Smoor, M. A., Merle, B. M. J., Papageorgiou, G., Ahmad, S., Mulder, M. T., Costa, M. A., Benlian, P., Bertelsen, G., Bron, A. M., Claes, B., Creuzot-Garcher, C., Erke, M. G., Fauser, S., ... European Eye Epidemiology Consortium (2019). Increased High-Density Lipoprotein Levels Associated with Age-Related Macular Degeneration Evidence from the EYE-RISK and European Eye Epidemiology Consortia. Ophthalmology, 126(3), 393-406. https://doi.org/10.1016/j.ophtha.2018.09.045

@article{c3f4bd557f2e4a9ab10481c848e49715,

title = "Increased High-Density Lipoprotein Levels Associated with Age-Related Macular Degeneration Evidence from the EYE-RISK and European Eye Epidemiology Consortia",

abstract = "Purpose: Genetic and epidemiologic studies have shown that lipid genes and high-density lipoproteins (HDLs) are implicated in age-related macular degeneration (AMD). We studied circulating lipid levels in relationship to AMD in a large European dataset.Design: Pooled analysis of cross-sectional data.Participants: Individuals (N = 30 953) aged 50 years or older participating in the European Eye Epidemiology (E3) consortium and 1530 individuals from the Rotterdam Study with lipid subfraction data.Methods: AMD features were graded on fundus photographs using the Rotterdam classification. Routine blood lipid measurements, genetics, medication, and potential confounders were extracted from the E3 database. In a subgroup of the Rotterdam Study, lipid subfractions were identified by the Nightingale biomarker platform. Random-intercepts mixed-effects models incorporating confounders and study site as a random effect were used to estimate associations.Main Outcome Measures: AMD features and stage; lipid measurements.Results: HDL was associated with an increased risk of AMD (odds ratio [OR], 1.21 per 1-mmol/l increase; 95% confidence interval [CI], 1.14-1.29), whereas triglycerides were associated with a decreased risk (OR, 0.94 per 1-mmol/l increase; 95% CI, 0.91-0.97). Both were associated with drusen size. Higher HDL raised the odds of larger drusen, whereas higher triglycerides decreases the odds. LDL cholesterol reached statistical significance only in the association with early AMD (P = 0.045). Regarding lipid subfractions, the concentration of extra-large HDL particles showed the most prominent association with AMD (OR, 1.24; 95% CI, 1.10-1.40). The cholesteryl ester transfer protein risk variant (rs17231506) for AMD was in line with increased HDL levels (P = 7.7 x 10(-7)), but lipase C risk variants (rs2043085, rs2070895) were associated in an opposite way (P = 1.0 x 10(-6) and P = 1.6 x 10(-4)).Conclusions: Our study suggested that HDL cholesterol is associated with increased risk of AMD and that triglycerides are negatively associated. Both show the strongest association with early AMD and drusen. Extra-large HDL subfractions seem to be drivers in the relationship with AMD, and variants in lipid genes play a more ambiguous role in this association. Whether systemic lipids directly influence AMD or represent lipid metabolism in the retina remains to be answered. (C) 2018 by the American Academy of Ophthalmology",

keywords = "ACTIVATION, CHOLESTEROL, DRUSEN, GENOME-WIDE ASSOCIATION, HEPATIC LIPASE, MACULOPATHY, PLASMA, PROGRESSION, PROTEINS, STATIN USE",

author = "Colijn, {Johanna M.} and {den Hollander}, Anneke and Ayse Demirkan and Audrey Cougnard-Gregoire and Timo Verzijden and Eveline Kersten and Meester-Smoor, {Magda A.} and Merle, {Benedicte M. J.} and Grigorios Papageorgiou and Shahzad Ahmad and Mulder, {Monique T.} and Costa, {Miguel Angelo} and Pascale Benlian and Geir Bertelsen and Bron, {Alain M.} and Birte Claes and Catherine Creuzot-Garcher and Erke, {Maja Gran} and Sascha Fauser and Foster, {Paul J.} and Hammond, {Christopher J.} and Hans-Werner Hense and Hoyng, {Carel B.} and Khawaja, {Anthony P.} and Jean-Francois Korobelnik and Stefano Piermarocchi and Tatiana Segato and Rufino Silva and Souied, {Eric H.} and Williams, {Katie M.} and {van Duijn}, {Cornelia M.} and Cecile Delcourt and Caroline Klaver and Niyazi Acar and Lebriz Altay and Eleftherios Anastosopoulos and Augusto Azuara-Blanco and Tos Berendschot and Arthur Bergen and Christine Binquet and Alan Bird and Martin Bobak and Larsen, {Morten Bogelund} and Camiel Boon and Rupert Bourne and Lionel Bretillon and Rebecca Broe and Alain Bron and Gabrielle Buitendijk and Theo Gorgels and {European Eye Epidemiology Consortium}",

