Genetic loci for retinal arteriolar microcirculation

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.

Figure 1. A) QQ-plot of –log₁₀(observed P-values) against –log₁₀(expected P-values) and B) Manhattan plot of –log₁₀ transformed P-values of retinal arteriolar caliber against their physical position.

Figure 2. Regional association plots at the two loci that exhibit genome-wide significance at discovery stage and one locus that showed suggestive evidence of association at P-value <10⁻⁶.

A) Chromosome 5 near TMEM161B and MEF2C, B) Chromosome 17 on SFRS2 and C) Chromosome 13 on FLT. In each regional plot, the index SNP is represented by a purple circle for the meta-analysis of the five discovery studies and a purple diamond for meta-analysis of discovery and replication studies. The remaining SNPs are colour coded according to pairwise linkage disequilibrium (LD) with the index SNP on a scale of r² from 0 (blue) to 1 (red). Estimated recombination rates reflect the local LD structure in the 500 kb buffer around the index SNP and plotted based on values on Hapmap II CEU. Data for gene annotations are obtained from the RefSeq track of the UCSC Gene Browser (See LocusZoom http://csg.sph.umich.edu/locuszoom/ more details).

Figure 3. Regional association plots for retinal arteriolar caliber conditioned on retinal venular caliber for A) Chromosome 5 near TMEM161B and MEF2C and B) Chromosome 17 on SFRS2.

All regional plots are centered on the index SNPs, with a 500 kb buffer on both sides of the index SNP.

Figure 4. Regional association plot at chromosome 5 locus using ARIC data, showing P-values for SNPs for retinal arteriolar caliber (CRAE), retinal venular caliber (CRVE), retinal arteriolar caliber conditioned on CRAE index SNP rs2194025 and retinal arteriolar caliber conditioned on CRVE implicated SNP rs17421627.