Researchers at the Institute of Health Informatics, University College London (UCL), and the International AMD Genomics Consortium (IAMDGC), have reported a significant study on an association of key modifiable factors with age related macular degeneration, most specifically, smoking and alcohol. Genetic evidence has reported that “smoking initiation and lifetime smoking were associated with elevated risk of advanced AMD, [and] genetically predicted smoking cessation was associated with decreased risk of advanced AMD”. The UK study used a mendelian inheritance (“MR”) study design benefitting an increased statistical power and allow independent large GWAS summary data sets to be used for both exposures and outcomes. The report should highlight public messaging on clinical practice and health policy in order to minimize the health burden of advanced AMD.
The researchers have flagged that the prevalence of AMD is projected to increase by almost 50% in the next 20 years, partly due to an aging population, and these projections will significantly impact on health care systems around the world. Anti-VEFG treatments globally are expensive and have limited effectiveness, therefore public health approaches need to support prevention of advanced AMD, especially the management of modifiable risk factors – smoking, alcohol consumption, obesity, blood pressure, glycemic traits and others. Research on these modifiable risk factors on AMD are well publicised however, the current researchers at UCL argue that a number of the findings of the risk factors “are inconsistent and cannot be established as causal owing to limitations introduced by confounding and reverse causality”. RCTs (randomized clinical trials) are valuable but there may be a lag time between the risk factor(s) and clinical manifestations of disease, and in addition, a number of these types of study design are expensive, time-consuming and infeasible for types of exposure factors, such as smoking alcohol and others. In contrast, the use of a mendelian inheritance (MR) study design may provide a considerable benefit which uses measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in observational studies. This MR approach reduces bias, increases statistical explanatory power and may provide more cost-effective designs, compared to the traditional RCTs.
In their recent study using the MR approach, results reported that 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) and that 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=0.003). In addition, genetically predicted increased lifetime smoking was associated with increased risk of advanced AMD (odds ratio [OR], 1.32; 95%CI, 1.09-1.59; P = .004). Beyond smoking, the UK study also showed genetically predicted alcohol consumption associated with higher risk of geographic atrophy (GA)(OR per 1-SD increase of log-transformed alcoholic drinks per week, 2.70; 95%CI, 1.48-4.94; P=0.001). Interestingly, an editorial commentary on the research work also stated that, “they provided interesting genetic evidence that increased alcohol consumption does indeed have a causal association with GA risk. Alcohol is a widely known neurotoxin with the potential to cause oxidative stress on the brain and by extension, the retina”. These data shall expect further debate on these modifiable risk factors over the coming months and, in conclusion on their paper, the researchers stated that, “we found genetic evidence that increased alcohol consumption has a potential causal association with risk of GA. We also present genetic evidence that smoking initiation and lifetime smoking behaviour may be casually associated with risk of advanced AMD, while smoking cessation results in a lower risk of advanced AMD than persistent smoking. These associations were stronger for nAMD than for GA. To reduce the prevalence of advanced AMD in aging populations, public health campaigns and programs to support smoking abstention, smoking cessation, and reduced alcohol intake should incorporate the evidence that these activities can lead to blindness.”