IOVS The FASEB Journal
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

(Investigative Ophthalmology and Visual Science. 2005;46:3850-3854.)
© 2005 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.05-0177
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Supplementary Tables
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Taarnhøj, N. C. B. B.
Right arrow Articles by Larsen, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Taarnhøj, N. C. B. B.
Right arrow Articles by Larsen, M.

Heritability of Cilioretinal Arteries: A Twin Study

Nina C. B. B. Taarnhøj,1 Inger C. Munch,1 Kirsten O. Kyvik,2 Birgit Sander,1 Line Kessel,1 Thorkild I. A. Sørensen,3 Jesper L. Hougaard,1 and Michael Larsen1

1From the Department of Ophthalmology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark; the 2Danish Twin Registry, University of Southern Denmark, Odense, Denmark; and the 3Danish Epidemiology Science Center, Institute of Preventive Medicine, Copenhagen University Hospital, Copenhagen, Denmark.


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
PURPOSE. To determine whether the presence of one or more cilioretinal arteries, a distinct element of the pattern of fundus vessels, is genetically programmed, influenced by environmental factors, or the result of random mechanisms of vascular development.

METHODS. The fundi of 112 pairs of healthy monozygotic and dizygotic twins were examined using digital fundus photography and visual assessment of grayscale fundus photographs and color transparencies to detect the presence of cilioretinal arteries.

RESULTS. Cilioretinal arteries were present in 45.1% of participants and 28.8% of eyes. The majority of cilioretinal arteries, 88.2%, were located temporally, and 11.8% were located nasally. Monozygotic twins had higher concordance rates for cilioretinal arteries than dizygotic twins. Tetrachoric correlations and Mantel-Haenszel odds ratios demonstrated statistically significant evidence of a genetic effect underlying the presence of cilioretinal arteries (P < 0.01). Statistical analysis supported the hypothesis that additive genetic factors influenced the presence of cilioretinal arteries with a heritability of 71.4%, the remaining variance being attributable to nonshared or random environmental factors.

CONCLUSIONS. The presence or absence of one or more cilioretinal arteries in healthy persons is markedly influenced by genetic factors.

Some vascular diseases in humans appear to be linked to the pattern of distribution of retinal blood vessels. Knowing whether a variation in the distribution of retinal vessels is attributable to genetic or environmental factors may facilitate elucidation of the pathogenesis of disease in the human retina. Consequently, retinal vascular patterns and the mechanisms whereby they are laid out are of fundamental interest for clinical ophthalmology. In primates, including humans, the inner retina is supplied primarily or exclusively by the central retinal branch of the ophthalmic artery. Occasionally the central retinal artery is assisted by one or more cilioretinal arteries. These arteries are derived directly from the circle of Zinn, which is formed by small branches from the short posterior ciliary arteries, which also supply the choroid. It is of clinical relevance that a temporal cilioretinal artery supplying the fovea may spare the fovea in case of central retinal artery occlusion.1 Furthermore, patients with advanced high-tension open-angle glaucoma have better preservation of the central visual field and visual acuity in the presence of a temporal cilioretinal artery, presumably because it is associated with a better blood supply to the prelaminar portion of the optic disc.2 In addition, the vascular layout of the retina may influence the pattern of distribution of diabetic retinopathy and branch retinal vein occlusion.3

The prevalence of one or more cilioretinal arteries has previously been reported to be 49.5% of individuals and 32.1% of eyes, based on a review of stereo fundus photographs and fluorescein angiograms from 1000 healthy persons.4 Using direct ophthalmoscopy, another study found a cilioretinal artery prevalence of 26% of individuals in a population of 172 healthy persons.5 In the present study, we examined fundus photographs of 112 pairs of healthy twins (224 persons, 448 eyes) to assess the relative influence of genetic and environmental factors on the presence of cilioretinal arteries.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Subjects and Protocol
We examined 59 monozygotic (MZ) and 55 dizygotic (DZ) same-sex twin pairs, aged 20 to 46 years. The persons were recruited from a population-based register comprising twins born in Denmark between 1870 and 1996 (The Danish Twin Registry, University of Southern Denmark, Odense, Denmark).6 Only subjects in self-assessed good health were invited to participate. Exclusion criteria for twin pairs were unclear refractive media, manifest eye disease, or fundus photographs of unacceptable quality in either member of the pair. One MZ and one DZ twin pair did not want to have their fundus photographs taken. A total of 58 MZ and 54 DZ twin pairs were included in the present study, and all fundus photographs were of good quality. Zygosity was determined by means of genetic markers, using nine microsatellite and restriction fragment length polymorphism markers. The study was approved by the Medical Ethics Committee of Copenhagen County and followed the tenets of the Helsinki Declaration, including informed consent. All persons underwent an ophthalmological examination including refraction, visual acuity determination, slit-lamp biomicroscopy, and fundus photography after pupil dilation (using 10% phenylephrine hydrochloride and 1% tropicamide) and a clinical examination including an oral glucose tolerance test and blood pressure measurement. Digital grayscale fundus photographs (20° and 50°, 1024 x 1024 pixels) were recorded in red-free illumination (filter: Wratten 54; Eastman Kodak, Inc., Rochester, NY) using a retinal camera (model TRC-50X; Topcon Corp., Tokyo, Japan). The study design and photography protocol were as described by Kessel et al.7 and Hougaard et al.,8 who conducted studies on the heritability of lens aging (autofluorescence) and retinal nerve fiber layer thickness in the present twin population.7 8

