IOVS Hypertension
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

(Investigative Ophthalmology and Visual Science. 2004;45:3929-3933.)
© 2004 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.04-0462
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
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 (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lee, K. E.
Right arrow Articles by Knudtson, M. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lee, K. E.
Right arrow Articles by Knudtson, M. D.

Familial Aggregation of Retinal Vessel Caliber in the Beaver Dam Eye Study

Kristine E. Lee, Barbara E. K. Klein, Ronald Klein, and Michael D. Knudtson

From the Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, Wisconsin.


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
PURPOSE. To describe familial correlations of retinal vessel measurements.

METHODS. A standardized examination and interview was administered to a population-based cohort of adults aged 43–86 years. Blood pressure was measured, and family relationships, current smoking status, and photographs of the retina were obtained. Computer-assisted grading was done to determine central retinal arteriole (CRAE) and venule equivalents (CRVE), and the arteriole-to-venule ratio (AVR) was computed. Familial correlations were calculated using FCOR in the SAGE software package. Analysis was done on the right eye measures for 871 sibling, 341 parent–child, 1362 cousin, 554 avuncular, and 887 spousal pairs.

RESULTS. After adjustment for age, gender, mean arterial blood pressure, and current smoking status, the correlations (and 95% confidence interval) between siblings for the CRVE, CRAE, and AVR were 0.23 (0.16, 0.31), 0.20 (0.12, 0.28) and 0.13 (0.05, 0.20), respectively. Parent–child correlations were very similar, and the avuncular correlations were about half as great. The cousin correlations were about half the avuncular correlations. Spousal correlations of 0.03, 0.04, and 0.01 for CRVE, CRAE, and AVR, respectively, were not significantly different from 0.

CONCLUSIONS. Retinal vessel equivalents were more highly correlated between relatives than between unrelated individuals. The relative magnitudes of these correlations were likely the result of shared genes. Because the vessel measurements have been shown to be predictive of cardiovascular and other systemic diseases, understanding the determinants of these familial relationships could have important health benefits.

Retinal vessels are easily imaged and provide a window to microvascular systems elsewhere in the body. A relationship between retinal vessel characteristics and hypertension has been reported,1 2 3 4 5 but until recently has been difficult to assess accurately.6 7 8 Quantification of generalized arteriolar narrowing using computer-assisted grading has been developed9 10 and is highly reproducible.9 11 12 Data from a number of studies have shown a relationship of hypertension to a narrowing of retinal arterioles.13 14 15 16 Reduced arteriolar diameter is also predictive of incident hypertension,17 stroke,18 and cardiovascular disease mortality19 in men and women, and coronary heart disease in women,20 independent of blood pressure and other risk factors.

Risk of hypertension,21 22 23 24 cardiovascular disease and mortality,25 26 27 28 and stroke29 30 31 are affected by family history of these disorders. These are complex diseases with multiple genetic and environmental factors influencing their development and manifestations. The familial aggregation observed for cardiovascular disease may be due to concomitant aggregation of these risk factors.26 Because retinal vessel caliber is associated with cardiovascular disease and stroke, understanding the familial determinants of retinal vessel caliber may provide insights into the pathogenesis of these complex diseases. To our knowledge, there have been no studies to date that have evaluated the possibility of genetic influence for retinal vessel caliber.

A first step to investigate the possibility of genetic influences is to examine correlations among various family members. Patterns of correlations that exist between family members, but not between unrelated individuals, provide insight into the existence of common genetic influences. The purpose of these analyses was to examine these familial correlations in the Beaver Dam Eye Study population.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
The Beaver Dam Eye Study is a population-based cohort study of age-related eye diseases. Procedures have been previously reported.32 Eighty-three percent (4926) of persons who were 43 to 86 years and living in Beaver Dam, WI, participated in the baseline examination from 1988 to 1990. The study adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from each subject, and institutional human experimentation committee approval was granted. As part of this baseline examination, blood pressure was measured using a random-zero sphygmomanometer according to the Hypertension Detection and Follow-up Program protocol,33 and information was collected about family members, medical history, and lifestyle information, including smoking. After the examination, casual blood specimens were obtained from which blood glucose and glycosylated hemoglobin were assayed.34 35 Participants tended to be younger than nonparticipants.32

