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Mendelian Randomization Implicates High-Density Lipoprotein Cholesterol-Associated Mechanisms in Etiology of Age-Related Macular Degeneration.
Ophthalmology. 2017 08; 124(8):1165-1174.O

Abstract

PURPOSE

Undertake a systematic investigation into associations between genetic predictors of lipid fractions and age-related macular degeneration (AMD) risk.

DESIGN

Two-sample Mendelian randomization investigation using published data.

PARTICIPANTS

A total of 33 526 individuals (16 144 cases, 17 832 controls) predominantly of European ancestry from the International Age-related Macular Degeneration Genomics Consortium.

METHODS

We consider 185 variants previously demonstrated to be associated with at least 1 of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides at a genome-wide level of significance, and test their associations with AMD. We particularly focus on variants in gene regions that are proxies for specific pharmacologic agents for lipid therapy. We then conduct a 2-sample Mendelian randomization investigation to assess the causal roles of LDL-cholesterol, HDL-cholesterol, and triglycerides on AMD risk. We also conduct parallel investigations for coronary artery disease (CAD) (viewed as a positive control) and Alzheimer's disease (a negative control) for comparison.

MAIN OUTCOME MEASURES

Diagnosis of AMD.

RESULTS

We find evidence that HDL-cholesterol is a causal risk factor for AMD, with an odds ratio (OR) estimate of 1.22 (95% confidence interval [CI], 1.03-1.44) per 1 standard deviation increase in HDL-cholesterol. No causal effect of LDL-cholesterol or triglycerides was found. Variants in the CETP gene region associated with increased circulating HDL-cholesterol also associate with increased AMD risk, although variants in the LIPC gene region that increase circulating HDL-cholesterol have the opposite direction of association with AMD risk. Parallel analyses suggest that lipids have a greater role for AMD compared with Alzheimer's disease, but a lesser role than for CAD.

CONCLUSIONS

Some genetic evidence suggests that HDL-cholesterol is a causal risk factor for AMD risk and that increasing HDL-cholesterol (particularly via CETP inhibition) will increase AMD risk.

Authors+Show Affiliations

MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom; Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom. Electronic address: sb452@medschl.cam.ac.uk.MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28456421

Citation

Burgess, Stephen, and George Davey Smith. "Mendelian Randomization Implicates High-Density Lipoprotein Cholesterol-Associated Mechanisms in Etiology of Age-Related Macular Degeneration." Ophthalmology, vol. 124, no. 8, 2017, pp. 1165-1174.
Burgess S, Davey Smith G. Mendelian Randomization Implicates High-Density Lipoprotein Cholesterol-Associated Mechanisms in Etiology of Age-Related Macular Degeneration. Ophthalmology. 2017;124(8):1165-1174.
Burgess, S., & Davey Smith, G. (2017). Mendelian Randomization Implicates High-Density Lipoprotein Cholesterol-Associated Mechanisms in Etiology of Age-Related Macular Degeneration. Ophthalmology, 124(8), 1165-1174. https://doi.org/10.1016/j.ophtha.2017.03.042
Burgess S, Davey Smith G. Mendelian Randomization Implicates High-Density Lipoprotein Cholesterol-Associated Mechanisms in Etiology of Age-Related Macular Degeneration. Ophthalmology. 2017;124(8):1165-1174. PubMed PMID: 28456421.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mendelian Randomization Implicates High-Density Lipoprotein Cholesterol-Associated Mechanisms in Etiology of Age-Related Macular Degeneration. AU - Burgess,Stephen, AU - Davey Smith,George, Y1 - 2017/04/26/ PY - 2016/12/12/received PY - 2017/03/20/revised PY - 2017/03/20/accepted PY - 2017/5/1/pubmed PY - 2017/8/2/medline PY - 2017/5/1/entrez SP - 1165 EP - 1174 JF - Ophthalmology JO - Ophthalmology VL - 124 IS - 8 N2 - PURPOSE: Undertake a systematic investigation into associations between genetic predictors of lipid fractions and age-related macular degeneration (AMD) risk. DESIGN: Two-sample Mendelian randomization investigation using published data. PARTICIPANTS: A total of 33 526 individuals (16 144 cases, 17 832 controls) predominantly of European ancestry from the International Age-related Macular Degeneration Genomics Consortium. METHODS: We consider 185 variants previously demonstrated to be associated with at least 1 of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides at a genome-wide level of significance, and test their associations with AMD. We particularly focus on variants in gene regions that are proxies for specific pharmacologic agents for lipid therapy. We then conduct a 2-sample Mendelian randomization investigation to assess the causal roles of LDL-cholesterol, HDL-cholesterol, and triglycerides on AMD risk. We also conduct parallel investigations for coronary artery disease (CAD) (viewed as a positive control) and Alzheimer's disease (a negative control) for comparison. MAIN OUTCOME MEASURES: Diagnosis of AMD. RESULTS: We find evidence that HDL-cholesterol is a causal risk factor for AMD, with an odds ratio (OR) estimate of 1.22 (95% confidence interval [CI], 1.03-1.44) per 1 standard deviation increase in HDL-cholesterol. No causal effect of LDL-cholesterol or triglycerides was found. Variants in the CETP gene region associated with increased circulating HDL-cholesterol also associate with increased AMD risk, although variants in the LIPC gene region that increase circulating HDL-cholesterol have the opposite direction of association with AMD risk. Parallel analyses suggest that lipids have a greater role for AMD compared with Alzheimer's disease, but a lesser role than for CAD. CONCLUSIONS: Some genetic evidence suggests that HDL-cholesterol is a causal risk factor for AMD risk and that increasing HDL-cholesterol (particularly via CETP inhibition) will increase AMD risk. SN - 1549-4713 UR - https://www.unboundmedicine.com/medline/citation/28456421/Mendelian_Randomization_Implicates_High_Density_Lipoprotein_Cholesterol_Associated_Mechanisms_in_Etiology_of_Age_Related_Macular_Degeneration_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0161-6420(16)32310-7 DB - PRIME DP - Unbound Medicine ER -