ARTICLE
Distribution of ABO and Rh Blood Groups in Patients With Keratoconus: A Case–Control Study Mohammad Naderan, M.D., Mohammad Taher Rajabi, M.D., Saeed Shoar, M.D., Mohammad Amin Kamaleddin, Ph.D., Morteza Naderan, M.D., Farzaneh Rezagholizadeh, Masoome Zolfaghari, M.D., and Rozhin Pahlevani, M.D.
Abstract: Association of keratoconus (KC) with genetic predisposition and environmental factors has been well documented. However, no single study has investigated the possible relationship between ABO and Rh blood groups and KC. Methods: A case–control study was designed in a university hospital enrolling 214 patients with KC in the case group and equal number of age- and sex-matched healthy subjects in the control group. Primary characteristics, ABO blood group, and Rh factors were compared between the two groups. Topographic findings of KC eyes and the severity of the diseases were investigated according to the distribution of the blood groups. Results: Blood group O and Rh+ phenotype were most frequent in both groups. There was no significant difference between the two groups in terms of ABO blood groups or Rh factors. Mean keratometery (K), central corneal thickness, thinnest corneal thickness, flat K, steep K, sphere and cylinder, spherical equivalent, and uncorrected visual acuity were all similar between ABO blood groups and Rh+ and Rh2 groups. However, the best spectacle-corrected visual acuity (BCVA) had the highest value in AB blood group (0.3560.22 logMAR, P=0.005). Moreover, the blood group AB revealed the highest frequency for grade 3 KC, followed by grades 1, 2, and 4 (P=0.003). Conclusion: We observed no significant excess of any particular blood group among KC cases compared with healthy subjects. Except BCVA, none of the keratometric or topographic findings was significantly different between blood groups. Key Words: Keratoconus—ABO blood groups—Rh factors—Keratoconus severity—Amsler–Krumeich. (Eye & Contact Lens 2015;41: 214–217)
K
eratoconus (KC) is a chronic progressive eye condition accounting for one of the most common cause of corneal ectasia.1,2 It usually presents in the second decade of life and progresses until it stabilizes 2 decades later.3,4 Keratoconus has been reported to associate with atopy, vernal keratoconjunctivitis, reti-
From the Eye Research Center, Farabi Eye Hospital (M.N., M.T.R., S.S., Mor.N., F.R., M.Z.), Tehran University of Medical Sciences, Tehran, Iran; Department of Biotechnology (M.A.K.), College of Science, University of Tehran, Tehran, Iran; and School of Medicine (R.P.), Iran University of Medical Sciences, Tehran, Iran. The authors have no funding or conflicts of interest to disclose. Address correspondence to Mohammad Naderan, M.D., Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Qazvin Square, Tehran 1336616351, Iran; e-mail: [email protected] Accepted September 7, 2014. DOI: 10.1097/ICL.0000000000000098
214
B.Sc.,
nitis pigmentosa, Leber congenital amaurosis, eye rubbing, hard contact lens wear, and noninflammatory connective tissue disorders.5–7 Now considered a multifactorial disease, genetic predisposition to KC has been well documented by increasing evidences being available from the genetic studies evaluating visual system homeobox gene 1, superoxide dismutase gene 1, and lysyl oxidase genes, genetic mutations, linkage studies in familial KC, genomewide association studies, and twins studies8–13; however, several predisposing factors such as atopy, eye rubbing, and hard contact lens wearing have been introduced for KC,5,14–16 although the potential role of blood groups has never been sufficiently investigated. Distribution of blood groups and their possible role has been studied in association with a number of diseases.17–20 Blood groups have been shown to confer susceptibility to or protect against some medical conditions.21,22 However, to the best of our knowledge, only one study has investigated the frequency of ABO blood groups and Rh factors in patients with KC.18 Since then, there has been a huge gap in the literature on this topic. This case– control study sought to investigate the possible relationship between blood groups and KC and the disease severity.
MATERIALS AND METHODS This is a case–control study conducted in the largest universityaffiliated eye hospital in Iran, between January 2013, and February 2014. To determine the minimum sample size required to achieve a statistical power of 90% with an a value of 0.05 and effect size of 0.2, a power calculation was performed and a minimum sample size of 207 patients were obtained. Consecutive patients referring to the corneal clinic of our hospital were assessed for eligibility to enter this research project. The KC diagnosis was based on the clinical diagnostic signs found by slitlamp biomicroscopy examination, including Fleischer ring, Vogt striae, Munson sign, or scissor reflex by retinoscopy, and corneal topographic pattern of the disease and anterior or posterior elevation map using Pentacam (Oculus Optikgerate GmbH, Wetzlar, Germany), made by a same attending ophthalmologist in the outpatient clinic of the corneal diseases. Patients with a history of ocular surgery or history of any ocular disease or any corneal pathology other than KC were excluded from the study. Patients signed an informed consent to enter this study, and the institutional review board of our hospital approved the research protocol. Eye & Contact Lens Volume 41, Number 4, July 2015
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Eye & Contact Lens Volume 41, Number 4, July 2015 TABLE 1.
ABO Blood Groups in Keratoconus
The Amsler–Krumeich Classification18
Grades
Characteristics
Grade 1
Eccentric steeping Myopia and astigmatism ,5.00 D Mean central K readings ,48.00 D Myopia and astigmatism from 5.00 to 8.00 D Mean central K readings ,53.00 D Absence of scarring Minimum corneal thickness .400 mm Myopia and astigmatism from 8.00 to 10.00 D Mean central K readings .53.00 D Absence of scarring Minimum corneal thickness from 300 to 400 mm Refraction not measurable Mean central K readings .55.00 D Central corneal scarring Minimum corneal thickness 200 mm
Grade 2
Grade 3
Grade 4
and primary characteristics of patients and blood groups and Rh factors were collected for each patient. Blood groups of the patients were obtained by evaluating medical history and laboratory examinations. Subjects with unknown blood groups were excluded from the study. Topographic and keratometric measurements of the KC eyes were also recorded. Keratoconus severity was graded according to the Amsler–Krumeich classification, as shown in Table 1.23 Statistical analysis was performed using SPSS for Windows (Version 21; Chicago, IL). Student’s t test and one-way analysis of variance for quantitative variables and chi-square for qualitative variables were applied. Data are presented as mean6SD and number (%), and a P,0.05 were considered statistically significant.
RESULTS
Stage is determined if one of the characteristics applies. Corneal thickness is the thinnest measured spot of the cornea. D, diopter; K, keratometery.
TABLE 2.
Distribution of ABO and Rh Blood Groups Among KC and Control Groups
Features
KC, N=214
Blood group (%) A B AB O Rh (%) Positive Negative
Control, N=214
P 0.483
68 37 24 85
(31.8) (17.2) (11.2) (39.8)
68 49 15 82
(31.8) (22.9) (7.0) (38.3) 0.162
198 (92.5) 16 (7.5)
(88.9) (11.1)
KC, keratoconus.
Patients with KC diagnosis were assigned to the case group (n=214), whereas age- and sex-matched healthy individuals attending cornea clinic for refractive errors in whom KC diagnosis was ruled out with corneal topographic imaging and clinical evaluation and had not fulfilled the inclusion criteria of patients with KC with the astigmatism of less than 2.00 diopter and no history of ocular surgery were assigned to the control group (n=214). Demographics TABLE 3. Features Age (yr) Gender, male (%) Mean K (D) CCT (mm) TCT (mm) Flat K (D) Steep K (D) Sphere (D) Cylinder (D) SE (D) Astigmatism UCVA (logMAR) BCVA (logMAR)
A total of 428 patients were equally assigned to the KC and the control group, and 214 patients were enrolled in each group. The KC group was consisted of 366 eyes of 214 patients. Mean6SD age was 24.765.7 years (range, 18–49 years) in the KC group and 25.165.3 years (range, 18–47 years) in the control group. Overall, there were 136 men and 78 women (36.5%). The two groups were matched for age and sex. Distribution of ABO blood groups and Rh factors has been compared between the 2 groups in Table 2. Blood group O was the most frequent blood group in both groups followed by A, B, and AB groups. Moreover, the majority of our study population was Rh+. There was no significant difference between the 2 groups in terms of ABO blood groups or Rh factors (Table 2). Table 3 summarizes ocular parameters of KC eyes according to the different ABO and Rh blood groups. It is perceived from the table that mean keratometery (K), central corneal thickness, thinnest corneal thickness, flat K, steep K, sphere and cylinder refraction, spherical equivalent, and uncorrected visual acuity were all similar between ABO blood groups and Rh+ and Rh2 groups. However, the best spectacle-corrected visual acuity (BCVA) had the highest value in AB blood group (0.3560.22 logMAR), followed by B (0.2860.25 logMAR) and A and O groups (0.2160.18 logMAR), which revealed a statistically significant difference (P=0.005).
Ocular Parameters of Patients With KC According to Different ABO and Rh Blood Groups
Blood Group A, N (%)=119 (32.5)
Blood Group B, N (%)=61 (16.7)
Blood Group AB, N (%)=37 (10.1)
Blood Group O, N (%)=149 (40.7)
P
Rh+, N (%)=339 (92.6)
Rh2, N (%)=27 (7.4)
P
25.265.5 73 (61.3) 48.865.0 456653 435640 45.764.2 49.464.5 22.4463.47 23.1963.54 24.1664.53 1.1164.02 0.4960.34 0.2160.18
25.665.5 39 (63.9) 48.765.6 459646 423631.3 45.464.2 49.564.5 22.4563.10 23.5162.73 24.4163.38 0.6064.47 0.5260.32 0.2860.25
26.966.4 20 (54.0) 48.964.9 450650 430642 45.563.1 50.265.7 22.6863.85 24.2062.99 24.7664.30 20.8865.17 0.5160.32 0.3560.22
26.065.9 106 (71.1) 49.065.9 451662 442646 45.563.2 49.464.6 22.6363.54 23.7163.97 24.1263.93 0.6464.44 0.5260.31 0.2160.18
0.588 0.330 0.982 0.758 0.659 0.963 0.877 0.971 0.662 0.923 0.161 0.947 0.005
25.865.8 219 (64.6) 48.965.3 453655 427641 45.663.7 49.664.6 22.6163.49 23.5763.52 24.4064.02 0.6264.39 0.5160.32 0.2460.20
25.265.4 19 (70.3) 49.066.5 458662 430634 44.563.0 48.665.2 21.8163.12 23.5163.17 22.6263.86 0.7364.89 0.4160.31 0.2260.23
0.612 0.417 0.879 0.712 0.065 0.227 0.357 0.269 0.955 0.126 0.909 0.241 0.781
All data are mean6SD (range). Bold item is statistically significant. BCVA, best spectacle-corrected visual acuity; CCT, central corneal thickness; D, diopter; K, keratometry; SE, spherical equivalent; TCT, thinnest corneal thickness; UCVA, uncorrected visual acuity.
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215
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Eye & Contact Lens Volume 41, Number 4, July 2015
M. Naderan et al. TABLE 4.
Grading of the Keratoconic Eyes According to Amsler–Krumeich Classification in the Different ABO and Rh Blood Groups
Grading
Blood Group A, N=119
Blood Group B, N=61
Blood Group AB, N=37
Blood Group O, N=149
Grade Grade Grade Grade
58 41 12 8
28 21 8 4
13 6 14 4
74 48 14 13
1 2 3 4
(48.7) [33.5] (34.5) [35.3] (10.1) [25.0] (6.7) [27.6]
(45.9) [16.2] (34.4) [18.1] (13.1) [16.7] (6.6) [13.8]
(35.1) (16.2) (37.8) (10.8)
[7.5] [5.2] [29.2] [13.8]
(49.7) [42.8] (32.2) [41.4] (9.4) [29.2] (8.7) [44.8]
P 0.003
Rh+, N=339 159 108 45 27
(46.9) [91.9] (31.9) [93.1] (13.3) [93.8] (8.0) [93.1]
Rh2, N=27 14 8 3 2
(51.9) [8.1] (29.6) [6.9] (11.1) [6.3] (7.4) [6.9]
P 0.966
Bold item is statistically significant. All data are in number of eyes (% within each blood group) [% within each grade group].
Grading of KC eyes according to the blood groups has been presented in Table 4. The frequency of Amsler–Krumeich classes decreases from grade 1 to grade 4 in all groups, except for blood group AB, in which the grade 3 has the highest frequency followed by grades 1, 2, and 4 (P=0.003), meaning that blood group AB may be associated with severer KC. However, there was no relationship between KC severity and Rh groups.
DISCUSSION Corneal thinning and protrusion in KC occurs through a noninflammatory mechanism.3 In advanced stages, corneal scarring and edema result in decreased visual acuity.2 Despite a potential association between a number of different genes and KC, there is no single inheritance pattern identified for this condition.10 Blood groups are genetic entities, in which their distribution pattern may represent a relationship with KC, its topographic findings, and disease severity. Distribution of blood groups has been investigated in relation to a variety of conditions. Anvari et al.17 reported that risk factors for developing vascular disease are more prevalent among patients with blood group A, and this blood group is associated with higher rates of ascending aorta aneurysm-related morbidity and mortality. Although the higher prevalence of blood group A may be simply representative of such a specific blood group in Iranian population, its association with adverse event suggests an investigative look in conditions such as KC. In contrast to the previous reports from Iran with a preponderance of blood group A among the study population,17,24 our Iranian population of patients with KC are consisted of O blood group, with the A blood group ranking the second. Although we observed no significant difference in the distribution of blood groups in patients with KC or their matched controls, BCVA had the highest value in AB blood group (0.3560.22 logMAR). Moreover, unlike other blood group categories, the group AB yielded the highest frequency of grade 3 KC, followed by grades 1, 2, and 4, meaning that blood group AB may be associated with severer KC. Unfortunately, there are a few studies evaluating the association between ABO blood group and corneal diseases, and there is no single study investigating the relationship between KC topographic finding and ABO blood groups. Gasset et al.17 compared 69 white KC patients with 1,465 healthy white individuals reporting no significant excess of any particular blood group among KC cases, and thus no relationship between blood groups and KC. In another study, Ardjomand et al.25 examined 39 diseased corneal buttons through immunohistochemical staining. Their study revealed an upregulation of blood group antigen A and/or B in corneal stromal and endothelial cells in diseased corneas, suggesting a possible role of blood groups in graft rejection after corneal transplantation. This concept has been later confirmed by 216
another study, investigating the extended expression of blood group antigen A and B in 22 failed corneal allografts.26 Blood group antigens have been shown to be expressed by corneal epithelium but not the stroma or endothelium in a similar pattern with the individual’s red blood cell phenotype.27 These findings all suggest a possible link between corneal components and immunologic vascular and blood counterparts. Our knowledge of the possible underlying mechanism by which blood group antigens may play a role in the corneal conditions such as KC is very primitive. There is a need for longitudinal studies to find out if any of ABO blood groups is associated with occurrence and development of KC and how the KC progression may be affected by a specific blood group. This was the largest and the only case–control study, which systematically assessed the distribution of ABO blood group in an Iranian KC population. Future studies are required to demonstrate histological association of ABO blood group with KC and its ocular characteristics. REFERENCES 1. Rabinowitz YS. Keratoconus. Surv Ophthalmol 1998;42:297–319. 2. Romero-Jimenez M, Santodomingo-Rubido J, Wolffsohn JS. Keratoconus: A review. Cont Lens Anterior Eye 2010;33:157–166; quiz 205. 3. Krachmer JH, Feder RS, Belin MW. Keratoconus and related noninflammatory corneal thinning disorders. Surv Ophthalmol 1984;28:293–322. 4. Olivares Jimenez JL, Guerrero Jurado JC, Bermudez Rodriguez FJ, et al. Keratoconus: Age of onset and natural history. Optom Vis Sci 1997;74: 147–151. 5. Bawazeer AM, Hodge WG, Lorimer B. Atopy and keratoconus: A multivariate analysis. Br J Ophthalmol 2000;84:834–836. 6. Robertson AM, Hodge WG, Lorimer B, et al. Atopy and keratoconus: a multivariate analysis. Br J Ophthalmol 2000;84:834–836. 7. Totan Y, Hepsen IF, Cekic O, et al. Incidence of keratoconus in subjects with vernal keratoconjuctivitis: a videokeratographic study. Ophthalmology 2001;108:824–827. 8. Karimian F, Aramesh S, Rabei HM, et al. Topographic evaluation of relatives of patients with keratoconus. Cornea 2008;27:874–878. 9. Kaya V, Utine CA, Altunsoy M, et al. Evaluation of corneal topography with Orbscan II in first-degree relatives of patients with keratoconus. Cornea 2008;27:531–534. 10. Wheeler J, Hauser MA, Afshari NA, et al. The genetics of keratoconus: A Review. Reprod Syst Sex Disord 2012;(Suppl 6):001. 11. Burdon KP, Vincent AL. Insights into keratoconus from a genetic perspective. Clin Exp Optom 2013;96:146–154. 12. Bykhovskaya Y, Li X, Epifantseva I, et al. Variation in the lysyl oxidase (LOX) gene is associated with keratoconus in family-based and case-control studies. Invest Ophthalmol Vis Sci 2012;53:4152–4157. 13. Saee-Rad S, Hashemi H, Miraftab M, et al. Mutation analysis of VSX1 and SOD1 in Iranian patients with keratoconus. Mol Vis 2011;17:3128–3136. 14. Balasubramanian SA, Pye DC, Willcox MD. Effects of eye rubbing on the levels of protease, protease activity and cytokines in tears: Relevance in keratoconus. Clin Exp Optom 2013;96:214–218. 15. Rahi A, Davies P, Ruben M, et al. Keratoconus and coexisting atopic disease. Br J Ophthalmol 1977;61:761–764.
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Eye & Contact Lens Volume 41, Number 4, July 2015 16. Gasset AR, Houde WL, Garcia-Bengochea M. Hard contact lens wear as an environmental risk in keratoconus. Am J Ophthalmol 1978;85:339–341. 17. Anvari MS, Boroumand MA, Shoar S, et al. Ascending aorta aneurysm and blood group A among Iranian patients. Thromb Res 2013;131:e51–e53. 18. Gasset AR, Hinson WA, Frias JL. Genetics in keratoconus: A, B, O blood groups. Ann Ophthalmol 1978;10:601–602. 19. Tsuboi K, Asao T, Ide M, et al. Alpha1,2fucosylation is a superior predictor of postoperative prognosis for colorectal cancer compared with blood group A, B, or sialyl Lewis X antigen generated within colorectal tumor tissues. Ann Surg Oncol 2007;14:1880–1889. 20. Ulger AF, Keklik T, Kumbasar OO, et al. Prognostic significance of blood group antigen expression of tumor tissue in lung cancer patients. Tumori 2002;88:395–399. 21. Forni D, Cleynen I, Ferrante M, et al. ABO histo-blood group might modulate predisposition to Crohn’s disease and affect disease behavior. J Crohns Colitis 2014;8:489–494.
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ABO Blood Groups in Keratoconus 22. Glass RI, Holmgren J, Haley CE, et al. Predisposition for cholera of individuals with O blood group. Possible evolutionary significance. Am J Epidemiol 1985;121:791–796. 23. Alio JL, Shabayek MH. Corneal higher order aberrations: A method to grade keratoconus. J Refract Surg 2006;22:539–545. 24. Amirzadegan A, Salarifar M, Sadeghian S, et al. Correlation between ABO blood groups, major risk factors, and coronary artery disease. Int J Cardiol 2006;110:256–258. 25. Ardjomand N, Reich ME, Radner H. Expression of blood group antigens A and/or B in diseased corneas. Curr Eye Res 1998;17:650–655. 26. Ardjomand N, Komericki P, Klein A, et al. ABO blood group expression in corneal allograft failures [in German]. Ophthalmologe 2005;102: 981–986. 27. Treseler PA, Foulks GN, Sanfilippo F. Expression of ABO blood group, hematopoietic, and other cell-specific antigens by cells in the human cornea. Cornea 1985;4:157–168.
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Distribution of ABO and Rh Blood Groups in Patients With Keratoconus: A Case–Control Study Mohammad Naderan, M.D., Mohammad Taher Rajabi, M.D., Saeed Shoar, M.D., Mohammad Amin Kamaleddin, Ph.D., Morteza Naderan, M.D., Farzaneh Rezagholizadeh, Masoome Zolfaghari, M.D., and Rozhin Pahlevani, M.D.
Abstract: Association of keratoconus (KC) with genetic predisposition and environmental factors has been well documented. However, no single study has investigated the possible relationship between ABO and Rh blood groups and KC. Methods: A case–control study was designed in a university hospital enrolling 214 patients with KC in the case group and equal number of age- and sex-matched healthy subjects in the control group. Primary characteristics, ABO blood group, and Rh factors were compared between the two groups. Topographic findings of KC eyes and the severity of the diseases were investigated according to the distribution of the blood groups. Results: Blood group O and Rh+ phenotype were most frequent in both groups. There was no significant difference between the two groups in terms of ABO blood groups or Rh factors. Mean keratometery (K), central corneal thickness, thinnest corneal thickness, flat K, steep K, sphere and cylinder, spherical equivalent, and uncorrected visual acuity were all similar between ABO blood groups and Rh+ and Rh2 groups. However, the best spectacle-corrected visual acuity (BCVA) had the highest value in AB blood group (0.3560.22 logMAR, P=0.005). Moreover, the blood group AB revealed the highest frequency for grade 3 KC, followed by grades 1, 2, and 4 (P=0.003). Conclusion: We observed no significant excess of any particular blood group among KC cases compared with healthy subjects. Except BCVA, none of the keratometric or topographic findings was significantly different between blood groups. Key Words: Keratoconus—ABO blood groups—Rh factors—Keratoconus severity—Amsler–Krumeich. (Eye & Contact Lens 2015;41: 214–217)
K
eratoconus (KC) is a chronic progressive eye condition accounting for one of the most common cause of corneal ectasia.1,2 It usually presents in the second decade of life and progresses until it stabilizes 2 decades later.3,4 Keratoconus has been reported to associate with atopy, vernal keratoconjunctivitis, reti-
From the Eye Research Center, Farabi Eye Hospital (M.N., M.T.R., S.S., Mor.N., F.R., M.Z.), Tehran University of Medical Sciences, Tehran, Iran; Department of Biotechnology (M.A.K.), College of Science, University of Tehran, Tehran, Iran; and School of Medicine (R.P.), Iran University of Medical Sciences, Tehran, Iran. The authors have no funding or conflicts of interest to disclose. Address correspondence to Mohammad Naderan, M.D., Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Qazvin Square, Tehran 1336616351, Iran; e-mail: [email protected] Accepted September 7, 2014. DOI: 10.1097/ICL.0000000000000098
214
B.Sc.,
nitis pigmentosa, Leber congenital amaurosis, eye rubbing, hard contact lens wear, and noninflammatory connective tissue disorders.5–7 Now considered a multifactorial disease, genetic predisposition to KC has been well documented by increasing evidences being available from the genetic studies evaluating visual system homeobox gene 1, superoxide dismutase gene 1, and lysyl oxidase genes, genetic mutations, linkage studies in familial KC, genomewide association studies, and twins studies8–13; however, several predisposing factors such as atopy, eye rubbing, and hard contact lens wearing have been introduced for KC,5,14–16 although the potential role of blood groups has never been sufficiently investigated. Distribution of blood groups and their possible role has been studied in association with a number of diseases.17–20 Blood groups have been shown to confer susceptibility to or protect against some medical conditions.21,22 However, to the best of our knowledge, only one study has investigated the frequency of ABO blood groups and Rh factors in patients with KC.18 Since then, there has been a huge gap in the literature on this topic. This case– control study sought to investigate the possible relationship between blood groups and KC and the disease severity.
MATERIALS AND METHODS This is a case–control study conducted in the largest universityaffiliated eye hospital in Iran, between January 2013, and February 2014. To determine the minimum sample size required to achieve a statistical power of 90% with an a value of 0.05 and effect size of 0.2, a power calculation was performed and a minimum sample size of 207 patients were obtained. Consecutive patients referring to the corneal clinic of our hospital were assessed for eligibility to enter this research project. The KC diagnosis was based on the clinical diagnostic signs found by slitlamp biomicroscopy examination, including Fleischer ring, Vogt striae, Munson sign, or scissor reflex by retinoscopy, and corneal topographic pattern of the disease and anterior or posterior elevation map using Pentacam (Oculus Optikgerate GmbH, Wetzlar, Germany), made by a same attending ophthalmologist in the outpatient clinic of the corneal diseases. Patients with a history of ocular surgery or history of any ocular disease or any corneal pathology other than KC were excluded from the study. Patients signed an informed consent to enter this study, and the institutional review board of our hospital approved the research protocol. Eye & Contact Lens Volume 41, Number 4, July 2015
Copyright @ Contact Lens Association of Opthalmologists, Inc. Unauthorized reproduction of this article is prohibited.
Eye & Contact Lens Volume 41, Number 4, July 2015 TABLE 1.
ABO Blood Groups in Keratoconus
The Amsler–Krumeich Classification18
Grades
Characteristics
Grade 1
Eccentric steeping Myopia and astigmatism ,5.00 D Mean central K readings ,48.00 D Myopia and astigmatism from 5.00 to 8.00 D Mean central K readings ,53.00 D Absence of scarring Minimum corneal thickness .400 mm Myopia and astigmatism from 8.00 to 10.00 D Mean central K readings .53.00 D Absence of scarring Minimum corneal thickness from 300 to 400 mm Refraction not measurable Mean central K readings .55.00 D Central corneal scarring Minimum corneal thickness 200 mm
Grade 2
Grade 3
Grade 4
and primary characteristics of patients and blood groups and Rh factors were collected for each patient. Blood groups of the patients were obtained by evaluating medical history and laboratory examinations. Subjects with unknown blood groups were excluded from the study. Topographic and keratometric measurements of the KC eyes were also recorded. Keratoconus severity was graded according to the Amsler–Krumeich classification, as shown in Table 1.23 Statistical analysis was performed using SPSS for Windows (Version 21; Chicago, IL). Student’s t test and one-way analysis of variance for quantitative variables and chi-square for qualitative variables were applied. Data are presented as mean6SD and number (%), and a P,0.05 were considered statistically significant.
RESULTS
Stage is determined if one of the characteristics applies. Corneal thickness is the thinnest measured spot of the cornea. D, diopter; K, keratometery.
TABLE 2.
Distribution of ABO and Rh Blood Groups Among KC and Control Groups
Features
KC, N=214
Blood group (%) A B AB O Rh (%) Positive Negative
Control, N=214
P 0.483
68 37 24 85
(31.8) (17.2) (11.2) (39.8)
68 49 15 82
(31.8) (22.9) (7.0) (38.3) 0.162
198 (92.5) 16 (7.5)
(88.9) (11.1)
KC, keratoconus.
Patients with KC diagnosis were assigned to the case group (n=214), whereas age- and sex-matched healthy individuals attending cornea clinic for refractive errors in whom KC diagnosis was ruled out with corneal topographic imaging and clinical evaluation and had not fulfilled the inclusion criteria of patients with KC with the astigmatism of less than 2.00 diopter and no history of ocular surgery were assigned to the control group (n=214). Demographics TABLE 3. Features Age (yr) Gender, male (%) Mean K (D) CCT (mm) TCT (mm) Flat K (D) Steep K (D) Sphere (D) Cylinder (D) SE (D) Astigmatism UCVA (logMAR) BCVA (logMAR)
A total of 428 patients were equally assigned to the KC and the control group, and 214 patients were enrolled in each group. The KC group was consisted of 366 eyes of 214 patients. Mean6SD age was 24.765.7 years (range, 18–49 years) in the KC group and 25.165.3 years (range, 18–47 years) in the control group. Overall, there were 136 men and 78 women (36.5%). The two groups were matched for age and sex. Distribution of ABO blood groups and Rh factors has been compared between the 2 groups in Table 2. Blood group O was the most frequent blood group in both groups followed by A, B, and AB groups. Moreover, the majority of our study population was Rh+. There was no significant difference between the 2 groups in terms of ABO blood groups or Rh factors (Table 2). Table 3 summarizes ocular parameters of KC eyes according to the different ABO and Rh blood groups. It is perceived from the table that mean keratometery (K), central corneal thickness, thinnest corneal thickness, flat K, steep K, sphere and cylinder refraction, spherical equivalent, and uncorrected visual acuity were all similar between ABO blood groups and Rh+ and Rh2 groups. However, the best spectacle-corrected visual acuity (BCVA) had the highest value in AB blood group (0.3560.22 logMAR), followed by B (0.2860.25 logMAR) and A and O groups (0.2160.18 logMAR), which revealed a statistically significant difference (P=0.005).
Ocular Parameters of Patients With KC According to Different ABO and Rh Blood Groups
Blood Group A, N (%)=119 (32.5)
Blood Group B, N (%)=61 (16.7)
Blood Group AB, N (%)=37 (10.1)
Blood Group O, N (%)=149 (40.7)
P
Rh+, N (%)=339 (92.6)
Rh2, N (%)=27 (7.4)
P
25.265.5 73 (61.3) 48.865.0 456653 435640 45.764.2 49.464.5 22.4463.47 23.1963.54 24.1664.53 1.1164.02 0.4960.34 0.2160.18
25.665.5 39 (63.9) 48.765.6 459646 423631.3 45.464.2 49.564.5 22.4563.10 23.5162.73 24.4163.38 0.6064.47 0.5260.32 0.2860.25
26.966.4 20 (54.0) 48.964.9 450650 430642 45.563.1 50.265.7 22.6863.85 24.2062.99 24.7664.30 20.8865.17 0.5160.32 0.3560.22
26.065.9 106 (71.1) 49.065.9 451662 442646 45.563.2 49.464.6 22.6363.54 23.7163.97 24.1263.93 0.6464.44 0.5260.31 0.2160.18
0.588 0.330 0.982 0.758 0.659 0.963 0.877 0.971 0.662 0.923 0.161 0.947 0.005
25.865.8 219 (64.6) 48.965.3 453655 427641 45.663.7 49.664.6 22.6163.49 23.5763.52 24.4064.02 0.6264.39 0.5160.32 0.2460.20
25.265.4 19 (70.3) 49.066.5 458662 430634 44.563.0 48.665.2 21.8163.12 23.5163.17 22.6263.86 0.7364.89 0.4160.31 0.2260.23
0.612 0.417 0.879 0.712 0.065 0.227 0.357 0.269 0.955 0.126 0.909 0.241 0.781
All data are mean6SD (range). Bold item is statistically significant. BCVA, best spectacle-corrected visual acuity; CCT, central corneal thickness; D, diopter; K, keratometry; SE, spherical equivalent; TCT, thinnest corneal thickness; UCVA, uncorrected visual acuity.
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M. Naderan et al. TABLE 4.
Grading of the Keratoconic Eyes According to Amsler–Krumeich Classification in the Different ABO and Rh Blood Groups
Grading
Blood Group A, N=119
Blood Group B, N=61
Blood Group AB, N=37
Blood Group O, N=149
Grade Grade Grade Grade
58 41 12 8
28 21 8 4
13 6 14 4
74 48 14 13
1 2 3 4
(48.7) [33.5] (34.5) [35.3] (10.1) [25.0] (6.7) [27.6]
(45.9) [16.2] (34.4) [18.1] (13.1) [16.7] (6.6) [13.8]
(35.1) (16.2) (37.8) (10.8)
[7.5] [5.2] [29.2] [13.8]
(49.7) [42.8] (32.2) [41.4] (9.4) [29.2] (8.7) [44.8]
P 0.003
Rh+, N=339 159 108 45 27
(46.9) [91.9] (31.9) [93.1] (13.3) [93.8] (8.0) [93.1]
Rh2, N=27 14 8 3 2
(51.9) [8.1] (29.6) [6.9] (11.1) [6.3] (7.4) [6.9]
P 0.966
Bold item is statistically significant. All data are in number of eyes (% within each blood group) [% within each grade group].
Grading of KC eyes according to the blood groups has been presented in Table 4. The frequency of Amsler–Krumeich classes decreases from grade 1 to grade 4 in all groups, except for blood group AB, in which the grade 3 has the highest frequency followed by grades 1, 2, and 4 (P=0.003), meaning that blood group AB may be associated with severer KC. However, there was no relationship between KC severity and Rh groups.
DISCUSSION Corneal thinning and protrusion in KC occurs through a noninflammatory mechanism.3 In advanced stages, corneal scarring and edema result in decreased visual acuity.2 Despite a potential association between a number of different genes and KC, there is no single inheritance pattern identified for this condition.10 Blood groups are genetic entities, in which their distribution pattern may represent a relationship with KC, its topographic findings, and disease severity. Distribution of blood groups has been investigated in relation to a variety of conditions. Anvari et al.17 reported that risk factors for developing vascular disease are more prevalent among patients with blood group A, and this blood group is associated with higher rates of ascending aorta aneurysm-related morbidity and mortality. Although the higher prevalence of blood group A may be simply representative of such a specific blood group in Iranian population, its association with adverse event suggests an investigative look in conditions such as KC. In contrast to the previous reports from Iran with a preponderance of blood group A among the study population,17,24 our Iranian population of patients with KC are consisted of O blood group, with the A blood group ranking the second. Although we observed no significant difference in the distribution of blood groups in patients with KC or their matched controls, BCVA had the highest value in AB blood group (0.3560.22 logMAR). Moreover, unlike other blood group categories, the group AB yielded the highest frequency of grade 3 KC, followed by grades 1, 2, and 4, meaning that blood group AB may be associated with severer KC. Unfortunately, there are a few studies evaluating the association between ABO blood group and corneal diseases, and there is no single study investigating the relationship between KC topographic finding and ABO blood groups. Gasset et al.17 compared 69 white KC patients with 1,465 healthy white individuals reporting no significant excess of any particular blood group among KC cases, and thus no relationship between blood groups and KC. In another study, Ardjomand et al.25 examined 39 diseased corneal buttons through immunohistochemical staining. Their study revealed an upregulation of blood group antigen A and/or B in corneal stromal and endothelial cells in diseased corneas, suggesting a possible role of blood groups in graft rejection after corneal transplantation. This concept has been later confirmed by 216
another study, investigating the extended expression of blood group antigen A and B in 22 failed corneal allografts.26 Blood group antigens have been shown to be expressed by corneal epithelium but not the stroma or endothelium in a similar pattern with the individual’s red blood cell phenotype.27 These findings all suggest a possible link between corneal components and immunologic vascular and blood counterparts. Our knowledge of the possible underlying mechanism by which blood group antigens may play a role in the corneal conditions such as KC is very primitive. There is a need for longitudinal studies to find out if any of ABO blood groups is associated with occurrence and development of KC and how the KC progression may be affected by a specific blood group. This was the largest and the only case–control study, which systematically assessed the distribution of ABO blood group in an Iranian KC population. Future studies are required to demonstrate histological association of ABO blood group with KC and its ocular characteristics. REFERENCES 1. Rabinowitz YS. Keratoconus. Surv Ophthalmol 1998;42:297–319. 