Acta Physiologica Hungarica, Volume 101 (3), pp. 309–320 (2014) DOI: 10.1556/APhysiol.101.2014.3.6
Genetic effects on refraction and correlation with hemodynamic variables: A twin study GZs Toth1*, AD Tarnoki2*, DL Tarnoki2*, A Racz1, Z Szekelyhidi1,3, L Littvay4, K Karlinger2, A Lannert5, AA Molnar6,7, Zs Garami8, V Berczi2, I Suveges1, J Nemeth1 1 Department of Ophthalmology, Semmelweis University, Budapest, Hungary Department of Radiology and Oncotherapy, Semmelweis University, Budapest, Hungary 3 Department of Ophthalmology, Szent György Hospital, Székesfehérvár, Hungary 4 Central European University, Budapest, Hungary 5 Semmelweis University, School of Pharmacy, Budapest, Hungary 6 Research Group for Inflammation Biology and Immunogenomics of Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary 7 Department of Cardiology, Military Hospital, Budapest, Hungary 8 The Methodist Hospital, DeBakey Heart and Vascular Center, Houston, TX, USA 2
Received: March 25, 2013 Accepted after revision: January 1, 2014 Spherical equivalent (SE) has not been linked to increased cardiovascular morbidity. Methods: 132 Hungarian twins (age 43.3±16.9 years) underwent refraction measurements (Huvitz MRK-3100 Premium AutoRefractokeratometer) and oscillometry (TensioMed Arteriograph). Results: Heritability analysis indicated major role for genetic components in the presence of right and left SE (82.7%, 95%CI, 62.9 to 93.7%, and 89.3%, 95%CI, 72.8 to 96.6%), while unshared environmental effects accounted for 17% (95%CI, 6.3% to 37%), and 11% (95%CI, 3.4% to 26.7%) of variations adjusted for age and sex. Bilateral SE showed weak age-dependent correlations with augmentation index (AIx), aortic pulse wave velocity (r ranging between 0.218 and 0.389, all p < 0.01), aortic systolic blood pressure and pulse pressure (r between 0.188 and 0.289, p < 0.05). Conclusions: These findings support heritability of spherical equivalent, which does not coexist with altered hemodynamics (e.g. accelerated arterial aging). Accordingly, SE and the investigated hemodynamic parameters seem neither phenotypically nor genetically associated. Keywords: arterial stiffness, augmentation index, genetics, heritability, refraction
The first “twin study” was published in 1922 by Walter Jablonski, the first ophthalmologist who used both monozygotic and dizygotic twins to examine the factors that determine the development of the refraction of the eye. He declared “the smaller differences are seen in the majority of monozygotic cases, while larger differences occur in dizygotic cases” (23). Since then, numerous articles discussed the role of inheritance, the genetic predisposition and the gene-environment interactions taking part in the formation of the refractive characteristics of the eye confirming that genetic factors account for 77–94% of the genetic variance (10, 25, 26, 43). However, a similar study in a wide-age range sample is still needed. In addition, despite heritability of refraction was thoroughly investigated in the studies
*These authors contributed equally to this work. Corresponding author: Adam Domonkos Tarnoki, MD, PhD Department of Radiology and Oncotherapy, Semmelweis University Üllői út 78/a, H-1082 Budapest, Hungary Phone: +36-30-6401183; Fax: +36-1-2780368; E-mail: [email protected] 0231–424X/$ 20.00 © 2014 Akadémiai Kiadó, Budapest
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conducted in Western European or American samples, it is a matter of a new investigation whether the high heritability estimates decline in an Eastern European sample where the incidence of cardiovascular diseases is still high. We hypothesized that the heritability of the spheric equivalent may decrease due to epigenetic factors in our Hungarian twin cohort. In the era of increasing cardiovascular morbidity and mortality, there is an increasing interest how cardiovascular diseases influence the refraction status of the eye. In our previous work, we investigated the genetic relationship of novel hemodynamic parameters with lung function, exhaled nitric oxide and body mass index which explored phenotypic and genotypic links between the investigated phenotypes (40, 41, 42). Therefore, literature still lacks a scientific explanation between novel cardiovascular and ophthalmologic parameters. A few inconsistent studies investigated the relationship between the refractive state of the eye with “traditional” cardiovascular phenotypes, such as blood pressure and arteriolar caliber. Essential arterial hypertension was strongly associated with hypermetropia in a Turkish study (15), however, another study showed no relationship (8). Several studies have shown an association between narrowing of retinal arteriolar caliber and refractive error (either spherical equivalent or axial length) in children and adults suggesting that myopia might have an effect on retinal microvasculature (20, 22). Although new risk factors have been determined in 2007 Guidelines for the Management of Arterial Hypertension including increased arterial stiffness (27), the association of this novel hemodynamic parameter and refraction of the eye has never been investigated. Endothelial function is a marker of increased cardiovascular risk (16). Arterial stiffness, characterized by pulse wave velocity (PWV) and augmentation index (AIx), can be estimated non-invasively and has an independent predictive value for cardiovascular events (18). In recent studies, pulse pressure (PP), a measure of the pulsatile component of blood pressure (BP), has been recognized as an important predictor of future cardiovascular events (6). Central BP, measured at the aortic root, is a more direct measure than peripheral BP of the hemodynamic stress imposed on the myocardium and the coronary and cerebral circulation, and may be a more robust predictor of future cardiovascular complications (3, 31, 33). These prognostic implications have stimulated interest in defining potential effect of arterial stiffness and relatively novel hemodynamic parameters on the refraction of eye. Of note, quantification of these novel hemodynamic measures (arterial stiffness, central blood pressure) is increasingly popular among physicians and researchers partly because of the more frequent availability of dedicated devices and the progressively enlarging spectrum of their clinical application (19). This technical development also stimulated our interest towards the possible interaction of these hemodynamic variables with a frequently used ophthalmologic parameter, the refraction of the eye. If a genetic link might exist between these phenotypes, accompanying screening of arterial stiffness and high central blood pressure could be beneficial for subjects with refractive disorders. To our knowledge, no study has been performed to investigate the correlation of refraction with central blood pressure, pulse pressure and arterial stiffness, and their biologic plausibility has not been established. Therefore, the hypothesis we tested in this study was that arterial wall properties and vascular endothelial function were impaired in patients with eye refraction abnormalities. Furthermore, this work aimed at estimating the precise measurements of influence of genetics as well as shared and unshared environmental components on spherical equivalent in a wide age range Hungarian twin cohort.