During the examination, both eyes were dilated and stereoscopic 30° color fundus photographs, centered on the optic disc, were taken (Diabetic Retinopathy Study Standard Field 1).36 The photographs for the right eyes were converted to digital images by a high-resolution scanner (Nikon LS2000; Nikon Inc., Tokyo, Japan). A grader identified the arterioles and venules, then used a semiautomated procedure to measure the vessel caliber (in microns) within a specified section of the photograph (zone B).9 Zone B was the portion of the photograph between circles with 0.5 and 1.0 disc diameters from the optic disc margin.

The measurements for the arterioles were combined into a central retinal artery equivalent (CRAE), while the measurements for the venules were combined into a central retinal vein equivalent (CRVE), using formulas described by Knudtson et al.10 The formulas were based on a modification of the Parr8 and Hubbard9 formulas where the six largest vessels were combined successively using the following formulas:


where W represents the width of the parent vessel, and w1 and w2 represent the width of each branching vessel.

Based on information collected at the baseline examination, such as names and residence of siblings, initial family relationships among participants were identified. The family relationships and extended pedigree information were confirmed during follow-up examinations and phone contact of at least one family member. To be a member of a pedigree, an individual needed to be eligible for participation in the Beaver Dam Eye Study and be related to another eligible person through a sibling, parent, child, first cousin, or avuncular (aunt/uncle, niece/nephew) relationship. There were a total of 2783 people in 602 families in the Beaver Dam Eye Study population. Of these 2783 persons, 427 were not examined, and 352 did not have measurable vessels. From the remaining 2004 persons, 160 no longer had a direct relative with data, which reduced the number of family groups from 602 to 441. Among these 441 families, 145 families (containing 332 individuals) were sibling groups only, 106 families (containing 247 individuals) were nuclear family units (at least one parent–child relationship), and the remaining 190 families (1265 individuals) were extended families with at least one avuncular or cousin relationship. Seventy-five percent of these extended families had at least one sibling group (two or more siblings with data), 43% had cousin but no avuncular relationships, 24% had avuncular relationships, and 33% had both cousin and avuncular relationships represented.

In addition to the people already in families, a number of people had a spouse in the study, but were not included in a family because they did not have a child that was part of the study. So that these people would be considered as spousal pairs in the SAGE program, we created children without data values, added 394 individuals who were married to someone already in a family, and 910 individuals as part of 455 spousal pairs.

Correlations between pairs of relatives were calculated using the FCOR procedure in the computer software program Statistical Analysis for Genetic Epidemiology (S.A.G.E.; Statistical Solutions, Ltd., Cork, Ireland) package.37 The procedure also produces standard errors, which were used to construct 95% confidence intervals around the correlations. A 95% confidence interval that does not include 0 indicates a significant correlation. SAS38 was used to adjust the central retinal equivalents and AVR for age, sex, mean arterial blood pressure, and smoking before analyses. Mean arterial blood pressure was calculated as two-thirds of the diastolic plus one-third of the systolic value. Hypertension was defined as systolic blood pressure ≥160 and/or diastolic blood pressure ≥95 and/or current use of antihypertensive medication. Diabetes was defined as a previous history of diabetes and/or hyperglycemia. Hyperglycemia was defined as glycosylated hemoglobin > 2 SDs above the mean for the appropriate age and sex group or a casual blood glucose level > 200 mg/dL (1.1 mM/L).


