Retinal arteriolar and venular calibers have a high phenotypic correlation yet have distinct phenotypic associations with CVD risk factors. To further investigate the complex relationship between these two traits, we performed a bivariate heritability analysis to assess the relative influences of genetic and environmental factors on the two traits. For both the U.K. and Australian twin samples, we report that approximately three fourths of the covariance between arteriolar and venular caliber was attributable to additive genetic effects, which suggests that shared genetic factors influence both arteriolar and venular calibers, even though each trait is reproducibly associated with different CVD risk factors. The genetic correlation for arteriolar and venular calibers was 65% in the U.K. cohort and 74% in the Australian cohort, indicating that most of the total genetic variance for arteriolar and venular caliber is attributable to the shared genetic covariance between them. However, the two traits are also individually heritable with specific genetic factors to each. Retinal arteriolar and venular caliber heritability was approximately 60% and 70%, respectively, for the U.K. and Australian cohorts, suggesting that the variance of each of these traits is also individually influenced by genetic factors.10,26
Overall, these results suggest that where pleiotropic effects exist, studies may be expected to have more power to detect genetic variants that influence both arteriolar and venular diameters. This finding implies a shared etiology between the vessel traits that may assist in understanding the etiology of CVD. By way of illustration, in a linkage study of 1762 individuals from 602 families, Xing et al.7
reported both distinct and overlapping signals for the two vessel traits. Among the list of candidate genes produced based on the overlapping signals, Tie1
, and HGF
are all genes encoding proteins that are involved in endothelium-derived nitric oxide synthase–related pathways. These genes may, therefore, be important in elucidating the role of endothelial dysfunction and inflammation in retinal vessel caliber changes.
We have reported in this study a novel association between venular caliber with β-cell function (HOMA2-%B) and insulin sensitivity (HOMA2-%S). Genetic variants influencing only venular caliber, may therefore also be related to glucose homeostasis-related phenotypes. We may also expect to find specific genetic variants that influence only arteriolar caliber and possibly blood pressure. The literature demonstrates that arteriolar compared with venular caliber is more consistently associated with increased blood pressure.5,6
Our findings support this notion, where the effect size was approximately twice as large for arterioles compared with venules in the univariate linear regressions. However, in addition to this finding, we have reported an independent correlation between arteriolar caliber and blood pressure, but not for venular caliber and blood pressure. This confounding result may explain why the association between venular caliber and blood pressure is much less consistent in the literature. It also suggests a difference in the mechanism by which blood pressure contributes to, or is affected by, arteriolar compared to venular caliber that may be physiologically relevant.
The combined effects of measured associated risk factors accounted for little of the total covariance between these two traits (5%). To the extent that the tested risk factors did influence the relationship between these vessel traits, insulin sensitivity was the most important individual risk factor, explaining approximately 3% of the covariance between retinal arteriolar and venular caliber. Nevertheless, the effect size of insulin sensitivity on the relationship between retinal vessel calibers was not sufficiently large to facilitate a formal variance components test for the relative importance of genetic and environmental factors.
The twin subjects in this study were volunteers, but had been validated against a population-based sample of singletons. With the exception of weight, no significant differences were found between the two groups.27
In this study, both vessel calibers and baseline characteristics were similar to population-based studies.6,28–32
A common environmental effect was detected for the Australian cohort. The Australian cohort included children and was, on average, younger than the U.K. cohort. The difference suggests that familial common environmental influences may be more readily detected during childhood and adolescence, presumably due to a greater number of shared familial experiences at that age compared with adulthood. MZ and DZ means for HOMA2-%B were lower than the reference population, whereas HOMA2-%S was higher than the normal reference population from which they are calculated ().
We have demonstrated the importance of the relationship between retinal arteriolar and venular caliber in CVD research. We report that the high phenotypic correlation (r = 0.59) observed between retinal arteriolar and venular calibers is primarily genetically mediated but with little or no influence from established measures of CVD risk. The observed high genetic correlation between retinal vessel calibers may have implications for CVD research and will assist in the detection of causal functional variants. Further work is needed to understand mechanisms underlying the correlation between retinal vessel calibers with CVD. Identifying causal variants that influence retinal arteriolar and venular diameters both individually and pleiotropically will provide a useful starting point for this task.