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Materials and Methods Subjects and study design The 132 twin subjects above the age of 18 (66 Hungarian twin pairs; 48 monozygotic [MZ] and 18 same-sex dizygotic [DZ] pairs; 26 males and 106 females) were tested in this crosssectional twin study (24). Exclusion criteria included history of serious ophthalmologic disease, pregnancy, and foreseeable lack of compliance with test procedures. In the absence of genotyping and in order to maximize the accuracy of zygosity classification, we used a multiple self-reported questionnaire. Zygosity was assigned according to a seven-part, selfreported response (11). All study subjects gave informed consent prior to entering the study after explanation of the nature and possible consequences of the study, which was conducted in full compliance with regulations of the Ethical Committee of Semmelweis University. The tenets of the Declaration of Helsinki were followed. Anthropometric and vascular measurements were obtained partly at two twin festivals in Hungary (Ágfalva and Szigethalom) and partly at two large hospitals in Budapest, Hungary (Department of Radiology and Oncotherapy, Semmelweis University, and Department of Cardiology, Military Hospital). Several weeks later or on the same day, participants underwent the ophthalmologic examination at Department of Ophthalmology, Semmelweis University and they were asked to complete a questionnaire in order to report any clinical symptoms, complete past medical history, and medication for cardiovascular or ophthalmologic conditions. Ophthalmologic examination Ophthalmologic examination consisted of recording the visual acuity, measurement of eye refraction and intraocular pressure. Eye refraction was measured by Huvitz MRK-3100 Premium Auto Refractokeratometer three times on bilateral eyes and then the averages of the measured values were given bilaterally. Spherical equivalent (SE) was calculated with the “spherical + cyl /2” formula. The visual acuity was recorded including uncorrected visual acuity (UCVA) and best corrected visual acuity (BCVA) in decimal using standard visual acuity boards from near and far, too. Following anesthetic (Humacain – oxibuprocainhydrochloride) administration by eye drops, intraocular pressure was measured by Goldmann applanation tonometry by the same investigator. Complete eye examination was carried out at each patients including fundus examination after mydriatic eye drop administration. Anthropometric data Weight measurements were carried out by a clinically validated OMRON BF500 body consistency monitor (Omron Healthcare Ltd., Kyoto, Japan). Current height was verified simultaneously in order to calculate the body mass index (BMI). Hemodynamic measurements Brachial and aortic augmentation indices (AIx) and aortic pulse wave velocity (PWVao) were assessed by non-invasive oscillometry using TensioMed Arteriograph (TensioMed Ltd., Budapest, Hungary) (1.10.1.1. software) (1, 12). Study subjects assumed supine position to decrease inter- and intra-observer variability and in accordance with guidelines recommended by the European Society of Cardiology (18). If the automatic quality control was appropriate at first (standard deviation for PWVao less than 1.0), only one measurement was performed, Acta Physiologica Hungarica 101, 2014
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otherwise the subject underwent at least three measurements. All subjects were restricted from smoking for three hours, eating for one hour, and drinking alcohol or coffee for ten hours prior to measurements. Statistical analysis A descriptive analysis (mean standard deviation, and percentage for categorical variables) for ophthalmic, anthropometric, and vascular parameters, Pearson and partial correlations were conducted by SPSS Statistics 17. P values less than 0.05 were considered significant by the comparison of two groups with independent samples t-test. Heritability estimates were determined based on the consideration that greater levels of MZ than DZ within pair similarity indicate a genetic influence on a phenotype, while similarity of co-twin correlations suggests that the variance is due to shared environmental sources. Structural equation modeling was performed by using the Mplus Version 6.1 maximum likelihood estimation (29). Empirical confidence intervals were calculated with a Bollen-Stine Bootstrap (2). Univariate quantitative genetic modeling was performed to decompose the phenotypic variance of the considered parameters into heritability (A), shared (C), and unshared (E) environmental effects (ACE analysis) (14). We know that identical twins share their genome (r = 1) while this correlates r = 0.5 for fraternal twins. We also know that on average, both MZ and DZ twins equally share their common environment (r = 1 for both MZ and DZ twins). The unique environment of the co-twins remains uncorrelated for both zygosities. In the structural equation model A, C and E components are latent variables but for both co-twins these latent variables are related to each other based on the described structure giving us the ability to estimate the proportions of interest. The additive genetic component (A) measures the effects due to genes at multiple loci or multiple alleles at one locus. The shared environmental component (C) estimates contribution of a common family environment for both twins (e.g., familiar socialization), whereas the unshared environmental component (E) estimates the effects that separately apply to each individual twin and accounts for measurement errors. The results are adjusted to age and sex. Results Subject characteristics Baseline characteristics of all study subjects and the subgroup of same-sex monozygotic and dizygotic twins according to zygosity are presented in Table I. Regardless of zygosity, female gender dominated in both groups (80.3%). Participating dizygotic twins were significantly older (p < 0.001). Of the 132 total subjects, 50 (37.8%) were myopic and 55 (41.7%) were hypermetropic. No significant difference was observed in vascular parameters between MZ and DZ twins except brachial and aortic AIx, aortic PWV and aortic systolic blood pressure (p < 0.05), most likely related to the vascular aging of older DZ twins. Similarly, the investigated ophthalmic parameters showed no significant differences according to zygosity except left-sided uncorrected visual acuity, right- and left-sided spherical refractions before dilation and right spherical equivalent (p < 0.05). However, this difference did not translate into the reason of the different intrapair correlations between MZ and DZ twins, since the heritability analysis was adjusted to age. The slight difference between right and left spherical equivalent across zygosity (borderline significance concerning left spherical equivalent) can be attributed to the higher age of dizygotic twins. Acta Physiologica Hungarica 101, 2014
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Table I. Baseline characteristics of study subjects Total (n = 132) Male:female
Monozygotic (n = 96)
Dizygotic (n = 36)
26:106
22:74
4:32
Age, years
43.3±16.9
39.5±16.8†
53.5±12.3†
Brachial SBP, mmHg
126.7±15.9
125.7±14.8
129.3±18.7
Brachial DBP, mmHg
74.4±11.5
73.5±10.8
76.7±13.2
MAP, mmHg
91.9±12.4
91.0±11.4
94.1±14.7
PP, mmHg
52.4±9.9
52.4±10.6
52.7±7.9
Brachial AIx, %
–27.2±34.1
–31.7±35.5$
–14.8±26.7$
Aortic AIx, %
23.8±17.2
21.4±17.8$
30.1±13.5$
8.8±2.7
8.4±2.8$
9.8±2.3$
Aortic SBP, mmHg
120.4±19.8
118.0±18.1$
127.0±22.6$
Aortic PP, mmHg
46.1±11.1
44.4±10.4
50.4±11.9
SAI, %
48.3±5.9
48.1±6.1
49.1±5.4
DAI, %
51.7±5.9
51.9±6.1
50.1±5.4
23.5%
20.8%
27.8%
BMI, kg/m2
25.0±4.8
24.5±4.6
26.3±5.1
UCVA right, decimal
0.8±0.3
0.8±0.3
0.7±0.3
UCVA left, decimal
0.8±0.3
0.8±0.3$
0.6±0.4$
BCVA right, decimal
0.9±0.2
0.9±0.2
0.9±0.2
BCVA left, decimal
0.9±0.3
0.9±0.3
0.8±0.2
Right spherical refraction before dilation
0.4±2.2
0.1±1.8$
1.1±2.7$
Right cylinder before dilation
–0.6±0.9
–0.6±1.0
–0.7±0.9
Right degree and axis of cylinder before dilation
Aortic PWV, m/s
Anti-hypertensive medication (%)
72.8±58.3
71.8±59.6
75.4±55.7
Left spherical refraction before dilation
0.4±2.2
0.1±2.0$
1.0±2.5$
Left cylinder before dilation
–0.7±0.8
–0.6±0.8
–0.8±1.1
Left degree and axis of cylinder before dilation
68.9±61.1
69.5±63.0
67.3±57.2
Right SE
0.2±2.3
–0.1±2.0$
0.8±2.8$
Left SE
0.0±2.3
–0.2±2.1
0.6±2.7
†, p < 0.001; $, p < 0.05; #, p < 0.01; AIx, augmentation index; BCVA, best corrected visual acuity; BMI, body mass index; DIA, diastolic area index; DBP, diastolic blood pressure; DZ, dizygotic; MAP, mean arterial pressure; MZ, monozygotic; PP, pulse pressure; PWV, pulse wave velocity; SAI, systolic area index; SBP, systolic blood pressure; SE, spherical equivalent, UCVA, uncorrected visual acuity. Data are shown as mean ± standard deviation where appropriate
Heritability analysis of spherical equivalents in twins The possible role of zygosity in the prevalence of spherical equivalents in our twin cohort was estimated by the base ACE analysis on 66 same-sex twin pairs. Genetic and environmental variance estimates of this analysis are presented in Table II. Age- and sex-adjusted intrapair correlations were higher in MZ compared to DZ twins concerning both right and left SE. Accordingly, genetic factors appeared to contribute to the variance of SE and the largest proportion of total variance are attributable to these genetic factors. Shared environmental Acta Physiologica Hungarica 101, 2014
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factors had no effect on the variance of SE. Unshared environmental effects had a moderate impact (10.7% and 17.3%, respectively) in this model. There was no remarkable difference in the value of model fit between the two eyes. Table II. Age and sex adjusted intrapair correlations (r) and univariate ACE analysis of SE heritability in twins r (MZ)
r (DZ)
A
C
E
Model fit
Left SE
0.894
0.513
0.893 (0.728–0.966)
0.000 (0.000–0.000)
0.107 (0.034–0.267)
0.7424
Right SE
0.827
0.444
0.827 (0.629–0.937)
0.000 (0.000–0.000)
0.173 (0.063–0.370)
0.8993
Measure
Data shown are parameter estimates (95% confidence intervals) of univariate models. r, age-adjusted intrapair correlation; MZ, monozygotic; DZ, dizygotic; A, heritability; C, shared environmental variance component; E, unique environmental variance component; SE, spherical equivalent; Model fit, Chi-square test of Model fit (p value)
Phenotypic correlation between spherical equivalents and vascular parameters Table III shows the results of the analysis aimed at estimating uncorrected and also age and sex corrected phenotypic correlations between bilateral spherical equivalents with peripheral and central blood pressure, pulse pressure, arterial stiffness and heart cycle. In both bivariate models, bilateral spherical equivalents had no or weak age-dependent correlations with brachial and central AIx, as well as with aortic PWV (r ranging between 0.218 and 0.389, all p < 0.01) and aortic SBP and PP (p < 0.05 and p < 0.005, respectively) (Figs 1 and 2). Brachial PP, mean arterial pressure, systolic and diastolic blood pressure and area indices showed no correlation with bilateral SE in the age-adjusted model.