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
The distribution of the vessel measurements among those in families (including spouse pairs) was similar to the full population of Beaver Dam (Table 1) . Sibling correlations for the CRAE and CRVE were 0.20 and 0.23, respectively (Table 2) . The sibling correlation for the AVR was 0.13. For all vessel measurements, the parent–child correlations were similar to the sibling correlations. The avuncular correlations were considerably lower for all measures and significantly different from zero for CRVE only. The cousin correlations were lower than the avuncular correlations. The spousal correlations were not different from zero. In general, the correlations for the arterioles and venules were similar and were higher than the correlations for the AVR.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Distribution of Retinal Vessel Equivalents in the Beaver Dam Eye Study, 1988–1990

 

View this table:
[in this window]
[in a new window]
  		TABLE 2. Familial Correlations of Retinal Vessel Equivalents in the Beaver Dam Eye Study, 1988–1990

 
Heritability was estimated by doubling the parent–child correlations and reflects the proportion of the overall population variation that can be attributable to genetic differences. Heritability above 0.30 is generally considered as high. The heritability of the CRAE, CRVE, and the AVR were 0.48, 0.54, and 0.32, respectively. In considering gender specific pairs (data not shown), there were no significant differences between brother–brother, sister–sister, and brother–sister pair correlations. Similarly, there were no differences between the father–daughter, father–son, mother–daughter, and mother–son correlations.

To further evaluate the effect of diabetes, hypertension, and smoking status, we reran the analyses in restricted subgroups of the population (Table 3) . In analyses restricted to persons free of diabetes, correlations were very similar to those in the whole population. The same was true when analyses were restricted to persons that were not current smokers. When restricted to persons that were normotensive, the correlations generally increased a little, but the number of pairs dropped substantially, so the confidence limits were quite wide.


View this table:
[in this window]
[in a new window]
  		TABLE 3. Familial Correlations of Retinal Vessel Equivalents among Subsets of People in the Beaver Dam Eye Study, 1988–1990

 
Refractive error or other optical phenomena could influence the absolute arteriole and venule calibers. The analyses were rerun adjusting for refraction along with the other covariates and no change to the correlation pattern was found (data not shown). The effect of refractive error was also adjusted for by calculation of the AVR. Since a ratio of two measures typically has higher variance than each individual measure, we considered an alternative approach that does not increase variability. The arteriole caliber was regressed on the venule caliber and the residuals used as a measure of the relative increase/decrease in arteriole caliber. The sibling, parent–child, avuncular, cousin, and spousal correlations from this approach were 0.14, 0.19, 0.06, 0.03, and 0.01, respectively. The heritability was 0.38, which is slightly higher than the heritability estimated using the AVR.


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The observed correlation patterns were consistent with a genetic influence on retinal vascular diameters. The parent–child and sibling correlations were similar. The avuncular correlations were about half the parent–child correlations, and the cousin correlations were about half again. The spousal correlations were no different from zero. The pattern of correlation most consistent with a genetic component was for the CRVE. Although the correlations were smaller for AVR, the pattern for this characteristic was also consistent with a genetic component. The CRAE also showed some genetic influence, but may have some additional environmental influence as reflected by a higher sibling correlation than parent–child correlation and similar cousin and avuncular correlations. These same relationships held even in subgroups free of diabetes, among nonsmokers only and among normotensives.

The slightly different pattern of correlations for CRAE may, in part, have been due to blood pressure influences, which would affect arterioles more than venules.9 14 15 16 This did not appear to have affected the AVR correlations, however. We adjusted for blood pressure before analyses, but there still may have been some residual effect. Another possible explanation was that the arteriole measures were more variable than the venule measures. In a small study of the effect of pulse cycle on the arteriole and venule measurements, Knudtson et al. 39 found that the larger source of variation on these measures was between graders and between photographs. This was less true, however, for the larger venules. The confidence intervals for the correlations, however, were no wider for the CRAE than for the CRVE in this analysis, so the increased variability of the CRAE did not appear to explain the different correlation pattern.

