Decreased retinal vascular complexity is an early biomarker of MI supported by a shared genetic control

Abstract

There is increasing evidence that the complexity of the retinal vasculature (measured as fractal dimension, Df) might offer earlier insights into the progression of coronary artery disease (CAD) before traditional biomarkers can be detected. This association could be partly explained by a common genetic basis; however, the genetic component of Df is poorly understood. We present here a genome-wide association study (GWAS) aimed to elucidate the genetic component of Df and to analyse its relationship with CAD. To this end, we obtained Df from retinal fundus images and genotyping information from ∼38,000 white-British participants in the UK Biobank. We discovered 9 loci associated with Df, previously reported in pigmentation, retinal width and tortuosity, hypertension, and CAD studies. Significant negative genetic correlation estimates endorse the inverse relationship between Df and CAD, and between Df and myocardial infarction (MI), one of CAD fatal outcomes. This strong association motivated us to developing a MI predictive model combining clinical information, Df, a CAD polygenic risk score and using a random forest algorithm. Internal cross validation evidenced a considerable improvement in the area under the curve (AUC) of our predictive model (AUC=0.770) when comparing with an established risk model, SCORE, (AUC=0.719). Our findings shed new light on the genetic basis of Df, unveiling a common control with CAD, and highlights the benefits of its application in individualised MI risk prediction.

Retinal Fractal Dimension Is a Potential Biomarker for Systemic Health—Evidence From a Mixed-Age, Primary-Care Population

“…We adjusted for image quality due to its strong association with FD, which is commonly done in the literature. 4 The underlying assumption is that image quality issues affect the computation of FD itself and thus must be adjusted for to recover retinal vascular complexity. This notion initially appears convincing, but upon reflection is potentially problematic.…”

“…The proportion of our images rated as poor or very poor (31.5%) is comparable to the 20% to 45% of images that are typically excluded in the UK Biobank. 2 , 4 , 5 Examples for each of the four quality levels are shown in Supplementary Figure S1 .…”

“…Retinal color fundus imaging rapidly and non-invasively captures a detailed picture of the retinal vasculature while being widely available and low cost. Thus, retinal image–derived traits are being investigated as biomarkers for systemic health, a field also known as “oculomics.” 1 – 3 Fractal dimension (FD), a retinal trait relating to the complexity of the retinal vasculature, has emerged as a particularly promising candidate that is associated with cardiovascular 4 , 5 and neurovascular 6 , 7 disease. FD is calculated from vessel segmentations and captures how complex the branching structure of the blood vessels is.…”

“…A lower FD indicates a less complex vasculature, which might be an indicator for poorer retinal vessel health. This in turn could indicate poorer vessel health systemically, and, indeed, individuals with lower FD are at higher risk of cardiovascular disease, 4 for example. Thus, retinal FD derived from color fundus images could serve as a potential biomarker for systemic health in research and clinical practice that could identify individuals at high risk who could then be examined in more detail.…”

“…Previous work looking at retinal vascular traits and systemic health is also limited by the exclusion of large amounts of data due to image quality, on the order of 20% to 45% even for datasets such as the UK Biobank that are specifically collected for research. 2 , 4 , 5 Even rejecting one in five images would drastically limit the utility of FD in clinical practice. Furthermore, older, less healthy, male, and non-White subjects are at higher risk of being excluded due to image quality.…”