Fig. 1. Correlation of right spheric equivalent and aortic pulse wave velocity
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0.054 .527
–0.030 .725
0.000 .998
0.182 .302
0.081 .650
0.137 .349
0.175 .229
0.118 .428
0.054 .716
Left SE (all twins, n = 136)
Right SE* (all twins, n = 136)
Left SE* (all twins, n = 136)
Right SE* (no refraction disorder, n = 36)
Left SE* (no refraction disorder, n = 35)
Right SE* (myopia, n = 50)
Left SE* (myopia, n = 50)
Right SE* (hypermetropia, n = 55)
Left SE* (hypermetropia, n = 52) –0.070 .642
0.000 .999
0.203 .162
0.108 .459
–0.014 .936
0.244 .164
–0.114 .185
–0.104 .228
0.057 .502
0.067 .422
Brachial DBP
–0.029 .845
0.044 .767
0.194 .182
0.121 .406
0.028 .875
0.222 .207
–0.065 .449
–0.075 .384
0.059 .484
0.050 .547
MAP
0.105 .484
0.132 .376
0.097 .509
0.123 .402
0.159 .369
0.013 .940
0.114 .184
0.056 .512
0.028 .745
–0.041 .624
Brachial PP
0.355 .000
0.356 .000
0.346 .015
0.350 .014
0.042 .779
0.042 .781
0.130 .385
0.402 .004
0.405 .004
0.130 .383
–0.176 .320
0.077 .666
0.068 .427
–0.173 .328
0.076 .670
0.067 .438
0.139 .105
0.389 .000
0.389 .000
0.136 .112
Aortic AIx
Brachial AIx
0.176 .236
0.083 .578
0.035 .812
–0.063 .670
0.206 .242
0.169 .339
0.120 .162
0.079 .357
0.223 .008
0.218 .008
Aortic PWV
0.041 .784
0.136 .361
0.258 .074
0.241 .095
–0.003 .987
0.197 .264
0.011 .898
0.013 .881
0.197 .019
0.188 .023
Aortic SBP
0.133 .374
0.221 .135
0.252 .081
0.304 .034
0.012 .946
0.080 .654
0.129 .133
0.122 .155
0.289 .001
0.264 .001
Aortic PP
0.073 .628
0.122 .415
0.192 .187
–0.073 .628
–0.122 .415
–0.192 .187
–0.174 .231
–0.383 .026
0.363 .035 0.174 .231
–0.268 .126
–0.043 .621
–0.092 .287
–0.163 .303
–0.160 .057
DAI
0.278 .112
0.043 .621
0.092 .285
0.163 .056
0.160 .056
SAI
Data shown as correlation (r) and p values. Significant correlations are marked (bold). *age adjusted values; AIx, augmentation index; DIA, diastolic area index; DBP, diastolic blood pressure; MAP, mean arterial pressure; PP, pulse pressure; PWV, pulse wave velocity; SAI, systolic area index; SBP, systolic blood pressure; SE, spherical equivalent
0.018 .829
Right SE (all twins, n = 136)
Brachial SBP
Table III. Pearson and age and sex corrected partial correlations of spherical equivalent and various pressure, arterial stiffness and heart cycle parameters in all twins, in twins without refraction disorder, in myopic and hypermetropic subjects
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Fig. 2. Correlation of left spheric equivalent and aortic pulse wave velocity
Discussion Our study replicated the heritability of spherical equivalent on a reasonable twin sample with a wide age range, which is the first study on an Eastern European (Hungarian) cohort in this setting. Previous twin studies from other countries demonstrated similar results (4, 10, 25, 26, 43). Ding et al. investigated the peripheral refraction and reported a 55–84% heritability, however, only young twin pairs (aged 8 to 20 years) were involved (4). A Danish twin study investigated also younger twins (aged 24 to 46 years) on a similar study sample size, reporting an 89–94% heritability of post-dilation refraction (26). The heritability of pre-dilation refraction was demonstrated in a large twin sample by Lopes et al., who found that the genetic factors play a role in 77%, while the common and unique environmental factors influence the variation in 7% and 16% (25). Our Hungarian sample justified similar results as this English one, however, our heritability estimate was slightly higher, and we reported no shared environmental factors. We found that the heritability estimate of the spheric equivalent remains still high even a wide-age range or an Eastern European sample is investigated. The high heritability estimates, reported from Western European or American studies, do not seem to decline in an Eastern European twin cohort despite of the evident high incidence of cardiovascular diseases and risk factors (as epigenetic factors). Since the prevalence of refractive disorders has been also increasing in Hungary, early prevention is warranted in those families where refractive disorders are present. In previous works we investigated the heritability of vascular parameters on a larger twin cohort and reported that low to moderate genetic variance is responsible for the determination of these arterial stiffness traits, heritability was 45–46% for brachial Aix, and 42–50% for aortic PWV (38, 39). Since we specifically wanted to see if these vascular parameters follow the refractory status, and found no relationship, only an age-dependent one, we can state that these parameters seem neither phenotypically nor genetically associated. Acta Physiologica Hungarica 101, 2014
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The major novelty of our study consists of the correlation of spherical equivalents and vascular parameters. We demonstrated that bilateral spherical equivalents had only agedependent correlations with brachial and central AIx, and aortic PWV, SBP and PP in all subjects. Brachial systolic and diastolic blood pressure, mean arterial pressure, brachial PP, SAI and DAI showed also no correlations with bilateral spherical equivalents. Most of these vascular parameters have not been investigated in any previous studies. Inconsistent results were highlighted concerning the relation of refractivity of eye and the peripheral blood pressure components et al. (8, 15). Our study clearly demonstrated that this relationship does not exist supporting the findings of Gundogan et al. (8). The central blood pressure, which affects the eye more sensitively than peripheral blood pressure, has not been investigated in this setting in any study. We found only an age-dependent correlation between central blood pressure, pulse pressure and spherical equivalent bilaterally. The correlation of arterial stiffness and refraction of the eye has not been investigated before. The effect of arterial stiffness components has been investigated in certain other ophthalmic disorders, mainly in glaucoma (7, 9, 13, 28, 30, 32, 36, 37, 44) but not in refractory disorders. Several studies have shown impaired vascular endothelial function in patients with normal-tension glaucoma (NTG) reporting that atherosclerotic cerebrovascular disease involves the eye vasculature by small artery occlusion and therefore, it is a risk factor for having glaucomatous optic disk appearance (9, 36). Not only in NTG subjects, but vascular endothelial dysfunction and increased carotid arterial stiffness is present also in primary open-angle glaucoma (OAG) patients (13, 37). The Rotterdam study reported that hightension or normal-tension OAG is related to high pulse pressure, low diastolic perfusion pressure and high diastolic BP (13). Chronic OAG is associated with increased arterial rigidity and decreased baroreflex function (44). Derived central BP is not altered in glaucoma, but a reduced pulse pressure was identified (7). However, this relationship cannot be transferred to our case since this mechanism corresponds to higher intraocular pressure which is not associated with refractive disorders. Recent studies have demonstrated an association between narrowing of retinal arteriolar caliber and spherical equivalent using retinal photography and measurement of retinal vascular calibers and suggested that myopia might have an effect on retinal microvasculature (20, 22). It is known that refractive errors