Refractive error was related to the arteriole and venule equivalent, but not to the AVR.40 Since refraction aggregated in families,41 the higher correlations for CRAE and CRVE compared to the AVR may have reflected different refractive errors. However, adjustment for refractive error did not attenuate the CRAE and CRVE correlations. Another possibility for the lower correlations for AVR may have been the increased variability inherent in ratios. Regression of the arterioles on the venules, rather than considering the AVR, did not increase the correlations to the level of the CRAE and CRVE, however.

Recent epidemiologic data have suggested that generalized retinal arteriolar narrowing may precede the development of hypertension, cardiovascular disease, and stroke. Results in the Atherosclerosis Risk in Communities (ARIC) study,13 Cardiovascular Health Study (CHS),14 Blue Mountains Eye Study,15 and Beaver Dam Eye Study16 populations have showed that persons with hypertension have lower AVR, and that, independent of hypertension, AVR was predictive of stroke18 and coronary heart disease in women.20 While generalized retinal arteriolar narrowing was thought to represent structural changes resulting from persistent high blood pressure, recent data17 suggest that generalized retinal arteriolar narrowing may precede hypertension. The data in our present study suggest that, beyond structural changes of vessels due to hypertension, the narrowing of the retinal arterioles may be, in part, genetically determined.

One of the limitations of our analysis was our inability to examine environmental influences and any gene and environment interactions. Observed correlations indicated similarity between relatives. This similarity could be from environmental and/or genetic influences. We adjusted for known measured environmental influences such as blood pressure and smoking, and still had strong sibling correlations. Because of the large number of extended pedigrees, we were also able to examine the pattern of correlations among the types of relatives which suggested stronger genetic, rather than environmental, influences. First-degree relatives, such as siblings and parents and children, have 50% of their genes in common. Second-degree relatives, such as half-siblings, avuncular, and grandparental relationships, share 25% of their genes, and third-degree relatives, such as first cousins, share half that again (12.5%). For a trait determined by a gene, correlations for first-degree relatives would be similar, correlations for second-degree relatives would be half as high, and correlations for third-degree relatives would be half that again. An environmental influence would change these correlation patterns. For example, an environmental influence affecting generations differently would cause sibling and cousin correlations to be higher/lower than expected compared to the parent–child and avuncular relationships. This may have occurred for the CRAE measures, but the CRVE and AVR measures showed correlation patterns consistent with a more genetic model.

In conclusion, evidence was found for a genetic component to retinal vessel caliber. Additional analyses are required to determine mode of inheritance, but multiple genes are probably contributing to retinal vessel caliber. Genes may directly or indirectly (through blood pressure, for example) affect the vessel caliber. Understanding the genetic and possible environmental mechanisms influencing retinal vessel caliber in the eye may provide insights into the role of microvascular disease in the pathogenesis of cardiovascular disease, stroke, and hypertension.


   Footnotes
 
Supported by Grants EY06594 (RK, BEKK) and EY13438 (BEKK) from the National Institutes of Health. Some of the results of this article were obtained by using the program package S.A.G.E., which is supported by a United States Public Health Service Resource Grant (RR03655) from the National Center for Research Resources.

Submitted for publication April 21, 2004; revised June 18, 2004; accepted July 2, 2004.

