Purpose

1. Heritability of Retinal Vessel Tortuosity - A Twin StudyN.C.B.B. Taarnhoj1, I.C. Munch1, B. Sander1, L. Kessel1, J.L. Hougaard1, T.I.A. Sørensen2, M. Larsen11) Department of Ophthalmology, Glostrup Hospital, University of Copenhagen, Denmark2) Danish Epidemiology Science Center, Institute of Preventive Medicine, University of Copenhagen, Denmark ARVO2007 4161/B323 Purpose To assess the relative contributions of genetic and environmental effects on retinal vessel tortuosity in a population of young healthy twins. Background Understanding the genetic and environmental influence on the layout of retinal blood vessels may facilitate elucidation of the pathogenesis of disease in the human retina. In the present study, we have examined the variation in retinal vessel tortuosity to assess the relation to various systemic variables and the effect of genetics and environment. Methods A cross-sectional study of 57 monozygotic (MZ) and 52 dizygotic (DZ) same-sex healthy twin pairs, aged 20 to 46 y, recruited from The Danish Twin Registry. Tortuosity was assessed by visual grading of digital fundus photographs (60 degree, 1024x1024) of right and left eyes by two independent graders. Retinal arteries were graded on a scale from 0 to 2 (figure 1-3), in order of increasing tortuosity. The classical twin model is based on the assumption that MZ twins have identical genotypes, for which reason all observed differences between the two twins in a pair are attributable to environmental factors. DZ twins, however, share on average 50% of their genes. The extent to which MZ twins are more alike than DZ twins is therefore assumed to reflect a genetic influence on the phenotype in question. Polychoric correlations, conditional probabilities and heritability was calculated by use of the MX software package (Neale M.C.). The genetic contribution (heritability) can be divided into an additive (A) genetic variance component and a non-additive (D) genetic variance component. The environmental component can be subdivided into a common (C) environmental variance component and an unshared (E) environmental variance component (includes random factors and measurement errors). Covariates were included in the model by letting them have a linear effect on the thresholds in the model. Results The relative proportion of the tortuosity classes were 36.2%, 50.5% and 13.3%, respectively, for grade 0, 1 and 2. The intra- and intergrader weighted kappa statistics were 0.79 (CI95 0.73, 0.86) and 0.68 (CI95 0.60, 0.77) (n=218), respectively, indicating good agreement. For concordant pairs, the conditional probabilities were higher for MZ than for DZ twins, whereas for discordant pairs, the conditional probabilities were smaller for MZ than for DZ twins, indicating a genetic effect on this phenotype (table 1). When correcting for age, gender and mean arterial blood pressure, the polychoric correlations were 0.80 (CI95 0.60, 0.92) for MZ twins and 0.44 (CI95 0.09, 0.69) for DZ twins (p = 0.37), and the heritability can be calculated as (0.80-0.44)x2x100% = 72%. When correcting for age, gender and body mass index (BMI), the polychoric correlations were 0.81 (CI95 0.61, 0.92) for MZ twins and 0.39 (CI95 0.03, 0.66) for DZ twins (p= 0.389), yielding a heritability of 84%. When correcting for age and gender in the ACE and ADE models, additive genetic factors explained 82% (CI95 64%, 92%) of the variation in tortuosity and unshared environmental factors explained 18% (CI95 8%, 36%). When correcting for age, gender and mean arterial blood pressure, the heritability of tortuosity was 68% (CI95 6%, 92%), whereas the effect of common environment was 12% (CI95 0%, 64%) and that of unshared environment was 20% (CI95 8%, 40%). Mean arterial blood pressure had an estimated regression coefficient of -0.018 (CI95 -0.035, -0.0008). When correcting for age, gender and BMI in the ACE model, the heritability was 79% (CI95 16%, 92%), common environment was 2% (CI95 0%, 56%) and unshared environment was 19% (CI95 8%, 39%). BMI had an estimated regression coefficient of -0.06 (CI95 -0.11, -0.02). Consequently, mean arterial blood pressure and body mass index were both found to have a significant effect on tortuosity. Additionally, these two factors, which are partly heritable, affect the apparent heritability of retinal arteriolar tortuosity. Age, gender, fasting blood glucose, LDL, HDL, triglycerides, total cholesterol, smoking (pack years), systolic blood pressure, diastolic blood pressure, central retinal artery equivalent, central retinal vein equivalent and artery-venous-ratio did not significantly influence the heritability. Conclusions The present study demonstrated that heritability is the overwhelming determinant of the degree of tortuosity of retinal arteries in healthy adults. Additionally, retinal vessel tortuosity was found to increase with decreasing mean arterial blood pressure and body-mass index. In summary, an initial estimation of conditional probabilities indicated that genetics affects the variation in retinal vessel tortuosity in the study population of healthy same-sex monozygotic and dizygotic twins. This was confirmed by subsequent analysis of polychoric correlations. Finally structural equation modeling was used to assess the relative contributions of additive genetic effects (A = 68%), common environmental effects (C = 12%) and unshared environmental effects (E = 20%), when including age, gender and mean arterial blood pressure as covariates in the model. Our results show that a single-session assessment of retinal vessel tortuosity cannot be used to assess the impact of blood pressure, but it does not rule out that the effect of ocular or systemic disease can be measured by comparative analysis of prospective fundus photographic data. Table 1. Conditional probabilities of retinal arterial tortuosity for MZ (black) and DZ (blue) twins Figure 1. Grade 0 Figure 2. Grade 1 Figure 3. Grade 2 Support:, The Juvenile Diabetes Research Foundation (8-2002-130), The Danish Medical Research Foundation, The Danish Eye Research Foundation, The Danish Eye Health Society, BIOP Graduate School, Diabetesforeningen and Norges Blindeforbund E mail: ninat@dadlnet.dk