are due to elongation of the eyeball are typical in myopic subjects. By the increase of SE in myopic subjects, the axis also elongates since the myopic subjects have larger bulbi and the axial length and refraction share common genes in their etiology (5, 17). This mechanical stretching and thinning of the choroid and retinal pigment epithelium with accompany with concomitant vascular and degenerative changes such as reduction of retinal blood flow velocity and decreased retinal vascular caliber and retinal vessel geometry (20, 21, 22, 34, 35). According to our finding, this volume-pressure association has no effect on the investigated systemic hemodynamic parameters, neither on augmentation index (peripheral vascular resistance) nor on systemic arterial stiffness (PWV) and other pressure values measured by oscillometry. Therefore, patients with refractive disorders might develop altered hemodynamics (e.g., accelerated arterial aging) independently of refractive status and vica versa. These findings do not support the “automatic” accompany screening of arterial stiffness and high central blood pressure in subjects with refractive disorders, since those cardiovascular screenings should be performed based on the cardiovascular risk status (nearly half genetic, half environmental, as we demonstrated in our previous work) independently of the presence of a refraction disorder (39). Acta Physiologica Hungarica 101, 2014
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Potential limitations of our study should be considered: 1) The proportion of dizygotic twins was relatively small compared to other twin studies, which may lead to biased estimates in quantitative genetic analysis. 2) One limitation of this study is that the relatively small twin sample did not allow us to decompose phenotypic variance into genetic and environmental factors in myopic and hypermetropic groups separately. 3) The feasibility of finding stronger associations with hemodynamic variables on the middle age people may be limited. Strength of our study is that we used a set of relatively novel measures of cardiovascular disease in a never studied Eastern European twin cohort. In conclusion, the present study has shown the high heritability of spherical equivalent which does not seem to be influenced by sample country. We found no correlations between bilateral SE and the investigated hemodynamic parameters. Accordingly, refractive disorder and altered hemodynamics (e.g., accelerated arterial aging) can develop independently of each other, there is neither phenotypic nor genotypic relationship between these refraction and hemodynamic phenotypes. Ophthalmologic and cardiovascular screening tests should be performed independently of each other based on the family history due to the moderate heritability of these measures. Acknowledgements The authors would like to disclose the financial support provided by Medexpert Ltd. in this study. The help of the assistants of the Department of Ophthalmology, Semmelweis University in the coordinator work is gratefully acknowledged. Dr. Toth and Dr. Tarnoki had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
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11. Heath AC, Nyholt DR, Neuman R, Madden PA, Bucholz KK, Todd RD, Nelson EC, Montgomery GW, Martin NG: Zygosity diagnosis in the absence of genotypic data: an approach using latent class analysis. Twin Res 6, 22–26 (2003) 12. Horvath IG, Nemeth A, Lenkey Z, Alessandri N, Tufano F, Kis P, Gaszner B, Cziráki A: Invasive validation of a new oscillometric device (Arteriograph) for measuring augmentation index, central blood pressure and aortic pulse wave velocity. J Hypertens 28, 2068–2075 (2010) 13. Hulsman CA, Vingerling JR, Hofman A, Witteman JC, de Jong PT: Blood pressure, arterial stiffness, and openangle glaucoma: the Rotterdam study. Arch Ophthalmol 125, 805–812 (2007) 14. Jinks JL, Fulker DW: Comparison of the biometrical genetical, MAVA, and classical approaches to the analysis of human behavior. Psychol Bull 73, 311–349 (1970) 15. Karadayi K, Akin T, Ciftci F, Top C, Keskin O, Kardesoglu E, Bilge AH: The association between hypermetropia and essential hypertension. Am J Ophthalmol 140, 446–453 (2005) 16. Kuvin JT, Patel AR, Sliney KA, Pandian NG, Rand WM, Udelson JE, Karas RH: Peripheral vascular endothelial function testing as a noninvasive indicator of coronary artery disease. J Am Coll Cardiol 38, 1843–1849 (2001) 17. Lam AK, Wong S, Lam CS, To CH: The effect of myopic axial elongation and posture on the pulsatile ocular blood flow in young normal subjects. Optom Vis Sci79, 300–305 (2002) 18. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, Pannier B, Vlachopoulos C, Wilkinson I, Struijker-Boudier H; European Network for Non-invasive Investigation of Large Arteries: Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 27, 2588– 2605 (2006) 19. Laurent S, Parati G: Heritability of arterial stiffness and central blood pressure: the Holy Grail for detecting patients at high cardiovascular risk? J Hypertens 30, 1511–1513 (2012) 20. Li LJ, Cheung CY, Gazzard G, Chang L, Mitchell P, Wong TY, Saw SM: Relationship of ocular biometry and retinal vascular caliber in preschoolers. Invest Ophthalmol Vis Sci 52, 9561–9566 (2011) 21. Lim LS, Yang X, Gazzard G, Lin X, Sng C, Saw SM, Qiu A: Variation in eye volume, surface area, and shape with refractive error in young children by magnetic resonance imaging analysis. Invest Ophthalmol Vis Sci 52, 8878–8883 (2011) 22. Lim LS, Cheung CY, Lin X, Mitchell P, Wong TY, Saw SM: Influence of refractive error and axial length on retinal vessel geometric characteristics. Invest Ophthalmol Vis Sci 52, 669–678 (2011) 23. Liew SH, Elsner H, Spector TD, Hammond CJ: The first “classical” twin study? Analysis of refractive error using monozygotic and dizygotic twins published in 1922. Twin Res Hum Genet 8, 198–200 (2005) 24. Littvay L, Métneki J, Tárnoki AD, Tárnoki DL: The Hungarian Twin Registry. Twin Res Hum Genet 16, 185– 189 (2013) 25. Lopes MC, Andrew T, Carbonaro F, Spector TD, Hammond CJ: Estimating heritability and shared environmental effects for refractive error in twin and family studies. Invest Ophthalmol Vis Sci 50, 126–131 (2009) 26. Lyhne N, Sjølie AK, Kyvik KO, Green A: The importance of genes and environment for ocular refraction and its determiners: a population based study among 20–45 years old twins. Br J Ophthalmol 85, 1470–1476 (2001) 27. Mancia G, de Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, Narkiewicz K, Ruilope L, Rynkiewicz A, Schmieder RE, Boudier HA, Zanchetti A; ESH-ESC Task Force on the Management of Arterial Hypertension: 2007 Guidelines for the Management of Arterial Hypertension. J Hypertens 25, 1105–1187 (2007) 28. Moore D, Harris A, Wudunn D, Kheradiya N, Siesky B: Dysfunctional regulation of ocular blood flow: A risk factor for glaucoma? Clin Ophthalmol 2, 849–861 (2008) 29. Muthén LK, Muthén BO (1998–2010): Mplus User’s Guide. Sixth ed. Los Angeles, CA: Muthén and Muthén. 30. Németh J, Michelson G, Harazny J: Retinal microcirculation correlates with ocular wall thickness, axial eye length, and refraction in glaucoma patients. J Glaucoma 10, 390–395 (2001) 31. Pini R, Cavallini MC, Palmieri V, Marchionni N, Di Bari M, Devereux RB, Masotti G, Roman MJ: Central but not brachial blood pressure predicts cardiovascular events in an unselected geriatric population: the ICARe Dicomano Study. J Am Coll Cardiol 51, 2432–2439 (2008) 32. Resch H, Garhofer G, Fuchsjäger-Mayrl G, Hommer A, Schmetterer L: Endothelial dysfunction in glaucoma. Acta Ophthalmol 87, 4–12 (2009) 33. Roman MJ, Devereux RB, Kizer JR, Lee ET, Galloway JM, Ali T, Umans JG, Howard BV: Central pressure more strongly relates to vascular disease and outcome than does brachial pressure: the Strong Heart Study. Hypertension 50, 197–203 (2007) 34. Saw SM, Gazzard G, Shih-Yen EC, Chua WH: Myopia and associated pathological complications. Ophthalmic Physiol Opt 25, 381–391 (2005) Acta Physiologica Hungarica 101, 2014
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35. Shimada N, Ohno-Matsui K, Harino S, Yoshida T, Yasuzumi K, Kojima A, Kobayashi K, Futagami S, Tokoro T, Mochizuki M: Reduction of retinal blood flow in high myopia. Graefes Arch Clin Exp Ophthalmol 242, 284–288 (2004) 36. Siasos G, Tousoulis D, Siasou G, Moschos MM, Oikonomou E, Zaromitidou M, Marinos G, Korompelis P, Papavassiliou AG, Stefanadis C: The association between glaucoma, vascular function and inflammatory process. Int J Cardiol 146, 113–115 (2011) 37. Su WW, Cheng ST, Ho WJ, Tsay PK, Wu SC, Chang SH: Glaucoma is associated with peripheral vascular endothelial dysfunction. Ophthalmology 115, 1173–1178 (2008) 38. Tarnoki AD, Tarnoki DL, Stazi MA, Medda E, Cotichini R, Lucatelli P, Boatta E, Zini C, Baracchini C, Meneghetti G, Nisticó L, Fagnani C, Fanelli F, Giannoni MF, Gazzetti M, Osztovits J, Jermendy G, Préda I, Kiss RG, Littvay L, Metneki J, Horvath T, Karlinger K, Lannert A, Yang EY, Nambi V, Molnar AA, Berczi V, Garami Z: Twins Lead to the Prevention of Atherosclerosis: Preliminary Findings of International Twin Study 2009. J Vasc Ultrasound 35, 61–71 (2011) 39. Tarnoki AD, Tarnoki DL, Stazi MA, Medda E, Cotichini R, Nisticò L, Fagnani C, Lucatelli P, Boatta E, Zini C, Fanelli F, Baracchini C, Meneghetti G, Osztovits J, Jermendy G, Préda I, Kiss RG, Metneki J, Horvath T, Karlinger K, Racz A, Lannert A, Molnar AA, Littvay L, Garami Z, Berczi V, Schillaci G: Heritability of central blood pressure and arterial stiffness: a twin study. J Hypertension 30, 1564–1571 (2012) 40. Tarnoki DL, Tarnoki AD, Medda E, Littvay L, Lazar Z, Toccaceli V, Fagnani C, Stazi MA, Nisticó L, Brescianini S, Penna L, Lucatelli P, Boatta E, Zini C, Fanelli F, Baracchini C, Meneghetti G, Koller A, Osztovits J, Jermendy G, Preda I, Kiss RG, Karlinger K, Lannert A, Horvath T, Schillaci G, Molnar AA, Garami Z, Berczi V, Horvath I: Genetic influence on the relation between exhaled nitric oxide and pulse wave reflection. J Breath Res 7, 026008 (2013) 41. Tarnoki DL, Tarnoki AD, Lazar Z, Medda E, Littvay L, Cotichini R, Fagnani C, Stazi MA, Nisticó L, Lucatelli P, Boatta E, Zini C, Fanelli F, Baracchini C, Meneghetti G, Jermendy G, Préda I, Kiss RG, Karlinger K, Lannert A, Schillaci G, Molnar AA, Garami Z, Berczi V, Horvath I: Genetic and environmental factors on the relation of lung function and arterial stiffness. Respir Med 107, 927–935 (2013) 42. Tarnoki AD, Tarnoki DL, Bogl LH, Medda E, Fagnani C, Nisticò L, Stazi MA, Brescianini S, Lucatelli P, Boatta E, Zini C, Fanelli F, Baracchini C, Meneghetti G, Osztovits J, Jermendy G, Kiss RG, Preda I, Karlinger K, Lannert A, Molnar AA, Littvay L, Garami Z, Berczi V, Pucci G, Baffy G, Schillaci G, Pietiläinen KH: Association of body mass index with arterial stiffness and blood pressure components: a twin study. Atherosclerosis 229, 388–395 (2013) 43. Teikari JM, Kaprio J, Koskenvuo MK, Vannas A: Heritability estimate for refractive errors – A population-based sample of adult twins. Genet Epidemiol 5, 171–181 (1988) 44. Visontai Z, Mersich B, Holló G: Carotid artery elasticity and baroreflex sensitivity in patients with glaucoma. J Glaucoma 14, 30–35 (2005)
Acta Physiologica Hungarica 101, 2014
Genetic effects on refraction and correlation with hemodynamic variables: A twin study GZs Toth1*, AD Tarnoki2*, DL Tarnoki2*, A Racz1, Z Szekelyhidi1,3, L Littvay4, K Karlinger2, A Lannert5, AA Molnar6,7, Zs Garami8, V Berczi2, I Suveges1, J Nemeth1 1 Department of Ophthalmology, Semmelweis University, Budapest, Hungary Department of Radiology and Oncotherapy, Semmelweis University, Budapest, Hungary 3 Department of Ophthalmology, Szent György Hospital, Székesfehérvár, Hungary 4 Central European University, Budapest, Hungary 5 Semmelweis University, School of Pharmacy, Budapest, Hungary 6 Research Group for Inflammation Biology and Immunogenomics of Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary 7 Department of Cardiology, Military Hospital, Budapest, Hungary 8 The Methodist Hospital, DeBakey Heart and Vascular Center, Houston, TX, USA 2
Received: March 25, 2013 Accepted after revision: January 1, 2014 Spherical equivalent (SE) has not been linked to increased cardiovascular morbidity. Methods: 132 Hungarian twins (age 43.3±16.9 years) underwent refraction measurements (Huvitz MRK-3100 Premium AutoRefractokeratometer) and oscillometry (TensioMed Arteriograph). Results: Heritability analysis indicated major role for genetic components in the presence of right and left SE (82.7%, 95%CI, 62.9 to 93.7%, and 89.3%, 95%CI, 72.8 to 96.6%), while unshared environmental effects accounted for 17% (95%CI, 6.3% to 37%), and 11% (95%CI, 3.4% to 26.7%) of variations adjusted for age and sex. Bilateral SE showed weak age-dependent correlations with augmentation index (AIx), aortic pulse wave velocity (r ranging between 0.218 and 0.389, all p < 0.01), aortic systolic blood pressure and pulse pressure (r between 0.188 and 0.289, p < 0.05). Conclusions: These findings support heritability of spherical equivalent, which does not coexist with altered hemodynamics (e.g. accelerated arterial aging). Accordingly, SE and the investigated hemodynamic parameters seem neither phenotypically nor genetically associated. Keywords: arterial stiffness, augmentation index, genetics, heritability, refraction
The first “twin study” was published in 1922 by Walter Jablonski, the first ophthalmologist who used both monozygotic and dizygotic twins to examine the factors that determine the development of the refraction of the eye. He declared “the smaller differences are seen in the majority of monozygotic cases, while larger differences occur in dizygotic cases” (23). Since then, numerous articles discussed the role of inheritance, the genetic predisposition and the gene-environment interactions taking part in the formation of the refractive characteristics of the eye confirming that genetic factors account for 77–94% of the genetic variance (10, 25, 26, 43). However, a similar study in a wide-age range sample is still needed. In addition, despite heritability of refraction was thoroughly investigated in the studies
*These authors contributed equally to this work. Corresponding author: Adam Domonkos Tarnoki, MD, PhD Department of Radiology and Oncotherapy, Semmelweis University Üllői út 78/a, H-1082 Budapest, Hungary Phone: +36-30-6401183; Fax: +36-1-2780368; E-mail: [email protected] 0231–424X/$ 20.00 © 2014 Akadémiai Kiadó, Budapest
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conducted in Western European or American samples, it is a matter of a new investigation whether the high heritability estimates decline in an Eastern European sample where the incidence of cardiovascular diseases is still high. We hypothesized that the heritability of the spheric equivalent may decrease due to epigenetic factors in our Hungarian twin cohort. In the era of increasing cardiovascular morbidity and mortality, there is an increasing interest how cardiovascular diseases influence the refraction status of the eye. In our previous work, we investigated the genetic relationship of novel hemodynamic parameters with lung function, exhaled nitric oxide and body mass index which explored phenotypic and genotypic links between the investigated phenotypes (40, 41, 42). Therefore, literature still lacks a scientific explanation between novel cardiovascular and ophthalmologic parameters. A few inconsistent studies investigated the relationship between the refractive state of the eye with “traditional” cardiovascular phenotypes, such as blood pressure and arteriolar caliber. Essential arterial hypertension was strongly associated with hypermetropia in a Turkish study (15), however, another study showed no relationship (8). Several studies have shown an association between narrowing of retinal arteriolar caliber and refractive error (either spherical equivalent or axial length) in children and adults suggesting that myopia might have an effect on retinal microvasculature (20, 22). Although new risk factors have been determined in 2007 Guidelines for the Management of Arterial Hypertension including increased arterial stiffness (27), the association of this novel hemodynamic parameter and refraction of the eye has never been investigated. Endothelial function is a marker of increased cardiovascular risk (16). Arterial stiffness, characterized by pulse wave velocity (PWV) and augmentation index (AIx), can be estimated non-invasively and has an independent predictive value for cardiovascular events (18). In recent studies, pulse pressure (PP), a measure of the pulsatile component of blood pressure (BP), has been recognized as an important predictor of future cardiovascular events (6). Central BP, measured at the aortic root, is a more direct measure than peripheral BP of the hemodynamic stress imposed on the myocardium and the coronary and cerebral circulation, and may be a more robust predictor of future cardiovascular complications (3, 31, 33). These prognostic implications have stimulated interest in defining potential effect of arterial stiffness and relatively novel hemodynamic parameters on the refraction of eye. Of note, quantification of these novel hemodynamic measures (arterial stiffness, central blood pressure) is increasingly popular among physicians and researchers partly because of the more frequent availability of dedicated devices and the progressively enlarging spectrum of their clinical application (19). This technical development also stimulated our interest towards the possible interaction of these hemodynamic variables with a frequently used ophthalmologic parameter, the refraction of the eye. If a genetic link might exist between these phenotypes, accompanying screening of arterial stiffness and high central blood pressure could be beneficial for subjects with refractive disorders. To our knowledge, no study has been performed to investigate the correlation of refraction with central blood pressure, pulse pressure and arterial stiffness, and their biologic plausibility has not been established. Therefore, the hypothesis we tested in this study was that arterial wall properties and vascular endothelial function were impaired in patients with eye refraction abnormalities. Furthermore, this work aimed at estimating the precise measurements of influence of genetics as well as shared and unshared environmental components on spherical equivalent in a wide age range Hungarian twin cohort.
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Materials and Methods Subjects and study design The 132 twin subjects above the age of 18 (66 Hungarian twin pairs; 48 monozygotic [MZ] and 18 same-sex dizygotic [DZ] pairs; 26 males and 106 females) were tested in this crosssectional twin study (24). Exclusion criteria included history of serious ophthalmologic disease, pregnancy, and foreseeable lack of compliance with test procedures. In the absence of genotyping and in order to maximize the accuracy of zygosity classification, we used a multiple self-reported questionnaire. Zygosity was assigned according to a seven-part, selfreported response (11). All study subjects gave informed consent prior to entering the study after explanation of the nature and possible consequences of the study, which was conducted in full compliance with regulations of the Ethical Committee of Semmelweis University. The tenets of the Declaration of Helsinki were followed. Anthropometric and vascular measurements were obtained partly at two twin festivals in Hungary (Ágfalva and Szigethalom) and partly at two large hospitals in Budapest, Hungary (Department of Radiology and Oncotherapy, Semmelweis University, and Department of Cardiology, Military Hospital). Several weeks later or on the same day, participants underwent the ophthalmologic examination at Department of Ophthalmology, Semmelweis University and they were asked to complete a questionnaire in order to report any clinical symptoms, complete past medical history, and medication for cardiovascular or ophthalmologic conditions. Ophthalmologic examination Ophthalmologic examination consisted of recording the visual acuity, measurement of eye refraction and intraocular pressure. Eye refraction was measured by Huvitz MRK-3100 Premium Auto Refractokeratometer three times on bilateral eyes and then the averages of the measured values were given bilaterally. Spherical equivalent (SE) was calculated with the “spherical + cyl /2” formula. The visual acuity was recorded including uncorrected visual acuity (UCVA) and best corrected visual acuity (BCVA) in decimal using standard visual acuity boards from near and far, too. Following anesthetic (Humacain – oxibuprocainhydrochloride) administration by eye drops, intraocular pressure was measured by Goldmann applanation tonometry by the same investigator. Complete eye examination was carried out at each patients including fundus examination after mydriatic eye drop administration. Anthropometric data Weight measurements were carried out by a clinically validated OMRON BF500 body consistency monitor (Omron Healthcare Ltd., Kyoto, Japan). Current height was verified simultaneously in order to calculate the body mass index (BMI). Hemodynamic measurements Brachial and aortic augmentation indices (AIx) and aortic pulse wave velocity (PWVao) were assessed by non-invasive oscillometry using TensioMed Arteriograph (TensioMed Ltd., Budapest, Hungary) (1.10.1.1. software) (1, 12). Study subjects assumed supine position to decrease inter- and intra-observer variability and in accordance with guidelines recommended by the European Society of Cardiology (18). If the automatic quality control was appropriate at first (standard deviation for PWVao less than 1.0), only one measurement was performed, Acta Physiologica Hungarica 101, 2014