Disclosure: K.E. Lee, None; B.E.K. Klein, None; R. Klein, None; M.D. Knudtson, 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: Kristine E. Lee, Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, 610 North Walnut Street, 4th Floor WARF, Madison, WI 53726-2336; klee{at}epi.ophth.wisc.edu.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Leishman R. The eye in general vascular disease: hypertension and arteriosclerosis. Br J Ophthalmol. 1957;41:641–701.
  2. Newell FW. Cardiovascular disease. Ophthalmology Principles and Concepts. 1969;401–409. Mosby St. Louis, MO.
  3. Klein R, Klein BE, Moss SE, Wang Q. Hypertension and retinopathy, arteriolar narrowing, and arteriovenous nicking in a population. Arch Ophthalmol. 1994;112:92–98.[Abstract]
  4. Klein R, Klein BE, Moss SE. The relation of systemic hypertension to changes in the retinal vasculature: the Beaver Dam Eye Study. Trans Am Ophthalmol Soc. 1997;95:329–348.[Medline][Order article via Infotrieve]
  5. Wong TY, Klein R, Klein BE, Tielsch JM, Hubbard L, Nieto FJ. Retinal microvascular abnormalities and their relationship with hypertension, cardiovascular disease, and mortality. Surv Ophthalmol. 2001;46:59–80.[CrossRef][ISI][Medline][Order article via Infotrieve]
  6. Kagan A, Aureli E, Dobree J. A note on signs in the fundus oculi and arterial hypertension: conventional assessment and significance. Bull World Health Organ. 1966;34:955–960.[ISI][Medline][Order article via Infotrieve]
  7. Kagan A, Aurell E, Tibblin G. Signs in the fundus oculi and arterial hypertension: unconventional assessment and significance. Bull World Health Organ. 1967;36:231–241.[ISI][Medline][Order article via Infotrieve]
  8. Parr JC, Spears GF. Mathematic relationships between the width of a retinal artery and the widths of its branches. Am J Ophthalmol. 1974;77:478–483.[ISI][Medline][Order article via Infotrieve]
  9. Hubbard LD, Brothers RJ, King WN, et al. Methods for evaluation of retinal microvascular abnormalities associated with hypertension/sclerosis in the Atherosclerosis Risk in Communities Study. Ophthalmology. 1999;106:2269–2280.[CrossRef][ISI][Medline][Order article via Infotrieve]
  10. Knudtson MD, Lee KE, Hubbard LD, Wong TY, Klein R, Klein BE. Revised formulas for summarizing retinal vessel diameters. Curr Eye Res. 2003;27:143–149.[CrossRef][ISI][Medline][Order article via Infotrieve]
  11. Couper DJ, Klein R, Hubbard LD, et al. Reliability of retinal photography in the assessment of retinal microvascular characteristics: the Atherosclerosis Risk in Communities Study. Am J Ophthalmol. 2002;133:78–88.[CrossRef][ISI][Medline][Order article via Infotrieve]
  12. Sherry LM, Wang JJ, Rochtchina E, et al. Reliability of computer-assisted retinal vessel measurement in a population. Clin Experiment Ophthalmol. 2002;30:179–182.[CrossRef][ISI][Medline][Order article via Infotrieve]
  13. Sharrett AR, Hubbard LD, Cooper LS, et al. Retinal arteriolar diameters and elevated blood pressure: the Atherosclerosis Risk in Communities Study. Am J Epidemiol. 1999;150:263–270.[Abstract/Free Full Text]
  14. Wong TY, Hubbard LD, Klein R, et al. Retinal microvascular abnormalities and blood pressure in older people: the Cardiovascular Health Study. Br J Ophthalmol. 2002;86:1007–1013.[Abstract/Free Full Text]
  15. Leung H, Wang JJ, Rochtchina E, et al. Relationships between age, blood pressure, and retinal vessel diameters in an older population. Invest Ophthalmol Vis Sci. 2003;44:2900–2904.[Abstract/Free Full Text]