Two independent observers evaluated the digital red-free grayscale fundus photographs to assess the presence, number, and location of cilioretinal arteries. A cilioretinal artery was defined as a retinal arterial branch noncontiguous with the central retinal artery, coursing through a near-180° hook as it emerges from underneath the retinal pigment epithelium at the rim of the optic disc. The location of a cilioretinal artery was classified as temporal or nasal with respect to the center of the optic disc. Discrepant classifications underwent independent arbitration by a third investigator, who decided the classification, using color transparencies when needed.

Statistics
The differences in sex, age, and blood pressure in persons with one or more cilioretinal arteries compared to persons with no cilioretinal arteries were assessed by {chi}2 tests and two-sided t-tests. We performed a test of proportions to compare the phenotype proportions for MZ and DZ twin pairs. Test significance was evaluated at the 5% level.

We compared MZ and DZ twin pairs by means of probandwise concordance rates, Mantel-Haenszel odds ratios, and tetrachoric correlations, as described elsewhere.9 10 11 Probandwise concordance rates estimate the risk of having a certain phenotype, given that one’s twin partner has this phenotype. The odds ratio estimates the increased risk of having a certain phenotype given that one’s twin partner has the phenotype, compared to the risk if one’s twin partner does not have the phenotype. The Mantel-Haenszel weighted odds ratio tests the difference between the odds ratios for MZ pairs and DZ pairs, using computer software (Epi Info; available at http://www.cdc.gov/epiinfo).12 A statistically significant Mantel-Haenszel test provides evidence for a genetic influence on the phenotype.

Tetrachoric correlations, as well as estimation of heritability and best-fitting etiological model by means of structural equation modeling, were carried out using computer software (MX; Michael C. Neale, Department of Psychiatry, Virginia Commonwealth University; available at www.vcu.edu/mx/).13 These calculations are based on a liability model, which assumes that the dichotomous distribution of cilioretinal arteries (present versus not present) reflects an underlying normally distributed liability of the population. When a threshold value of the liability is exceeded, an individual is affected, otherwise not. The threshold reflects the prevalence of the trait. These are standard assumptions in quantitative genetic analysis of categorical traits.14 The classical twin model is based on the assumption that MZ twin pairs share all their genes, while DZ twin pairs, like other siblings, share on average 50% of their genes, and that both MZ and DZ twin pairs share a common environment to the same extent. This means that a greater similarity among MZ than among DZ twin partners for a certain phenotype can be due only to genetic factors.15 Structural equation modeling quantifies sources of individual variation by decomposing the observed phenotypic variance into genetic and environmental variance. The genetic contribution can be further divided into an additive (A) genetic variance component (representing the influence of alleles at multiple loci acting in an additive manner) and a nonadditive (D) genetic variance component (representing intralocus interaction [dominance] and interlocus interaction [epistatis] of alleles). The environmental component is subdivided into a common (C) environmental variance component (representing environmental factors affecting both twins in a pair, a source of similarity) and a nonshared or random (E) environmental variance component (representing environmental factors not shared by twins, a source of dissimilarity). The latter component (E) also includes random factors and measurement errors.16 Heritability is defined as the proportion of the total phenotypic variance attributable to genetic variance. The components C and D cannot be estimated simultaneously in a twin study. We fitted the ACE and ADE models and the submodels AE, CE, and E to the data. The criteria for best-fitting model were based on Akaike’s information criterion (AIC), goodness-of-fit {chi}2 test, degrees of freedom, and P-value. The model with the lowest negative AIC reflects the best balance between goodness of fit and parsimony.

