HDL-cholesterol levels and risk of age-related macular degeneration: a multiethnic genetic study using Mendelian randomization

Dyslipidemia, particularly high-density lipoprotein cholesterol (HDL-C), has recently been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss. However, epidemiological studies have yielded conflicting results. We investigated the causal role of...

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Published inInternational journal of epidemiology Vol. 46; no. 6; pp. 1891 - 1902
Main Authors Fan, Qiao, Maranville, Joseph C, Fritsche, Lars, Sim, Xueling, Cheung, Chui Ming Gemmy, Chen, Li Jia, Gorski, Mathias, Yamashiro, Kenji, Ahn, Jeeyun, Laude, Augustinus, Dorajoo, Rajkumar, Lim, Tock Han, Teo, Yik-Ying, Blaustein, Robert O, Yoshimura, Nagahisa, Park, Kyu-Hyung, Pang, Chi Pui, Tai, E Shyong, Khor, Chiea Chuen, Wong, Tien Yin, Runz, Heiko, Cheng, Ching-Yu
Format Journal Article
LanguageEnglish
Published England Oxford University Press 01.12.2017
Subjects
Adult
Aged
Asian Continental Ancestry Group - genetics
Case-Control Studies
Cholesterol, HDL - blood
European Continental Ancestry Group - genetics
Female
Genetic Predisposition to Disease
Humans
Macular Degeneration - blood
Macular Degeneration - genetics
Male
Mendelian Randomization Analysis
Middle Aged
Models, Genetic
Polymorphism, Single Nucleotide
Risk Factors
Vision
AMD
genetic association
lipids
Mendelian randomization
HDL-cholesterol
Online AccessGet full text
ISSN0300-5771
1464-3685
1464-3685
DOI10.1093/ije/dyx189

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Abstract Dyslipidemia, particularly high-density lipoprotein cholesterol (HDL-C), has recently been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss. However, epidemiological studies have yielded conflicting results. We investigated the causal role of plasma lipid levels in AMD in multiethnic populations comprising 16 144 advanced AMD cases and 17 832 controls of European descent, together with 2219 cases and 5275 controls of Asian descent, using Mendelian randomization in three models. Model 1 is a conventional meta-analysis which does not account for pleiotropy of instrumental variable (IV) effects. Model 2 is a univariate, inverse variance weighted regression analysis that accounts for potential unbalanced pleiotropy using MR-Egger method. Finally, Model 3 is a multivariate regression analysis that addresses pleiotropy by MR-Egger method and by adjusting for effects on other lipid traits. A 1 standard deviation (SD) higher HDL-cholesterol level was associated with an odds ratio (OR) for AMD of 1.17 (95% confidence interval: 1.07-1.29) in Europeans (P = 6.88 × 10-4) and of 1.58 (1.24-2.00) in Asians (P = 2.92 × 10-4) in Model 3. The corresponding OR estimates were 1.30 (1.09-1.55) in Europeans (P = 3.18 × 10-3) and 1.42 (1.11-1.80) in Asians (P = 4.42 × 10-3) in Model 1, and 1.21 (1.11-1.31) in Europeans (P = 3.12 × 10-5) and 1.51 (1.20-1.91) in Asians (P = 7.61 × 10-4) in Model 2. Conversely, neither LDL-C (Europeans: OR = 0.96, P = 0.272; Asians: OR = 1.02, P = 0.874; Model 3) nor triglyceride levels (Europeans: OR = 0.91, P = 0.102; Asians: OR = 1.06, P = 0.613) were associated with AMD. We also assessed the association between lipid levels and polypoidal choroidal vasculopathy (PCV) in Asians, a subtype of AMD, and found a similar trend for association of PCV with HDL-C levels. Our study shows that high levels of plasma HDL-C are causally associated with an increased risk for advanced AMD in European and Asian populations, implying that strategies reducing HDL-C levels may be useful to prevent and treat AMD.