  16. Wong TY, Klein R, Klein BE, Meuer SM, Hubbard LD. Retinal vessel diameters and their associations with age and blood pressure. Invest Ophthalmol Vis Sci. 2003;44:4644–4650.[Abstract/Free Full Text]
  17. Wong TY, Klein R, Sharrett AR, et al. Retinal arteriolar diameter and risk for hypertension. Ann Intern Med. 2004;140:248–255.[Abstract/Free Full Text]
  18. Wong TY, Klein R, Couper DJ, et al. Retinal microvascular abnormalities and incident stroke: the Atherosclerosis Risk in Communities Study. Lancet. 2001;358:1134–1140.[CrossRef][ISI][Medline][Order article via Infotrieve]
  19. Wong TY, Klein R, Nieto FJ, et al. Retinal microvascular abnormalities and 10-year cardiovascular mortality: a population-based case-control study. Ophthalmology. 2003;110:933–940.[CrossRef][ISI][Medline][Order article via Infotrieve]
  20. Wong TY, Klein R, Sharrett AR, et al. Retinal arteriolar narrowing and risk of coronary heart disease in men and women. The Atherosclerosis Risk in Communities Study. JAMA. 2002;287:1153–1159.[Abstract/Free Full Text]
  21. Stamler R, Stamler J, Riedlinger WF, Algera G, Roberts RH. Family (parental) history and prevalence of hypertension. Results of a nationwide screening program. JAMA. 1979;241:43–46.[Abstract]
  22. Havlik RJ, Garrison RJ, Feinleib M, Kannel WB, Castelli WP, McNamara PM. Blood pressure aggregation in families. Am J Epidemiol. 1979;110:304–312.[Abstract/Free Full Text]
  23. Harrap SB, Stebbing M, Hopper JL, Hoang HN, Giles GG. Familial patterns of covariation for cardiovascular risk factors in adults: The Victorian Family Heart Study. Am J Epidemiol. 2000;152:704–715.[Abstract/Free Full Text]
  24. Hong Y, de Faire U, Heller DA, McClearn GE, Pedersen N. Genetic and environmental influences on blood pressure in elderly twins. Hypertension. 1994;24:663–670.[Abstract/Free Full Text]
  25. Snowden CB, McNamara PM, Garrison RJ, Feinleib M, Kannel WB, Epstein FH. Predicting coronary heart disease in siblings–a multivariate assessment: the Framingham Heart Study. Am J Epidemiol. 1982;115:217–222.[Abstract/Free Full Text]
  26. Perkins KA. Family history of coronary heart disease: is it an independent risk factor?. Am J Epidemiol. 1986;124:182–194.[Free Full Text]
  27. Phillips AN, Shaper AG, Pocock SJ, Walker M. Parental death from heart disease and the risk of heart attack. Eur Heart J. 1988;9:243–251.[Abstract/Free Full Text]
  28. Zdravkovic S, Wienke A, Pedersen NL, Marenberg ME, Yashin AI, de Faire U. Heritability of death from coronary heart disease: a 36-year follow-up of 20966 Swedish twins. J Intern Med. 2002;252:247–254.[CrossRef][ISI][Medline][Order article via Infotrieve]
  29. Wannamethee SG, Shaper AG, Ebrahim S. History of parental death from stroke or heart trouble and the risk of stroke in middle-aged men. Stroke. 1996;27:1492–1498.[Abstract/Free Full Text]
  30. Jousilahti P, Rastenyte D, Tuomilehto J, Sarti C, Vartiainen E. Parental history of cardiovascular disease and risk of stroke. A prospective follow-up of 14371 middle-aged men and women in Finland. Stroke. 1997;28:1361–1366.[Abstract/Free Full Text]
  31. Flossmann E, Schulz UG, Rothwell PM. Systematic review of methods and results of studies of the genetic epidemiology of ischemic stroke. Stroke. 2004;35:212–227.[Abstract/Free Full Text]
  32. Klein R, Klein BE, Linton KL, De Mets DL. The Beaver Dam Eye Study: visual acuity. Ophthalmology. 1991;98:1310–1315.[ISI][Medline][Order article via Infotrieve]
  33. The hypertension detection and follow-up program: Hypertension detection and follow-up program cooperative group. Prev Med. 1976;5:207–215.[CrossRef][ISI][Medline][Order article via Infotrieve]
