Abstract
Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10−8. This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10−12 in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.
Highlights
The retinal microcirculation provides a unique window for noninvasive visualization of the human microcirculation in vivo
The Manhattan plot of minus log-transformed P-values for each single nucleotide polymorphism (SNP) against its physical position showed two loci reaching genome-wide significance, one on chromosome 5 and the other on chromosome 17 (Figure 1B). These included a cluster of 31 SNPs in high linkage disequilibrium on chromosome 5 between the genes TMEM161B and MEF2C and 2 SNPs on chromosome 17, with a number of genes spanning the region including SFRS2, MFSD11, JMJD6 and MXRA7
We identified one new locus on chromosome 5 which harbor variants convincingly associated with retinal arteriolar caliber in the meta-analysis of five cohorts of European ancestry
Summary
The retinal microcirculation provides a unique window for noninvasive visualization of the human microcirculation in vivo. Retinal vascular caliber has been shown to predict cardiovascular diseases [1,2,3,4]. Narrow retinal arterioles have been documented to be a risk factor for subsequent development of hypertension [5,6,7,8], diabetes mellitus [9,10,11], stroke [12], coronary heart disease [3,4,13] and cerebral small vessel disease [14,15,16]. Recent studies suggest that genetic factors may influence retinal vascular caliber [19,20,21,22]. The identification of genetic determinants of retinal vascular caliber may provide further insights into the relationship between retinal vessels and cardiovascular diseases. There was no genomewide significant association between any single nucleotide polymorphism (SNP) and retinal arteriolar caliber [23]
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