The phenotype any eye means that a person has one or more cilioretinal arteries in one eye or in two (both) eyes, meaning that a person is affected by any kind of cilioretinal artery. The phenotype both eyes denotes a person with one or more cilioretinal arteries in each eye. Any location denotes the presence of a cilioretinal artery at any location—nasal, temporal, or both.

In this study, ascertainment is independent of affection status in that all twin pairs were enrolled in the study and then examined to asses the prevalence of cilioretinal arteries. A proband is the affected part in a twin pair. In discordant twin pairs there is one proband, and in concordant twin pairs there are two probands.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
The per-person prevalence of cilioretinal arteries, i.e., the presence of one or more cilioretinal arteries in either of a subject’s two eyes, was 45.1% (95% confidence interval [CI]: 38.6%–51.6%), 101 participants in a study population of 224. In MZ twins, the per-person prevalence of one or more cilioretinal arteries was 44.8% (95% CI: 35.8%–53.9%), and among DZ twins it was 45.4% (95% CI: 36.0%–54.8%). The per-eye prevalence of cilioretinal arteries, i.e., the presence of one or more cilioretinal arteries in a given eye, was 28.8% (95% CI: 24.6%–33.0%; n = 448) for the entire study population, being 28.9% (95% CI: 23.0%–34.7%) in MZ twins and 28.7% (95% CI: 22.7%–34.7%) in DZ twins. Of the total number of cilioretinal arteries, 88.2% (95% CI: 82.8%–93.7%) were located temporally and 11.8% (95% CI: 6.3%–17.2%) were located nasally. The per-person prevalence of cilioretinal arteries was 49.0% (95% CI: 39.1%–58.9%) in men and 42.1% (95% CI: 33.4%–50.7%) in women. There was no impact of sex ({chi}2, P = 0.30), age (t-test, P = 0.29), or mean arterial blood pressure (P = 0.76) on the presence of cilioretinal arteries. Clinical characteristics and cilioretinal phenotypes of the participants are described in Table 1 ; there was no significant difference in the proportions (prevalence) of phenotypes between MZ and DZ twins.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Clinical Characteristics and Cilioretinal Artery Phenotype of Study Participants

 
Probandwise concordance rates for cilioretinal artery phenotypes were consistently higher in MZ twins than in DZ twins for all phenotypes, but the difference did not reach statistical significance for any single phenotype (Table 2) .


View this table:
[in this window]
[in a new window]
  		TABLE 2. Probandwise Concordance Rates for the Presence and Location of Cilioretinal Arteries in Study Participants*

 
Odds ratios were significantly higher for MZ twins than for DZ twins for all phenotypes when using the Mantel-Haenszel weighted odds ratio test for zygosity (Table 3) . The odds ratio results agreed with the tetrachoric correlations, where there was a significantly higher correlation in MZ than in DZ twins for all phenotypes (Table 3) .


View this table:
[in this window]
[in a new window]
  		TABLE 3. Tetrachoric Correlations and Zygosity-Specific Mantel-Haenszel Odds Ratios for the Cilioretinal Artery Phenotypes

 
Tetrachoric correlations and structural equation modeling of the phenotypes both eyes (Table 4) , one eye only, any eye, right eye, right eye only, left eye, and left eye only (Supplementary Tables, http://www.iovs.org/cgi/content/full/46/10/3850/DC1) support that an AE model comprising additive genetic effects and random environmental effects was the best-fitting liability model and most aptly describes all phenotypes. In both eyes, one eye only, any eye, left eye only, and right eye, 71% to 74% of the phenotypic variance was due to additive genetic factors. In right eye only, the heritability was 84%, and in left eye it was 55%. This means that factors identified as influencing the presence or absence of cilioretinal arteries include additive genetic factors (heritability) and nonshared or random environmental factors unique to the individual. By convention, the latter includes random variation. We found sex to be insignificant when included in the heritability analysis.


View this table:
[in this window]
[in a new window]
  		TABLE 4. Result of Structural Equation Modeling for Phenotype Both Eyes, Any Location

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The present study demonstrated that within a population of 224 twins, the presence or absence of one or more cilioretinal arteries was mainly influenced by genetic factors in all phenotypes. The average heritability of all phenotypes was 71.4%. The relative influence of specific genes versus environmental or random processes was not assessed, because this requires candidate genetic or environmental factors. For cilioretinal arteries, nongenetic effects may include the effects of nonshared intrauterine environment as well as random mechanisms of morphogenesis and measurement errors. The patterns of distribution of retinal vessels are laid out completely at full-term birth.

Some support for a potential impact of preterm health on retinal vessel layout has been found in the observation that preterm birth with a median birth weight of 1250 g is associated with a greater length index for arterioles and fewer numbers of branching points compared with those of children born full term. These vascular abnormalities persist into adulthood.17 The development of retinal vessels is driven by relative anoxia of the immature avascular retina. The ontogeny of the intraocular blood supply involves programmed elimination of vessels, most notably the hyaloid artery. During these processes of vessel formation, reorganization, and disappearance, cilioretinal arteries may develop, hypothetically, as an enlargement of the anastomoses of the posterior ciliary arteries with small branches from the hyaloid artery on the disc.18 This theory was supported by a small study of 15 children with birth weights ≤ 2500 g whose prevalence of cilioretinal arteries, 53.3% ({chi}2 = 5,7; 0,01 < P < 0,05), was greater than that of 370 children with normal birth weights (27.3%).19 Despite the risk of uneven intrauterine nutrition in MZ twins, because of their shared placenta and the risk of anastomoses and transfusion syndrome, this did not have any detectable influence on the prevalence of cilioretinal arteries in this study, as seen by the equal prevalence of cilioretinal arteries in MZ twins and DZ twins. We did not have information about birth weights in the study population, but twins are normally born three to four weeks before term and are on average 1000 g lighter than singletons. This did not appear to have any detectable influence on the development of cilioretinal arteries in this study, since the prevalence of cilioretinal arteries was found to be comparable to that in a previous study of a population with few or no twins.4 This could be because the twins were healthy and perhaps had almost normal birth weights.

In a phylogenetic perspective there is a systematic variation between species, meaning that the layout of the retinal vessels must be governed by genetics. We found a consistent trend toward MZ twin pairs having higher probandwise concordance rates, odds ratios, and tetrachoric correlations. Insofar as vascular diseases of the posterior pole of the eye are influenced by the layout of the vascular bed, the implication is that there must be an element of congenital hereditary disposition to such disease. All confidence intervals for tetrachoric correlations were wide, suggesting that a larger study may have detected an even stronger genetic effect in all phenotypes. A twin study of the present size does not have enough power to detect a common environmental variance component (C) or a nonadditive genetic variance component (D), which is indicated also by the wide 95% CI of A and E.

In summary, structural equation modeling demonstrated a marked additive genetic effect (heritability of 71.4%) and a random environmental effect (28.6%) on the layout of the arterial blood supply of the retina, as represented by the presence or absence of cilioretinal arteries in a population of healthy twins. Understanding the genetic and environmental influence on the architecture of retinal vessels may facilitate elucidation of the pathogenesis of vascular disease in the human retina.


   Footnotes
 
Supported by the Danish Eye Health Society; The Danish Association of the Blind; Center for Biomedical Optics and New Laser Systems (BIOP) Graduate School; The Danish Research Agency; and a Research Career Award (Grant 8–2002-130) from the Juvenile Diabetes Research Foundation (ML).

Submitted for publication February 10, 2005; revised May 27, 2005; accepted August 19, 2005.

Disclosure: N.C.B.B. Taarnhøj, None; I.C. Munch, None; K.O. Kyvik, None; B. Sander, None; L. Kessel, None; T.I.A. Sørensen, None; J.L. Hougaard, None; M. Larsen, None