  34. Stein M. D-glucose determination with hexokinase and glucose-6-phosphate dehydrogenase. Bergmeyer HC eds. Methods of Enzymatic Analysis. 1963; Academic Press New York.
  35. Klenk DC, Hermanson GT, Krohn RI, et al. Determination of glycosylated hemoglobin by affinity chromatography: comparison with colorimetric and ion-exchange methods, and effects of common interferences. Clin Chem. 1982;28:2088–2094.[Abstract/Free Full Text]
  36. Diabetic Retinopathy Study Research Group. Report Number 7. A modification of the Airlie House classification of diabetic retinopathy. Invest Ophthalmol Vis Sci. 1981;21:210–226.[ISI][Medline][Order article via Infotrieve]
  37. Keen KJ, Elston RC. Robust asymptotic sampling theory for correlations in pedigrees. Stat Med. 2003;22:3229–3247.[CrossRef][ISI][Medline][Order article via Infotrieve]
  38. SAS Institute Inc. SAT/STAT User’s Guide, Version 8. 1999; SAS Institute Inc Cary, NC.
  39. Knudtson MD, Klein BE, Klein R, et al. Variation associated with measurement of retinal vessel diameters at different points in the pulse cycle. Br J Ophthalmol. 2004;88:57–61.[Abstract/Free Full Text]
  40. Wong TY, Knudtson MD, Klein R, Klein BE, Meuer SM, Hubbard LD. Computer-assisted measurement of retinal vessel diameters in the Beaver Dam Eye Study: methodology, correlation between eyes, and effect of refractive errors. Ophthalmology. 2004;111:1183–1190.[CrossRef][ISI][Medline][Order article via Infotrieve]
  41. Lee KE, Klein BE, Klein R, Fine JP. Aggregation of refractive error and 5-year changes in refractive error among families in the Beaver Dam Eye Study. Arch Ophthalmol. 2001;119:1679–1685.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 IOVSHome page
F. J. de Jong, M. K. Ikram, D. D. G. Despriet, A. G. Uitterlinden, A. Hofman, M. M. B. Breteler, and P. T. V. M. de Jong
Complement Factor H Polymorphism, Inflammatory Mediators, and Retinal Vessel Diameters: The Rotterdam Study
Invest. Ophthalmol. Vis. Sci., July 1, 2007; 48(7): 3014 - 3018.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
N. C. B. B. Taarnhoj, M. Larsen, B. Sander, K. O. Kyvik, L. Kessel, J. L. Hougaard, and T. I. A. Sorensen
Heritability of retinal vessel diameters and blood pressure: a twin study.
Invest. Ophthalmol. Vis. Sci., August 1, 2006; 47(8): 3539 - 3544.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
T. Y. Wong, F. M. A. Islam, R. Klein, B. E. K. Klein, M. F. Cotch, C. Castro, A. R. Sharrett, and E. Shahar
Retinal Vascular Caliber, Cardiovascular Risk Factors, and Inflammation: The Multi-Ethnic Study of Atherosclerosis (MESA).
Invest. Ophthalmol. Vis. Sci., June 1, 2006; 47(6): 2341 - 2350.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
R. Klein and B. E. K. Klein
The Epidemiology of Eye Disease: From Glycemia to Genetics The Friedenwald Lecture
Invest. Ophthalmol. Vis. Sci., May 1, 2006; 47(5): 1747 - 1753.
[Full Text] [PDF]

Home page
 HypertensionHome page
C. Xing, B. E.K. Klein, R. Klein, G. Jun, K. E. Lee, and S. K. Iyengar
Genome-Wide Linkage Study of Retinal Vessel Diameters in the Beaver Dam Eye Study
Hypertension, April 1, 2006; 47(4): 797 - 802.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
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 (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lee, K. E.
Right arrow Articles by Knudtson, M. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lee, K. E.
Right arrow Articles by Knudtson, M. D.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS