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

Abstract

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.

Figure.. Association of Genetically Predicted Modifiable Risk Factors With Advanced Age-Related Macular Degeneration (AMD) and its Subtypes

Odds ratios under the inverse-variance weighted mendelian randomization method are shown for a 1-SD increase in the logodds of ever having smoked regularly, 1-SD increase in the logodds of smoking cessation (former vs current smoking), 1-SD increase in the lifetime smoking index, 1-SD increase of the age at which an individual started smoking regularly, 1-SD increase of log-transformed alcoholic drinks per week, 1-SD increase in body mass index (calculated as 4.8 kg/m²); 10-mm Hg increase in systolic and diastolic pressure; 1-SD increase in the logodds of having type 2 diabetes; 1% increase in glycated hemoglobin (HbA_1c); 18.02-mg/dL (to convert to mmol/L, multiply by 0.0555) increase in fasting glucose; and 1 log-transformed (pmol/L) increase in fasting insulin.