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Nina C. B. B. Taarnhøj, Department of Ophthalmology, Herlev Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark; ninat{at}dadlnet.dk.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Brown GC, Shields JA. Cilioretinal arteries and retinal arterial occlusion. Arch Ophthalmol. 1979;97:84–92.[Abstract]
  2. Lee SS, Schwartz B. Role of the temporal cilioretinal artery in retaining central visual field in open-angle glaucoma. Ophthalmology. 1992;99:696–699.[ISI][Medline][Order article via Infotrieve]
  3. Christoffersen N, Larsen M. Unilateral diabetic macular oedema secondary to central retinal vein congestion. Acta Ophthalmol Scand. 2004;82:591–595.[Medline][Order article via Infotrieve]
  4. Justice J, Lehmann RP. Cilioretinal arteries. A study based on review of stereo fundus photographs and fluorescein angiographic findings. Arch Ophthalmol.. 1976;94:1355–1358.[Abstract]
  5. Lorentzen SE. Incidence of cilioretinal arteries. Acta Ophthalmol (Copenh). 1970;48:518–524.
  6. Kyvik KO, Christensen K, Skytthe A, Harvald B, Holm NV. The Danish Twin Register. Dan Med Bull. 1996;43:467–470.[ISI][Medline][Order article via Infotrieve]
  7. Kessel L, Hougaard JL, Sander B, Kyvik KO, Sørensen TIA, Larsen M. Lens ageing as an indicator of tissue damage associated with smoking and non-enzymatic glycation—a twin study. Diabetologia. 2002;45:1457–1462.[CrossRef][ISI][Medline][Order article via Infotrieve]
  8. Hougaard JL, Kessel L, Sørensen TIA, Kyvik KO, Larsen M. Evaluation of heredity as a determinant of retinal nerve fiber layer thickness as measured by optical coherence tomography. Invest Ophthalmol Vis Sci. 2003;44:3011–3016.[Abstract/Free Full Text]
  9. Hopper JL. Twin concordance. Armitage P Colton T eds. Encyclopedia of Biostatistics. 1998;6:4626–4629. Wiley London.
  10. Kyvik KO, Green A, Beck-Nielsen H. Concordance rates of insulin dependent diabetes mellitus: a population based study of young Danish twins. BMJ. 1995;311:913–917.[Abstract/Free Full Text]
  11. Ramakrishnan V, Goldberg J, Henderson WG, et al. Elementary methods for the analysis of dichotomous outcomes in unselected samples of twins. Genet Epidemiol. 1992;9:273–287.[Medline][Order article via Infotrieve]
  12. Epi Info Version 3.3 [computer program]. 2004; Division of Public Health Surveillance and Informatics, Epidemiology Program Office, U.S. Department of Health and Human Services Available at: http://www.cdc.gov/epiinfo. Accessed June 2005
  13. Neale MC, Boker SM, Xle G, Maes HH. MX Statistical Modeling. 2002; 6th ed. Richmond, VA.
  14. Falconer DS, Mackay TFC. Introduction to Quantitative Genetics. 1996; 4th ed. Longman Group London.
  15. Day INM, Humphries SE. Genetics of Common Diseases. 1997;19–32. BIOS Scientific Publishers Oxford, UK.
  16. Plomin R, DeFries JC, McClearn GE, Rutter M. Behavioral Genetics. 1997; 3rd ed. 305–310. WH Freeman New York.
  17. Kistner A, Jacobson L, Jacobson SH, Svensson E, Hellstrom A. Low gestational age associated with abnormal retinal vascularization and increased blood pressure in adult women. Pediatr Res. 2002;51:675–680.[CrossRef][ISI][Medline][Order article via Infotrieve]
  18. Hayreh SS. The cilio-retinal arteries. Br J Ophthalmol. 1963;47:71–89.
  19. Erkkila H, Laatikainen L. Characteristics of optic disc in healthy school children. Acta Ophthalmol (Copenh). 1979;57:914–921.



This article has been cited by other articles:


Home page
 Br. J. Ophthalmol.Home page
N C B B Taarnhoj, I C Munch, B Sander, L Kessel, J L Hougaard, K Kyvik, T I A Sorensen, and M Larsen
Straight versus tortuous retinal arteries in relation to blood pressure and genetics
Br. J. Ophthalmol., August 1, 2008; 92(8): 1055 - 1060.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
A. W. Hewitt, J. P. Poulsen, W. L. M. Alward, S. L. Bennett, W. M. Budde, R. L. Cooper, J. E. Craig, J. H. Fingert, P. J. Foster, D. F. Garway-Heath, et al.
Heritable Features of the Optic Disc: A Novel Twin Method for Determining Genetic Significance
Invest. Ophthalmol. Vis. Sci., June 1, 2007; 48(6): 2469 - 2475.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
I. C. Munch, B. Sander, L. Kessel, J. L. Hougaard, N. C. B. B. Taarnhoj, T. I. A. Sorensen, K. O. Kyvik, and M. Larsen
Heredity of Small Hard Drusen in Twins Aged 20-46 Years
Invest. Ophthalmol. Vis. Sci., February 1, 2007; 48(2): 833 - 838.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Supplementary Tables
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Taarnhøj, N. C. B. B.
Right arrow Articles by Larsen, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Taarnhøj, N. C. B. B.
Right arrow Articles by Larsen, M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS