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Alcohol use and smoking are genetic predictors of advanced age-related macular degeneration (AMD), according to results from a recent investigation published in JAMA Ophthalmology.

In their study, methotrexate drug side ef Valerie Kuan, PhD, of the Institute of Health Informatics at the University College London, and colleagues performed a two-sample mendelian randomization (MR) of genetic variants from genome-wide association studies associated with smoking (genetic predisposition to start or stop smoking as well as smoking status), alcohol consumption per week, type 2 diabetes, glycated hemoglobin, fasting glucose level, and fasting insulin level, blood pressure, and body mass index (BMI). Data on advanced AMD from 16,144 people with AMD and 17,832 individuals in a control group were derived from the International AMD Genomics Consortium 2016 data set.

Kuan and colleagues used univariable inverse-variance–weighted (IVW) 2-sample MR analyses to determine causal associations between each variable and risk of advanced AMD and its subtypes, neurovascular AMD, and geographic atrophy. Sensitivity analyses were conducted with weighted median, MR-Egger, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods, and multivariable MR (MVMR).

The researchers found that individuals with a genetic predisposition to start smoking had an increased risk of advanced AMD in the IVW (odds ratio [OR], 1.26; 95% CI, 1.13 – 1.40; P < .001), MVMR (OR, 1.19; 95% CI, 1.05 – 1.36; P = .007), and weighted-median analyses (OR, 1.20; 95% CI, 1.02 – 1.40; P = .03). Individuals with a genetic predisposition to start smoking were also at an increased risk for developing neovascular AMD in the IVW (OR, 1.26; 95% CI, 1.11 – 1.43; P < .001), MVMR (OR, 1.18; 95% CI, 1.02 – 1.37), and weighted-median analyses (OR, 1.29; 95% CI, 1.08 – 1.54; P = .005). There was no significant association between individuals who started smoking and geographic atrophy.

People with a genetic predisposition to stop smoking had an increased likelihood of protection against advanced AMD in comparison with people who continued smoking according to IVW (OR, 0.66; 95% CI, 0.50 – 0.87; P = .003), MVMR (OR, 0.71; 95% CI, 0.57 – 0.88; P = .002), and MR-Egger (OR, 0.43; 95% CI, 0.21 – 0.87; P = .02) analyses. Those with a genetic predisposition for smoking cessation had no association with developing neurovascular AMD or geographic atrophy, the researchers say.

Among individuals with a genetic predisposition for a composite index of “lifetime smoking” consisting of smoking duration, frequency, and cessation, there was a higher likelihood of developing advanced AMD in IVW (OR, 1.32; 95% CI, 1.09 – 1.59; P = .004), MVMR (OR, 1.48; 95% CI, 1.14 – 1.94; P = .004), and weighted-median (OR, 1.42; 95% CI, 1.11 – 1.81; P = .005) analyses. Similar odds of developing neurovascular AMD were also seen for this group, but there was no significant association between the lifetime smoking composite index and geographic atrophy.

Alcohol use as a genetic predisposition was not associated with an increased likelihood of developing advanced AMD or neurovascular AMD, but consuming alcohol was strongly associated with geographic atrophy in the IVW (OR, 2.70; 95% CI, 1.48 – 4.94; P = .001), MVMR (OR, 2.83; 95% CI, 1.64 – 4.88; P < .001), and MR-PRESSO (OR, 2.50; 95% CI, 1.42 – 4.42; P = .002) analyses.

“There was insufficient evidence to suggest a potential causal association with the other exposures, namely BMI, blood pressure, or glycemic risk factors, on advanced AMD risk,” Kuan and colleagues write.

Counseling Patients on Smoking, Alcohol Use

Although observational studies in the past have shown a potential association between smoking status and advanced AMD, “this study not only finds an increased risk of the most severe form of macular degeneration, known as neovascular (or wet) macular degeneration, but also demonstrates clearly that smoking cessation reduces the risk,” Howard R. Krauss, MD, a surgical neuro-ophthalmologist and clinical professor of ophthalmology and neurosurgery at Saint John’s Cancer Institute at Providence Saint John’s Health Center in Santa Monica, California, who was not involved with the research, said in an interview with Medscape Medical News.

The study also shows a genetic link between alcohol use and geographic atrophy, a subtype of AMD with no commercially available treatments, David Eichenbaum, MD, a board-certified ophthalmologist and director of research at Retina Vitreous Associates in Tampa, Florida, also not involved with the research, told Medscape in an interview.

A strength of the study is the mendelian randomization technique, Eichenbaum said, which “helps to address the bias and limitations of the previously completed observational studies.”

Limitations of the study by Kuan and colleagues include a small number of AMD cases, which contributed to an inability to determine statistical significance for factors such as BMI, glycemic risk, and hypertension, Krauss said.

Another limitation is “not knowing if in some cases there may be genetic linkages between predispositions to macular degeneration with predispositions to nicotine or alcohol use, although the demonstration of reduced risk of advanced macular degeneration in association with cessation of smoking would suggest that not be the case,” he noted.

When it comes to counseling patients about their risk of developing advanced AMD and its subtypes, the study by Kuan and colleagues now provides evidence that smoking cessation has a protective effect against developing advanced AMD, according to Robert W. Wong, MD, a board-certified ophthalmologist with Austin Retina Associates in Austin, Texas, who was not involved with the research.

“For decades, we ophthalmologists have stressed to our patients who have dry, non-exudative intermediate macular degeneration to ‘don’t smoke and don’t start.’ Now, we can add that smoking cessation can lower their risk of advanced disease,” he said in an interview with Medscape.

Counseling about alcohol use has not typically been a part of educating patients about macular degeneration, Wong said.

“In the past, ophthalmologists have not made any strong recommendations with regards to alcohol consumption as to how it affects macular degeneration. I certainly haven’t mentioned alcohol to any of my patients,” he said.

“However, the findings of this study now suggest a causal relationship between weekly alcohol consumption and the risk of advanced geographic atrophy,” he explained. “From this, it is possible that for patients with AMD, reducing or limiting alcohol intake may be recommended in patients with developing atrophy. Should a patient ask what they can do to reduce their risk of advancing atrophy, I will counsel them to reduce or stop drinking alcohol.”

Eichenbaum agreed that both smoking and alcohol consumption should be mentioned in messaging intended to reduce risk factors for advanced AMD.

“Both smoking and alcohol are causal, modifiable risk factors for advanced AMD and can be reduced or eliminated with behavior change,” Eichenbaum said. “Results from this study underscore the importance of public health messaging, such as developing campaigns or conversations that show smoking or excessive alcohol intake can increase risk of vision loss, to encourage behavior changes.”

The study was funded by the NIHR Cambridge Biomedical Research Centre. The authors report financial relationships with Dunhill Medical Trust, Apellis, Bayer, Genentech/Roche, Heidelberg Engineering, IVERIC Bio, and Novartis in the form of grants and personal fees. They also report being supported by the BHF Research Accelerator Award, Biomedical Research Centre for Ophthalmology, Dunhill Medical Trust, National Institute for Health Research, the Royal Society, Sir Henry Dale Fellowship, University College London Hospitals Biomedical Research Centre, and the Wellcome Trust. Eichenbaum reports he has been an investigator, consultant, and speaker for Genentech (Susvimo) as well as a consultant and speaker for Apellis (pegcetacoplan). Wong and Krauss reports no relevant conflicts of interest.

JAMA Ophthalmol. Published online November 4, 2021. Full text

Jeff Craven is an independent journalist living in Wilmington, Delaware.

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