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Association of Smoking, Alcohol Consumption, Blood Pressure, Body Mass Index, and Glycemic Risk Factors With Age-Related Macular DegenerationA Mendelian Randomization Study

Educational Objective
To assess whether smoking, alcohol consumption, blood pressure, body mass index, and glycemic traits are associated with increased risk of advanced age-related macular degeneration (AMD).
1 Credit CME
Key Points

Question  Are smoking, alcohol intake, blood pressure, body mass index, and glycemic traits associated with age-related macular degeneration (AMD)?

Findings  In this mendelian randomization study, genetically predicted smoking initiation and lifetime smoking were associated with elevated risk of advanced AMD, genetically predicted smoking cessation was associated with decreased risk of advanced AMD, and genetically predicted alcohol intake was associated with increased risk of geographic atrophy.

Meaning  These findings support a potential causal association of alcohol consumption with an increased risk of geographic atrophy, smoking initiation and lifetime smoking with an increased risk of advanced AMD, and smoking cessation with a decreased risk of advanced AMD.


Importance  Advanced age-related macular degeneration (AMD) is a leading cause of blindness in Western countries. Causal, modifiable risk factors need to be identified to develop preventive measures for advanced AMD.

Objective  To assess whether smoking, alcohol consumption, blood pressure, body mass index, and glycemic traits are associated with increased risk of advanced AMD.

Design, Setting, Participants  This study used 2-sample mendelian randomization. Genetic instruments composed of variants associated with risk factors at genome-wide significance (P < 5 × 10−8) were obtained from published genome-wide association studies. Summary-level statistics for these instruments were obtained for advanced AMD from the International AMD Genomics Consortium 2016 data set, which consisted of 16 144 individuals with AMD and 17 832 control individuals. Data were analyzed from July 2020 to September 2021.

Exposures  Smoking initiation, smoking cessation, lifetime smoking, age at smoking initiation, alcoholic drinks per week, body mass index, systolic and diastolic blood pressure, type 2 diabetes, glycated hemoglobin, fasting glucose, and fasting insulin.

Main Outcomes and Measures  Advanced AMD and its subtypes, geographic atrophy (GA), and neovascular AMD.

Results  A 1-SD increase in logodds of genetically predicted smoking initiation was associated with higher risk of advanced AMD (odds ratio [OR], 1.26; 95% CI, 1.13-1.40; P < .001), while a 1-SD increase in logodds of genetically predicted smoking cessation (former vs current smoking) was associated with lower risk of advanced AMD (OR, 0.66; 95% CI, 0.50-0.87; P = .003). Genetically predicted increased lifetime smoking was associated with increased risk of advanced AMD (OR per 1-SD increase in lifetime smoking behavior, 1.32; 95% CI, 1.09-1.59; P = .004). Genetically predicted alcohol consumption was associated with higher risk of GA (OR per 1-SD increase of log-transformed alcoholic drinks per week, 2.70; 95% CI, 1.48-4.94; P = .001). There was insufficient evidence to suggest that genetically predicted blood pressure, body mass index, and glycemic traits were associated with advanced AMD.

Conclusions and Relevance  This study provides genetic evidence that increased alcohol intake may be a causal risk factor for GA. As there are currently no known treatments for GA, this finding has important public health implications. These results also support previous observational studies associating smoking behavior with risk of advanced AMD, thus reinforcing existing public health messages regarding the risk of blindness associated with smoking.

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Article Information

Accepted for Publication: September 20, 2021.

Published Online: November 4, 2021. doi:10.1001/jamaophthalmol.2021.4601

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Kuan V et al. JAMA Ophthalmology.

Corresponding Author: Valerie Kuan, PhD, Institute of Health Informatics, University College London, 222 Euston Rd, London NW1 2DA, United Kingdom (v.kuan@ucl.ac.uk).

Author Contributions: Dr Kuan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kuan, Hingorani, Tufail, Sofat.

Acquisition, analysis, or interpretation of data: Kuan, Warwick, Tufail, Cipriani, Burgess, Sofat.

Drafting of the manuscript: Kuan, Warwick.

Critical revision of the manuscript for important intellectual content: Kuan, Hingorani, Tufail, Cipriani, Burgess, Sofat.

Statistical analysis: Kuan, Warwick, Cipriani, Burgess.

Obtained funding: Cipriani, Sofat.

Administrative, technical, or material support: Kuan, Tufail.

Supervision: Hingorani, Tufail, Sofat.

Conflict of Interest Disclosures: Dr Kuan reports grants from Dunhill Medical Trust. Dr Tufail reports personal fees from Apellis, Bayer, Genentech/Roche, IVERIC Bio, and Heidelberg Engineering, and personal fees and grants from Novartis. No other disclosures were reported.

Funding/Support: Dr Kuan is funded by the Dunhill Medical Trust (RPGF1806\67). Dr Warwick is supported by the Wellcome Trust (220558/Z/20/Z). Dr Hingorani is supported by a BHF Research Accelerator Award (AA/18/6/34223). Dr Tufail is supported by the National Institute for Health Research to Moorfields Eye Hospital and the Biomedical Research Centre for Ophthalmology. Dr Burgess is supported by Sir Henry Dale Fellowship, jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z) Dr Sofat is supported by the National Institute for Health Research, University College London Hospitals Biomedical Research Centre. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

The International AMD Genomics Consortium (IAMDGC): The group members are listed in Supplement 2.

Disclaimer: The views expressed are those of the authors and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care.

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Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 credit toward the CME [and Self-Assessment requirements] of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

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