AbstractList Dyslipidemia, particularly high-density lipoprotein cholesterol (HDL-C), has recently been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss. However, epidemiological studies have yielded conflicting results. We investigated the causal role of plasma lipid levels in AMD in multiethnic populations comprising 16 144 advanced AMD cases and 17 832 controls of European descent, together with 2219 cases and 5275 controls of Asian descent, using Mendelian randomization in three models. Model 1 is a conventional meta-analysis which does not account for pleiotropy of instrumental variable (IV) effects. Model 2 is a univariate, inverse variance weighted regression analysis that accounts for potential unbalanced pleiotropy using MR-Egger method. Finally, Model 3 is a multivariate regression analysis that addresses pleiotropy by MR-Egger method and by adjusting for effects on other lipid traits. A 1 standard deviation (SD) higher HDL-cholesterol level was associated with an odds ratio (OR) for AMD of 1.17 (95% confidence interval: 1.07-1.29) in Europeans (P = 6.88 × 10-4) and of 1.58 (1.24-2.00) in Asians (P = 2.92 × 10-4) in Model 3. The corresponding OR estimates were 1.30 (1.09-1.55) in Europeans (P = 3.18 × 10-3) and 1.42 (1.11-1.80) in Asians (P = 4.42 × 10-3) in Model 1, and 1.21 (1.11-1.31) in Europeans (P = 3.12 × 10-5) and 1.51 (1.20-1.91) in Asians (P = 7.61 × 10-4) in Model 2. Conversely, neither LDL-C (Europeans: OR = 0.96, P = 0.272; Asians: OR = 1.02, P = 0.874; Model 3) nor triglyceride levels (Europeans: OR = 0.91, P = 0.102; Asians: OR = 1.06, P = 0.613) were associated with AMD. We also assessed the association between lipid levels and polypoidal choroidal vasculopathy (PCV) in Asians, a subtype of AMD, and found a similar trend for association of PCV with HDL-C levels. Our study shows that high levels of plasma HDL-C are causally associated with an increased risk for advanced AMD in European and Asian populations, implying that strategies reducing HDL-C levels may be useful to prevent and treat AMD.
Dyslipidemia, particularly high-density lipoprotein cholesterol (HDL-C), has recently been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss. However, epidemiological studies have yielded conflicting results.BackgroundDyslipidemia, particularly high-density lipoprotein cholesterol (HDL-C), has recently been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss. However, epidemiological studies have yielded conflicting results.We investigated the causal role of plasma lipid levels in AMD in multiethnic populations comprising 16 144 advanced AMD cases and 17 832 controls of European descent, together with 2219 cases and 5275 controls of Asian descent, using Mendelian randomization in three models. Model 1 is a conventional meta-analysis which does not account for pleiotropy of instrumental variable (IV) effects. Model 2 is a univariate, inverse variance weighted regression analysis that accounts for potential unbalanced pleiotropy using MR-Egger method. Finally, Model 3 is a multivariate regression analysis that addresses pleiotropy by MR-Egger method and by adjusting for effects on other lipid traits.MethodsWe investigated the causal role of plasma lipid levels in AMD in multiethnic populations comprising 16 144 advanced AMD cases and 17 832 controls of European descent, together with 2219 cases and 5275 controls of Asian descent, using Mendelian randomization in three models. Model 1 is a conventional meta-analysis which does not account for pleiotropy of instrumental variable (IV) effects. Model 2 is a univariate, inverse variance weighted regression analysis that accounts for potential unbalanced pleiotropy using MR-Egger method. Finally, Model 3 is a multivariate regression analysis that addresses pleiotropy by MR-Egger method and by adjusting for effects on other lipid traits.A 1 standard deviation (SD) higher HDL-cholesterol level was associated with an odds ratio (OR) for AMD of 1.17 (95% confidence interval: 1.07-1.29) in Europeans (P = 6.88 × 10-4) and of 1.58 (1.24-2.00) in Asians (P = 2.92 × 10-4) in Model 3. The corresponding OR estimates were 1.30 (1.09-1.55) in Europeans (P = 3.18 × 10-3) and 1.42 (1.11-1.80) in Asians (P = 4.42 × 10-3) in Model 1, and 1.21 (1.11-1.31) in Europeans (P = 3.12 × 10-5) and 1.51 (1.20-1.91) in Asians (P = 7.61 × 10-4) in Model 2. Conversely, neither LDL-C (Europeans: OR = 0.96, P = 0.272; Asians: OR = 1.02, P = 0.874; Model 3) nor triglyceride levels (Europeans: OR = 0.91, P = 0.102; Asians: OR = 1.06, P = 0.613) were associated with AMD. We also assessed the association between lipid levels and polypoidal choroidal vasculopathy (PCV) in Asians, a subtype of AMD, and found a similar trend for association of PCV with HDL-C levels.ResultsA 1 standard deviation (SD) higher HDL-cholesterol level was associated with an odds ratio (OR) for AMD of 1.17 (95% confidence interval: 1.07-1.29) in Europeans (P = 6.88 × 10-4) and of 1.58 (1.24-2.00) in Asians (P = 2.92 × 10-4) in Model 3. The corresponding OR estimates were 1.30 (1.09-1.55) in Europeans (P = 3.18 × 10-3) and 1.42 (1.11-1.80) in Asians (P = 4.42 × 10-3) in Model 1, and 1.21 (1.11-1.31) in Europeans (P = 3.12 × 10-5) and 1.51 (1.20-1.91) in Asians (P = 7.61 × 10-4) in Model 2. Conversely, neither LDL-C (Europeans: OR = 0.96, P = 0.272; Asians: OR = 1.02, P = 0.874; Model 3) nor triglyceride levels (Europeans: OR = 0.91, P = 0.102; Asians: OR = 1.06, P = 0.613) were associated with AMD. We also assessed the association between lipid levels and polypoidal choroidal vasculopathy (PCV) in Asians, a subtype of AMD, and found a similar trend for association of PCV with HDL-C levels.Our study shows that high levels of plasma HDL-C are causally associated with an increased risk for advanced AMD in European and Asian populations, implying that strategies reducing HDL-C levels may be useful to prevent and treat AMD.ConclusionsOur study shows that high levels of plasma HDL-C are causally associated with an increased risk for advanced AMD in European and Asian populations, implying that strategies reducing HDL-C levels may be useful to prevent and treat AMD.
