Quantitative retinal traits and their association with cardiovascular disease and cardio-metabolic genetic variants in people with type 2 diabetes
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Date
27/07/2020Item status
Restricted AccessEmbargo end date
27/07/2021Author
Sandoval Garcia, Emmanuel
Metadata
Abstract
Introduction: Type 2 diabetes (T2D) is one of the most prevalent noncommunicable diseases in the world and its cardiovascular complications
present a huge socio-economic burden. In 2015, in the UK alone, 3.8 million
people have been diagnosed with T2D and cardiovascular disease accounts
for almost 1.7 million episodes throughout the country. Early diagnosis of
cardiovascular disease in people with T2D thus becomes critical.
The retina gives a unique opportunity to study the human microcirculation,
which can then offer insights into the pathophysiology of cardiovascular
disease. By using semi-automatic software, retinal images can provide
quantitative traits derived from the microvasculature. Previous research has
found that arteriolar and venular calibres are associated with cardiovascular
outcomes such as hypertension and stroke. Moreover, retinal vascular
tortuosity, a novel quantitative biomarker which measures the degree to
which blood vessels visible in the retina twist and turn, has been associated
with traditional cardiovascular risk factors in the general population. However,
this area needs to be further explored, especially in the population with T2D
and in prospective analyses.
Aims: To determine whether quantitative retinal traits such as vessel widths,
vessel tortuosity and multifractal dimensions are associated with the
subsequent development of major cardiovascular events such as ischaemic
heart disease and stroke in people with T2D. Also, to use a genome-wide
association approach to investigate if these quantitative retinal traits are
associated with cardio-metabolic genetic variants, which could help identify
novel biomarkers of cardiovascular disease for future research.
Methods: Analyses used the Edinburgh Type 2 Diabetes Study, a
prospective cohort of 1066 men and women with T2D aged 60-75 years at
baseline with eight years of follow-up for cardiovascular events. A total of
1028 retinal images from baseline were analysed using the semi-automatic
retinal software VAMPIRE (Vascular Assessment and Measurement Platform
for Images of the Retina). Cross-sectional analyses including ANOVA and
Chi-square test were performed along with prospective analysis using Cox
regression. Additionally, a genome-wide association study was performed to
explore the association of 12 quantitative retinal traits with cardio-metabolic
genetic variants. Imputation of variants included in the MetaboChip array was
used.
Results: In an unadjusted model, there was a significant association
between arteriolar tortuosity and incident stroke (Hazard Ratio (HR) 1.26;
95% CI 1.02, 1.57; p=0.03). This association remained significant after full
adjustment for age, sex, cardiovascular risk factors (body mass index, HbA1c,
total cholesterol, duration of diabetes, renal dysfunction) and previous
cardiovascular events (HR 1.26; 95% CI 1.01, 1.58; p=0.04). Multifractal
dimensions, a novel retinal biomarker which provides an insight into vascular
geometry, was inversely associated with incident stroke (unadjusted HR
0.73; 95% CI 0.57, 0.94; p=0.01). This association also remained significant
after adjustment for age, sex, cardiovascular risk factors and previous
cardiovascular event (HR 0.73; 95% CI 0.56, 0.94 p=0.02). Associations
between other retinal traits and stroke, and between traits and ischaemic
heart disease, tended not to be statistically significant, especially after
multivariable adjustment.
The genome-wide association analysis of arteriovenous ratio (ratio of
arteriolar to venular vessel width) revealed a genome wide significant locus,
rs73198094 (p = 5.27 x 10-8), an intergenic variant located between ASAH1
and LOC101929066 genes in chromosome 8. The ASAH1 gene has been
associated with atrial fibrillation. Although no further single nucleotide polymorphisms reached genome-wide significance, some additional
promising findings emerged. Analysis for retinal arteriolar width revealed a
genome-wide suggestive intronic locus, rs4944903 (p= 8.5x10-7), of the gene
POLD3 in chromosome 11. Identified loci for minimum arteriolar tortuosity,
rs7991332 (p=1.54 x 10-6) and rs2172724 (p=2.46 x10-6), are located in the
COL4A2 gene in chromosome 13 and another identified variant, rs7319323
(p=3.53 x 10-6), is located in an intron of the neighbouring COL4A1 gene.
Previous studies showed the relevance of these genes including an
association with stroke and intracerebral haemorrhage. These two genes
encode collagen protein chains, which are major components of the vascular
basement membrane. Another promising variant identified was the
rs34013641 locus, associated with minimum venular tortuosity (p=2.81 x 10-
6), which is located in the MYH11 gene in chromosome 2. This gene encodes
smooth muscle myosin heavy chain protein, which is highly expressed in
human arteries. Finally, identified loci for the multifractal dimension D0,
rs10963694 (p=8.53 x 10-7) and rs4977506 (p=4.95 x 10-6), located on the
ADAMTSL-1 gene in chromosome 9, are also strong candidates in the
pathophysiology of vascular disorders.
Conclusions: In older people with T2D, arteriolar tortuosity and multifractal
dimensions were significantly and independently associated with incident
stroke. GWAS findings for these and other quantitative retinal traits offer
insight into pathophysiological changes of the vasculature, which may result
in cardiovascular disease. These findings, in the context of further research,
could potentially be used to reveal biological mechanisms related to major
cardiovascular complications of T2D and to guide efforts on prevention and
early interventions.