2. Romero-Jimenez M, Santodomingo-Rubido J, Wolffsohn JS. Keratoconus: A review. Cont Lens Anterior Eye 2010;33:157–166; quiz 205. 3. Krachmer JH, Feder RS, Belin MW. Keratoconus and related noninflammatory corneal thinning disorders. Surv Ophthalmol 1984;28:293–322. 4. Olivares Jimenez JL, Guerrero Jurado JC, Bermudez Rodriguez FJ, et al. Keratoconus: Age of onset and natural history. Optom Vis Sci 1997;74: 147–151. 5. Bawazeer AM, Hodge WG, Lorimer B. Atopy and keratoconus: A multivariate analysis. Br J Ophthalmol 2000;84:834–836. 6. Robertson AM, Hodge WG, Lorimer B, et al. Atopy and keratoconus: a multivariate analysis. Br J Ophthalmol 2000;84:834–836. 7. Totan Y, Hepsen IF, Cekic O, et al. Incidence of keratoconus in subjects with vernal keratoconjuctivitis: a videokeratographic study. Ophthalmology 2001;108:824–827. 8. Karimian F, Aramesh S, Rabei HM, et al. Topographic evaluation of relatives of patients with keratoconus. Cornea 2008;27:874–878. 9. Kaya V, Utine CA, Altunsoy M, et al. Evaluation of corneal topography with Orbscan II in first-degree relatives of patients with keratoconus. Cornea 2008;27:531–534. 10. Wheeler J, Hauser MA, Afshari NA, et al. The genetics of keratoconus: A Review. Reprod Syst Sex Disord 2012;(Suppl 6):001. 11. Burdon KP, Vincent AL. Insights into keratoconus from a genetic perspective. Clin Exp Optom 2013;96:146–154. 12. Bykhovskaya Y, Li X, Epifantseva I, et al. Variation in the lysyl oxidase (LOX) gene is associated with keratoconus in family-based and case-control studies. Invest Ophthalmol Vis Sci 2012;53:4152–4157. 13. Saee-Rad S, Hashemi H, Miraftab M, et al. Mutation analysis of VSX1 and SOD1 in Iranian patients with keratoconus. Mol Vis 2011;17:3128–3136. 14. Balasubramanian SA, Pye DC, Willcox MD. Effects of eye rubbing on the levels of protease, protease activity and cytokines in tears: Relevance in keratoconus. Clin Exp Optom 2013;96:214–218. 15. Rahi A, Davies P, Ruben M, et al. Keratoconus and coexisting atopic disease. Br J Ophthalmol 1977;61:761–764.
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Eye & Contact Lens Volume 41, Number 4, July 2015 16. Gasset AR, Houde WL, Garcia-Bengochea M. Hard contact lens wear as an environmental risk in keratoconus. Am J Ophthalmol 1978;85:339–341. 17. Anvari MS, Boroumand MA, Shoar S, et al. Ascending aorta aneurysm and blood group A among Iranian patients. Thromb Res 2013;131:e51–e53. 18. Gasset AR, Hinson WA, Frias JL. Genetics in keratoconus: A, B, O blood groups. Ann Ophthalmol 1978;10:601–602. 19. Tsuboi K, Asao T, Ide M, et al. Alpha1,2fucosylation is a superior predictor of postoperative prognosis for colorectal cancer compared with blood group A, B, or sialyl Lewis X antigen generated within colorectal tumor tissues. Ann Surg Oncol 2007;14:1880–1889. 20. Ulger AF, Keklik T, Kumbasar OO, et al. Prognostic significance of blood group antigen expression of tumor tissue in lung cancer patients. Tumori 2002;88:395–399. 21. Forni D, Cleynen I, Ferrante M, et al. ABO histo-blood group might modulate predisposition to Crohn’s disease and affect disease behavior. J Crohns Colitis 2014;8:489–494.
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ABO Blood Groups in Keratoconus 22. Glass RI, Holmgren J, Haley CE, et al. Predisposition for cholera of individuals with O blood group. Possible evolutionary significance. Am J Epidemiol 1985;121:791–796. 23. Alio JL, Shabayek MH. Corneal higher order aberrations: A method to grade keratoconus. J Refract Surg 2006;22:539–545. 24. Amirzadegan A, Salarifar M, Sadeghian S, et al. Correlation between ABO blood groups, major risk factors, and coronary artery disease. Int J Cardiol 2006;110:256–258. 25. Ardjomand N, Reich ME, Radner H. Expression of blood group antigens A and/or B in diseased corneas. Curr Eye Res 1998;17:650–655. 26. Ardjomand N, Komericki P, Klein A, et al. ABO blood group expression in corneal allograft failures [in German]. Ophthalmologe 2005;102: 981–986. 27. Treseler PA, Foulks GN, Sanfilippo F. Expression of ABO blood group, hematopoietic, and other cell-specific antigens by cells in the human cornea. Cornea 1985;4:157–168.
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