note = "Funding Information: Supported by the European Union's Horizon 2020 research and innovation programme (grant no.: 634479). Publisher Copyright: {\textcopyright} 2018 American Academy of Ophthalmology",

year = "2019",

month = mar,

doi = "10.1016/j.ophtha.2018.09.045",

language = "English",

volume = "126",

pages = "393--406",

journal = "Ophthalmology",

issn = "0161-6420",

publisher = "Elsevier Science",

number = "3",

}

Colijn, JM, den Hollander, A, Demirkan, A, Cougnard-Gregoire, A, Verzijden, T, Kersten, E, Meester-Smoor, MA, Merle, BMJ, Papageorgiou, G, Ahmad, S, Mulder, MT, Costa, MA, Benlian, P, Bertelsen, G, Bron, AM, Claes, B, Creuzot-Garcher, C, Erke, MG, Fauser, S, Foster, PJ, Hammond, CJ, Hense, H-W, Hoyng, CB, Khawaja, AP, Korobelnik, J-F, Piermarocchi, S, Segato, T, Silva, R, Souied, EH, Williams, KM, van Duijn, CM, Delcourt, C, Klaver, C, Acar, N, Altay, L, Anastosopoulos, E, Azuara-Blanco, A, Berendschot, T, Bergen, A, Binquet, C, Bird, A, Bobak, M, Larsen, MB, Boon, C, Bourne, R, Bretillon, L, Broe, R, Bron, A, Buitendijk, G, Gorgels, T & European Eye Epidemiology Consortium 2019, 'Increased High-Density Lipoprotein Levels Associated with Age-Related Macular Degeneration Evidence from the EYE-RISK and European Eye Epidemiology Consortia', Ophthalmology, vol. 126, no. 3, pp. 393-406. https://doi.org/10.1016/j.ophtha.2018.09.045

TY - JOUR

T1 - Increased High-Density Lipoprotein Levels Associated with Age-Related Macular Degeneration Evidence from the EYE-RISK and European Eye Epidemiology Consortia

AU - Colijn, Johanna M.

AU - den Hollander, Anneke

AU - Demirkan, Ayse

AU - Cougnard-Gregoire, Audrey

AU - Verzijden, Timo

AU - Kersten, Eveline

AU - Meester-Smoor, Magda A.

AU - Merle, Benedicte M. J.

AU - Papageorgiou, Grigorios

AU - Ahmad, Shahzad

AU - Mulder, Monique T.

AU - Costa, Miguel Angelo

AU - Benlian, Pascale

AU - Bertelsen, Geir

AU - Bron, Alain M.

AU - Claes, Birte

AU - Creuzot-Garcher, Catherine

AU - Erke, Maja Gran

AU - Fauser, Sascha

AU - Foster, Paul J.

AU - Hammond, Christopher J.

AU - Hense, Hans-Werner

AU - Hoyng, Carel B.

AU - Khawaja, Anthony P.

AU - Korobelnik, Jean-Francois

AU - Piermarocchi, Stefano

AU - Segato, Tatiana

AU - Silva, Rufino

AU - Souied, Eric H.

AU - Williams, Katie M.

AU - van Duijn, Cornelia M.

AU - Delcourt, Cecile

AU - Klaver, Caroline

AU - Acar, Niyazi

AU - Altay, Lebriz

AU - Anastosopoulos, Eleftherios

AU - Azuara-Blanco, Augusto

AU - Berendschot, Tos

AU - Bergen, Arthur

AU - Binquet, Christine

AU - Bird, Alan

AU - Bobak, Martin

AU - Larsen, Morten Bogelund

AU - Boon, Camiel

AU - Bourne, Rupert

AU - Bretillon, Lionel

AU - Broe, Rebecca

AU - Bron, Alain

AU - Buitendijk, Gabrielle

AU - Gorgels, Theo

AU - European Eye Epidemiology Consortium

PY - 2019/3

Y1 - 2019/3

N2 - Purpose: Genetic and epidemiologic studies have shown that lipid genes and high-density lipoproteins (HDLs) are implicated in age-related macular degeneration (AMD). We studied circulating lipid levels in relationship to AMD in a large European dataset.Design: Pooled analysis of cross-sectional data.Participants: Individuals (N = 30 953) aged 50 years or older participating in the European Eye Epidemiology (E3) consortium and 1530 individuals from the Rotterdam Study with lipid subfraction data.Methods: AMD features were graded on fundus photographs using the Rotterdam classification. Routine blood lipid measurements, genetics, medication, and potential confounders were extracted from the E3 database. In a subgroup of the Rotterdam Study, lipid subfractions were identified by the Nightingale biomarker platform. Random-intercepts mixed-effects models incorporating confounders and study site as a random effect were used to estimate associations.Main Outcome Measures: AMD features and stage; lipid measurements.Results: HDL was associated with an increased risk of AMD (odds ratio [OR], 1.21 per 1-mmol/l increase; 95% confidence interval [CI], 1.14-1.29), whereas triglycerides were associated with a decreased risk (OR, 0.94 per 1-mmol/l increase; 95% CI, 0.91-0.97). Both were associated with drusen size. Higher HDL raised the odds of larger drusen, whereas higher triglycerides decreases the odds. LDL cholesterol reached statistical significance only in the association with early AMD (P = 0.045). Regarding lipid subfractions, the concentration of extra-large HDL particles showed the most prominent association with AMD (OR, 1.24; 95% CI, 1.10-1.40). The cholesteryl ester transfer protein risk variant (rs17231506) for AMD was in line with increased HDL levels (P = 7.7 x 10(-7)), but lipase C risk variants (rs2043085, rs2070895) were associated in an opposite way (P = 1.0 x 10(-6) and P = 1.6 x 10(-4)).Conclusions: Our study suggested that HDL cholesterol is associated with increased risk of AMD and that triglycerides are negatively associated. Both show the strongest association with early AMD and drusen. Extra-large HDL subfractions seem to be drivers in the relationship with AMD, and variants in lipid genes play a more ambiguous role in this association. Whether systemic lipids directly influence AMD or represent lipid metabolism in the retina remains to be answered. (C) 2018 by the American Academy of Ophthalmology

AB - Purpose: Genetic and epidemiologic studies have shown that lipid genes and high-density lipoproteins (HDLs) are implicated in age-related macular degeneration (AMD). We studied circulating lipid levels in relationship to AMD in a large European dataset.Design: Pooled analysis of cross-sectional data.Participants: Individuals (N = 30 953) aged 50 years or older participating in the European Eye Epidemiology (E3) consortium and 1530 individuals from the Rotterdam Study with lipid subfraction data.Methods: AMD features were graded on fundus photographs using the Rotterdam classification. Routine blood lipid measurements, genetics, medication, and potential confounders were extracted from the E3 database. In a subgroup of the Rotterdam Study, lipid subfractions were identified by the Nightingale biomarker platform. Random-intercepts mixed-effects models incorporating confounders and study site as a random effect were used to estimate associations.Main Outcome Measures: AMD features and stage; lipid measurements.Results: HDL was associated with an increased risk of AMD (odds ratio [OR], 1.21 per 1-mmol/l increase; 95% confidence interval [CI], 1.14-1.29), whereas triglycerides were associated with a decreased risk (OR, 0.94 per 1-mmol/l increase; 95% CI, 0.91-0.97). Both were associated with drusen size. Higher HDL raised the odds of larger drusen, whereas higher triglycerides decreases the odds. LDL cholesterol reached statistical significance only in the association with early AMD (P = 0.045). Regarding lipid subfractions, the concentration of extra-large HDL particles showed the most prominent association with AMD (OR, 1.24; 95% CI, 1.10-1.40). The cholesteryl ester transfer protein risk variant (rs17231506) for AMD was in line with increased HDL levels (P = 7.7 x 10(-7)), but lipase C risk variants (rs2043085, rs2070895) were associated in an opposite way (P = 1.0 x 10(-6) and P = 1.6 x 10(-4)).Conclusions: Our study suggested that HDL cholesterol is associated with increased risk of AMD and that triglycerides are negatively associated. Both show the strongest association with early AMD and drusen. Extra-large HDL subfractions seem to be drivers in the relationship with AMD, and variants in lipid genes play a more ambiguous role in this association. Whether systemic lipids directly influence AMD or represent lipid metabolism in the retina remains to be answered. (C) 2018 by the American Academy of Ophthalmology

KW - ACTIVATION

KW - CHOLESTEROL

KW - DRUSEN

KW - GENOME-WIDE ASSOCIATION

KW - HEPATIC LIPASE

KW - MACULOPATHY

KW - PLASMA

KW - PROGRESSION

KW - PROTEINS

KW - STATIN USE

U2 - 10.1016/j.ophtha.2018.09.045

DO - 10.1016/j.ophtha.2018.09.045

M3 - Article

C2 - 30315903

SN - 0161-6420

VL - 126

SP - 393

EP - 406

JO - Ophthalmology

JF - Ophthalmology

IS - 3

ER -