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otherwise the subject underwent at least three measurements. All subjects were restricted from smoking for three hours, eating for one hour, and drinking alcohol or coffee for ten hours prior to measurements. Statistical analysis A descriptive analysis (mean standard deviation, and percentage for categorical variables) for ophthalmic, anthropometric, and vascular parameters, Pearson and partial correlations were conducted by SPSS Statistics 17. P values less than 0.05 were considered significant by the comparison of two groups with independent samples t-test. Heritability estimates were determined based on the consideration that greater levels of MZ than DZ within pair similarity indicate a genetic influence on a phenotype, while similarity of co-twin correlations suggests that the variance is due to shared environmental sources. Structural equation modeling was performed by using the Mplus Version 6.1 maximum likelihood estimation (29). Empirical confidence intervals were calculated with a Bollen-Stine Bootstrap (2). Univariate quantitative genetic modeling was performed to decompose the phenotypic variance of the considered parameters into heritability (A), shared (C), and unshared (E) environmental effects (ACE analysis) (14). We know that identical twins share their genome (r = 1) while this correlates r = 0.5 for fraternal twins. We also know that on average, both MZ and DZ twins equally share their common environment (r = 1 for both MZ and DZ twins). The unique environment of the co-twins remains uncorrelated for both zygosities. In the structural equation model A, C and E components are latent variables but for both co-twins these latent variables are related to each other based on the described structure giving us the ability to estimate the proportions of interest. The additive genetic component (A) measures the effects due to genes at multiple loci or multiple alleles at one locus. The shared environmental component (C) estimates contribution of a common family environment for both twins (e.g., familiar socialization), whereas the unshared environmental component (E) estimates the effects that separately apply to each individual twin and accounts for measurement errors. The results are adjusted to age and sex. Results Subject characteristics Baseline characteristics of all study subjects and the subgroup of same-sex monozygotic and dizygotic twins according to zygosity are presented in Table I. Regardless of zygosity, female gender dominated in both groups (80.3%). Participating dizygotic twins were significantly older (p < 0.001). Of the 132 total subjects, 50 (37.8%) were myopic and 55 (41.7%) were hypermetropic. No significant difference was observed in vascular parameters between MZ and DZ twins except brachial and aortic AIx, aortic PWV and aortic systolic blood pressure (p < 0.05), most likely related to the vascular aging of older DZ twins. Similarly, the investigated ophthalmic parameters showed no significant differences according to zygosity except left-sided uncorrected visual acuity, right- and left-sided spherical refractions before dilation and right spherical equivalent (p < 0.05). However, this difference did not translate into the reason of the different intrapair correlations between MZ and DZ twins, since the heritability analysis was adjusted to age. The slight difference between right and left spherical equivalent across zygosity (borderline significance concerning left spherical equivalent) can be attributed to the higher age of dizygotic twins. Acta Physiologica Hungarica 101, 2014
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Table I. Baseline characteristics of study subjects Total (n = 132) Male:female
Monozygotic (n = 96)
Dizygotic (n = 36)
26:106
22:74
4:32
Age, years
43.3±16.9
39.5±16.8†
53.5±12.3†
Brachial SBP, mmHg
126.7±15.9
125.7±14.8
129.3±18.7
Brachial DBP, mmHg
74.4±11.5
73.5±10.8
76.7±13.2
MAP, mmHg
91.9±12.4
91.0±11.4
94.1±14.7
PP, mmHg
52.4±9.9
52.4±10.6
52.7±7.9
Brachial AIx, %
–27.2±34.1
–31.7±35.5$
–14.8±26.7$
Aortic AIx, %
23.8±17.2
21.4±17.8$
30.1±13.5$
8.8±2.7
8.4±2.8$
9.8±2.3$
Aortic SBP, mmHg
120.4±19.8
118.0±18.1$
127.0±22.6$
Aortic PP, mmHg
46.1±11.1
44.4±10.4
50.4±11.9
SAI, %
48.3±5.9
48.1±6.1
49.1±5.4
DAI, %
51.7±5.9
51.9±6.1
50.1±5.4
23.5%
20.8%
27.8%
BMI, kg/m2
25.0±4.8
24.5±4.6
26.3±5.1
UCVA right, decimal
0.8±0.3
0.8±0.3
0.7±0.3
UCVA left, decimal
0.8±0.3
0.8±0.3$
0.6±0.4$
BCVA right, decimal
0.9±0.2
0.9±0.2
0.9±0.2
BCVA left, decimal
0.9±0.3
0.9±0.3
0.8±0.2
Right spherical refraction before dilation
0.4±2.2
0.1±1.8$
1.1±2.7$
Right cylinder before dilation
–0.6±0.9
–0.6±1.0
–0.7±0.9
Right degree and axis of cylinder before dilation
Aortic PWV, m/s
Anti-hypertensive medication (%)
72.8±58.3
71.8±59.6
75.4±55.7
Left spherical refraction before dilation
0.4±2.2
0.1±2.0$
1.0±2.5$
Left cylinder before dilation
–0.7±0.8
–0.6±0.8
–0.8±1.1
Left degree and axis of cylinder before dilation
68.9±61.1
69.5±63.0
67.3±57.2
Right SE
0.2±2.3
–0.1±2.0$
0.8±2.8$
Left SE
0.0±2.3
–0.2±2.1
0.6±2.7
†, p < 0.001; $, p < 0.05; #, p < 0.01; AIx, augmentation index; BCVA, best corrected visual acuity; BMI, body mass index; DIA, diastolic area index; DBP, diastolic blood pressure; DZ, dizygotic; MAP, mean arterial pressure; MZ, monozygotic; PP, pulse pressure; PWV, pulse wave velocity; SAI, systolic area index; SBP, systolic blood pressure; SE, spherical equivalent, UCVA, uncorrected visual acuity. Data are shown as mean ± standard deviation where appropriate
Heritability analysis of spherical equivalents in twins The possible role of zygosity in the prevalence of spherical equivalents in our twin cohort was estimated by the base ACE analysis on 66 same-sex twin pairs. Genetic and environmental variance estimates of this analysis are presented in Table II. Age- and sex-adjusted intrapair correlations were higher in MZ compared to DZ twins concerning both right and left SE. Accordingly, genetic factors appeared to contribute to the variance of SE and the largest proportion of total variance are attributable to these genetic factors. Shared environmental Acta Physiologica Hungarica 101, 2014
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factors had no effect on the variance of SE. Unshared environmental effects had a moderate impact (10.7% and 17.3%, respectively) in this model. There was no remarkable difference in the value of model fit between the two eyes. Table II. Age and sex adjusted intrapair correlations (r) and univariate ACE analysis of SE heritability in twins r (MZ)
r (DZ)
A
C
E
Model fit
Left SE
0.894
0.513
0.893 (0.728–0.966)
0.000 (0.000–0.000)
0.107 (0.034–0.267)
0.7424
Right SE
0.827
0.444
0.827 (0.629–0.937)
0.000 (0.000–0.000)
0.173 (0.063–0.370)
0.8993
Measure
Data shown are parameter estimates (95% confidence intervals) of univariate models. r, age-adjusted intrapair correlation; MZ, monozygotic; DZ, dizygotic; A, heritability; C, shared environmental variance component; E, unique environmental variance component; SE, spherical equivalent; Model fit, Chi-square test of Model fit (p value)
Phenotypic correlation between spherical equivalents and vascular parameters Table III shows the results of the analysis aimed at estimating uncorrected and also age and sex corrected phenotypic correlations between bilateral spherical equivalents with peripheral and central blood pressure, pulse pressure, arterial stiffness and heart cycle. In both bivariate models, bilateral spherical equivalents had no or weak age-dependent correlations with brachial and central AIx, as well as with aortic PWV (r ranging between 0.218 and 0.389, all p < 0.01) and aortic SBP and PP (p < 0.05 and p < 0.005, respectively) (Figs 1 and 2). Brachial PP, mean arterial pressure, systolic and diastolic blood pressure and area indices showed no correlation with bilateral SE in the age-adjusted model.