Author Park, Kyu-Hyung
Laude, Augustinus
Pang, Chi Pui
Cheng, Ching-Yu
Maranville, Joseph C
Dorajoo, Rajkumar
Chen, Li Jia
Ahn, Jeeyun
Teo, Yik-Ying
Runz, Heiko
Fritsche, Lars
Sim, Xueling
Blaustein, Robert O
Yoshimura, Nagahisa
Lim, Tock Han
Yamashiro, Kenji
Fan, Qiao
Cheung, Chui Ming Gemmy
Tai, E Shyong
Gorski, Mathias
Khor, Chiea Chuen
Wong, Tien Yin
AuthorAffiliation dyx189-2 Merck Research Laboratories, Kenilworth, NJ, USA
dyx189-12 Department of Statistics and Applied Probability, National University of Singapore, Singapore
dyx189-6 Department of Ophthalmology and Visual Sciences, Chinese University of Hong Kong, Hong Kong, China
dyx189-10 National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore
dyx189-11 Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore
dyx189-3 Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, USA
dyx189-13 Department of Medicine, National University Health System and National University of Singapore, Singapore and
dyx189-9 Department of Ophthalmology, Seoul National University Bundang Hospital, Gyeonggi, Korea
dyx189-1 Center for Quantitative Medicine, Duke-NUS Medical School, Singapore
dyx189-5 Singapore Eye Research Institute, Singapore National Eye Center, Singapore
dyx189-14 Clinical Sciences, Duke-NUS Medical School, Singapore
dyx189
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/29025108$$D View this record in MEDLINE/PubMed
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Copyright The Author 2017. Published by Oxford University Press on behalf of the International Epidemiological Association
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ID FETCH-LOGICAL-c444t-2451cd61a8e5da88908ddab21bca213d44710e7e79b13ae4b4fa5825f034f0d33
ISSN 0300-5771
1464-3685
IngestDate Thu Aug 21 14:13:22 EDT 2025
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Thu Apr 03 07:02:47 EDT 2025
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IsDoiOpenAccess true
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Issue 6
Keywords AMD
genetic association
lipids
Mendelian randomization
HDL-cholesterol
Language English
License The Author 2017. Published by Oxford University Press on behalf of the International Epidemiological Association
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
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content type line 23
Tien Yin Wong, Heiko Runz and Ching-Yu Cheng contributed equally to this work.
Qiao Fan and Joseph C Maranville contributed equally to this work.
OpenAccessLink https://pubmed.ncbi.nlm.nih.gov/PMC5837540
PMID 29025108
PQID 1976439845
PQPubID 23479
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ParticipantIDs pubmedcentral_primary_oai_pubmedcentral_nih_gov_5837540
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crossref_citationtrail_10_1093_ije_dyx189
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  year: 2017
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PublicationTitle International journal of epidemiology
PublicationTitleAlternate Int J Epidemiol
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Snippet Dyslipidemia, particularly high-density lipoprotein cholesterol (HDL-C), has recently been implicated in the pathogenesis of age-related macular degeneration...
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StartPage 1891
SubjectTerms Adult
Aged
Asian Continental Ancestry Group - genetics
Case-Control Studies
Cholesterol, HDL - blood
European Continental Ancestry Group - genetics
Female
Genetic Predisposition to Disease
Humans
Macular Degeneration - blood
Macular Degeneration - genetics
Male
Mendelian Randomization Analysis
Middle Aged
Models, Genetic
Polymorphism, Single Nucleotide
Risk Factors
Vision
Title HDL-cholesterol levels and risk of age-related macular degeneration: a multiethnic genetic study using Mendelian randomization
URI https://www.ncbi.nlm.nih.gov/pubmed/29025108
https://www.proquest.com/docview/1976439845
https://pubmed.ncbi.nlm.nih.gov/PMC5837540
Volume 46
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