Fig. 1. Correlation of right spheric equivalent and aortic pulse wave velocity
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0.054 .527
–0.030 .725
0.000 .998
0.182 .302
0.081 .650
0.137 .349
0.175 .229
0.118 .428
0.054 .716
Left SE (all twins, n = 136)
Right SE* (all twins, n = 136)
Left SE* (all twins, n = 136)
Right SE* (no refraction disorder, n = 36)
Left SE* (no refraction disorder, n = 35)
Right SE* (myopia, n = 50)
Left SE* (myopia, n = 50)
Right SE* (hypermetropia, n = 55)
Left SE* (hypermetropia, n = 52) –0.070 .642
0.000 .999
0.203 .162
0.108 .459
–0.014 .936
0.244 .164
–0.114 .185
–0.104 .228
0.057 .502
0.067 .422
Brachial DBP
–0.029 .845
0.044 .767
0.194 .182
0.121 .406
0.028 .875
0.222 .207
–0.065 .449
–0.075 .384
0.059 .484
0.050 .547
MAP
0.105 .484
0.132 .376
0.097 .509
0.123 .402
0.159 .369
0.013 .940
0.114 .184
0.056 .512
0.028 .745
–0.041 .624
Brachial PP
0.355 .000
0.356 .000
0.346 .015
0.350 .014
0.042 .779
0.042 .781
0.130 .385
0.402 .004
0.405 .004
0.130 .383
–0.176 .320
0.077 .666
0.068 .427
–0.173 .328
0.076 .670
0.067 .438
0.139 .105
0.389 .000
0.389 .000
0.136 .112
Aortic AIx
Brachial AIx
0.176 .236
0.083 .578
0.035 .812
–0.063 .670
0.206 .242
0.169 .339
0.120 .162
0.079 .357
0.223 .008
0.218 .008
Aortic PWV
0.041 .784
0.136 .361
0.258 .074
0.241 .095
–0.003 .987
0.197 .264
0.011 .898
0.013 .881
0.197 .019
0.188 .023
Aortic SBP
0.133 .374
0.221 .135
0.252 .081
0.304 .034
0.012 .946
0.080 .654
0.129 .133
0.122 .155
0.289 .001
0.264 .001
Aortic PP
0.073 .628
0.122 .415
0.192 .187
–0.073 .628
–0.122 .415
–0.192 .187
–0.174 .231
–0.383 .026
0.363 .035 0.174 .231
–0.268 .126
–0.043 .621
–0.092 .287
–0.163 .303
–0.160 .057
DAI
0.278 .112
0.043 .621
0.092 .285
0.163 .056
0.160 .056
SAI
Data shown as correlation (r) and p values. Significant correlations are marked (bold). *age adjusted values; AIx, augmentation index; DIA, diastolic area index; DBP, diastolic blood pressure; MAP, mean arterial pressure; PP, pulse pressure; PWV, pulse wave velocity; SAI, systolic area index; SBP, systolic blood pressure; SE, spherical equivalent
0.018 .829
Right SE (all twins, n = 136)
Brachial SBP
Table III. Pearson and age and sex corrected partial correlations of spherical equivalent and various pressure, arterial stiffness and heart cycle parameters in all twins, in twins without refraction disorder, in myopic and hypermetropic subjects
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Fig. 2. Correlation of left spheric equivalent and aortic pulse wave velocity
Discussion Our study replicated the heritability of spherical equivalent on a reasonable twin sample with a wide age range, which is the first study on an Eastern European (Hungarian) cohort in this setting. Previous twin studies from other countries demonstrated similar results (4, 10, 25, 26, 43). Ding et al. investigated the peripheral refraction and reported a 55–84% heritability, however, only young twin pairs (aged 8 to 20 years) were involved (4). A Danish twin study investigated also younger twins (aged 24 to 46 years) on a similar study sample size, reporting an 89–94% heritability of post-dilation refraction (26). The heritability of pre-dilation refraction was demonstrated in a large twin sample by Lopes et al., who found that the genetic factors play a role in 77%, while the common and unique environmental factors influence the variation in 7% and 16% (25). Our Hungarian sample justified similar results as this English one, however, our heritability estimate was slightly higher, and we reported no shared environmental factors. We found that the heritability estimate of the spheric equivalent remains still high even a wide-age range or an Eastern European sample is investigated. The high heritability estimates, reported from Western European or American studies, do not seem to decline in an Eastern European twin cohort despite of the evident high incidence of cardiovascular diseases and risk factors (as epigenetic factors). Since the prevalence of refractive disorders has been also increasing in Hungary, early prevention is warranted in those families where refractive disorders are present. In previous works we investigated the heritability of vascular parameters on a larger twin cohort and reported that low to moderate genetic variance is responsible for the determination of these arterial stiffness traits, heritability was 45–46% for brachial Aix, and 42–50% for aortic PWV (38, 39). Since we specifically wanted to see if these vascular parameters follow the refractory status, and found no relationship, only an age-dependent one, we can state that these parameters seem neither phenotypically nor genetically associated. Acta Physiologica Hungarica 101, 2014
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The major novelty of our study consists of the correlation of spherical equivalents and vascular parameters. We demonstrated that bilateral spherical equivalents had only agedependent correlations with brachial and central AIx, and aortic PWV, SBP and PP in all subjects. Brachial systolic and diastolic blood pressure, mean arterial pressure, brachial PP, SAI and DAI showed also no correlations with bilateral spherical equivalents. Most of these vascular parameters have not been investigated in any previous studies. Inconsistent results were highlighted concerning the relation of refractivity of eye and the peripheral blood pressure components et al. (8, 15). Our study clearly demonstrated that this relationship does not exist supporting the findings of Gundogan et al. (8). The central blood pressure, which affects the eye more sensitively than peripheral blood pressure, has not been investigated in this setting in any study. We found only an age-dependent correlation between central blood pressure, pulse pressure and spherical equivalent bilaterally. The correlation of arterial stiffness and refraction of the eye has not been investigated before. The effect of arterial stiffness components has been investigated in certain other ophthalmic disorders, mainly in glaucoma (7, 9, 13, 28, 30, 32, 36, 37, 44) but not in refractory disorders. Several studies have shown impaired vascular endothelial function in patients with normal-tension glaucoma (NTG) reporting that atherosclerotic cerebrovascular disease involves the eye vasculature by small artery occlusion and therefore, it is a risk factor for having glaucomatous optic disk appearance (9, 36). Not only in NTG subjects, but vascular endothelial dysfunction and increased carotid arterial stiffness is present also in primary open-angle glaucoma (OAG) patients (13, 37). The Rotterdam study reported that hightension or normal-tension OAG is related to high pulse pressure, low diastolic perfusion pressure and high diastolic BP (13). Chronic OAG is associated with increased arterial rigidity and decreased baroreflex function (44). Derived central BP is not altered in glaucoma, but a reduced pulse pressure was identified (7). However, this relationship cannot be transferred to our case since this mechanism corresponds to higher intraocular pressure which is not associated with refractive disorders. Recent studies have demonstrated an association between narrowing of retinal arteriolar caliber and spherical equivalent using retinal photography and measurement of retinal vascular calibers and suggested that myopia might have an effect on retinal microvasculature (20, 22). It is known that refractive errors are due to elongation of the eyeball are typical in myopic subjects. By the increase of SE in myopic subjects, the axis also elongates since the myopic subjects have larger bulbi and the axial length and refraction share common genes in their etiology (5, 17). This mechanical stretching and thinning of the choroid and retinal pigment epithelium with accompany with concomitant vascular and degenerative changes such as reduction of retinal blood flow velocity and decreased retinal vascular caliber and retinal vessel geometry (20, 21, 22, 34, 35). According to our finding, this volume-pressure association has no effect on the investigated systemic hemodynamic parameters, neither on augmentation index (peripheral vascular resistance) nor on systemic arterial stiffness (PWV) and other pressure values measured by oscillometry. Therefore, patients with refractive disorders might develop altered hemodynamics (e.g., accelerated arterial aging) independently of refractive status and vica versa. These findings do not support the “automatic” accompany screening of arterial stiffness and high central blood pressure in subjects with refractive disorders, since those cardiovascular screenings should be performed based on the cardiovascular risk status (nearly half genetic, half environmental, as we demonstrated in our previous work) independently of the presence of a refraction disorder (39). Acta Physiologica Hungarica 101, 2014
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Potential limitations of our study should be considered: 1) The proportion of dizygotic twins was relatively small compared to other twin studies, which may lead to biased estimates in quantitative genetic analysis. 2) One limitation of this study is that the relatively small twin sample did not allow us to decompose phenotypic variance into genetic and environmental factors in myopic and hypermetropic groups separately. 3) The feasibility of finding stronger associations with hemodynamic variables on the middle age people may be limited. Strength of our study is that we used a set of relatively novel measures of cardiovascular disease in a never studied Eastern European twin cohort. In conclusion, the present study has shown the high heritability of spherical equivalent which does not seem to be influenced by sample country. We found no correlations between bilateral SE and the investigated hemodynamic parameters. Accordingly, refractive disorder and altered hemodynamics (e.g., accelerated arterial aging) can develop independently of each other, there is neither phenotypic nor genotypic relationship between these refraction and hemodynamic phenotypes. Ophthalmologic and cardiovascular screening tests should be performed independently of each other based on the family history due to the moderate heritability of these measures. Acknowledgements The authors would like to disclose the financial support provided by Medexpert Ltd. in this study. The help of the assistants of the Department of Ophthalmology, Semmelweis University in the coordinator work is gratefully acknowledged. Dr. Toth and Dr. Tarnoki had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
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