Kajo Bućan

New loci associated with central cornea thickness include COL5A1, AKAP13 and AVGR8

Central corneal thickness (CCT) is a highly heritable trait, which has been proposed to influence disorders of the anterior segment of the eye. A genome-wide association study (GWAS) of CCT was performed in 2269 individuals from three Croatian and one Scottish population. In the discovery set (1445 individuals), two genome-wide significant associations were identified for single nucleotide polymorphisms rs12447690 (β = 0.23 SD, P = 4.4 × 10(-9)) and rs1536482 (β = 0.22 SD, P = 7.1 × 10(-8)) for which the closest candidate genes (although ≥90 kb away) were zinc finger 469 (ZNF469) on 16q24.2 and collagen 5 alpha 1 (COL5A1) on 9q34.2, respectively. Only the ZNF469 association was confirmed in our replication set (824 individuals, P = 8.0 × 10(-4)) but COL5A1 remained a suggestive association in the combined sample (β = 0.16 SD, P = 1.1 × 10(-6)). Following a larger meta-analysis including recently published CCT GWAS summary data, COL5A1 was genome-wide significant (β = 0.13 SD, P = 5.1 × 10(-8)), together with two additional novel loci. The second new locus (defined by rs1034200) was 5 kb from the AVGR8 gene, encoding a putative transcription factor with typical ZNF and KRAB domains, in chromosomal region 13q12.11 (β = 0.14 SD, P = 3.5 × 10(-9)). The third new locus (rs6496932), on 15q25.3 (β = 0.13, P = 1.4 × 10(-8)), was within a wide linkage disequilibrium block extending into the 5 end of the AKAP13 gene, encoding a scaffold protein concerned with signal transduction from the cell surface. These associations offer mechanistic insights into the regulation of CCT and offer new candidate genes for susceptibility to common disorders in which CCT has been implicated, including primary open-angle glaucoma and keratoconus.

Heritabilities of Ocular Biometrical Traits in Two Croatian Isolates with Extended Pedigrees

PURPOSEnTo assess the effects of body stature and years of education, in addition to age and sex, on six oculometric traits and to estimate the heritabilities of these quantitative traits in two Croatian cross-population studies.nnnMETHODSnAdult subjects living on the two Croatian islands of Vis and Korcula were recruited for a large epidemiologic and genetic study that included eye biometry, keratometry, and autorefraction. Effects and heritabilities were estimated by using general linear mixed models for axial length (AL), anterior chamber depth (ACD), corneal curvature (CC), corneal thickness (CT), lens thickness (LT), and spherical equivalent refraction (SER). Both cohorts were genotyped with dense SNP arrays, allowing the use of kinship coefficients derived from genotypic data (realized kinship) rather than from pedigree information (expected kinship).nnnRESULTSnAcross cohorts, body mass index (BMI) did not consistently influence any of the ocular traits adjusted for age and/or sex, whereas height and years in education (YrEd) did, explaining up to an additional 5% of the variance (in CC). CT was the trait least influenced by covariates. Estimated heritabilities in Vis and Korcula, respectively, were 84% and 52% for CC, 75% and 71% for CT, 37% and 32% for LT, 59% and 45% for ACD, 37% and 74% for AL, and 0% and 17% for SER.nnnCONCLUSIONSnWhile heritabilities of CT and CC seemed uniformly high across studies of Caucasian datasets, estimates for SER varied widely and were at the lower end of the spectrum of published observations in our study.

Association of Age-Related Macular Degeneration with Erythrocyte Antioxidant Enzymes Activity and Serum Total Antioxidant Status

The aim was to estimate association of the oxidative stress with the occurrence of age-related macular degeneration (AMD). The activities of erythrocyte antioxidant enzymes: superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) and additionally serum total antioxidant status (TAS) were used as indicators of the oxidative stress level. 57 AMD patients (32 early and 25 late AMD) and 50 healthy, age and gender matched controls were included. GPx activity (P < 0.001) and serum TAS (P = 0.015) were significantly lower in AMD patients. The difference was not significant for SOD or CAT activities. Significant interaction between GPx and SOD was detected (P = 0.003). At high levels of SOD activity (over 75th percentile), one standard deviation decrease in GPx increases the odds for AMD for six times (OR = 6.22; P < 0.001). ROC analysis revealed that combined values of GPx activity and TAS are significant determinants of AMD status. Accuracy, sensitivity, specificity, and positive and negative predictive values were 75%, 95%, 52%, 69%, and 90%, respectively. The study showed that low GPx activity and TAS are associated with AMD. SOD modulates the association of GPx and AMD. The results suggest that erythrocyte antioxidant enzymes activity and serum TAS could be promising markers for the prediction of AMD.

Effects of Isolation and Inbreeding on Human Quantitative Traits: An Example of Biochemical Markers of Hemostasis and Inflammation

Abstract Isolation is a known force in evolutionary biology and one of the main factors in speciation. One of the main consequences of severe isolation is reduced mate choice, which results in the occurrence of inbreeding as a result of isolation. We investigated the effects of individual genome-wide heterozygosity measured as the multilocus heterozygosity (MLH) on biochemical markers of hemostasis and inflammation in 1,041 individuals from the island of Vis, Croatia, where inbreeding is prevalent and a wide range of variation in the genome-wide heterozygosity is expected. Assessment of individual genome-wide heterozygosity was based on genome-wide scans using 800 microsatellite (STR) and 317,503 single nucleotide (SNP) polymorphic markers in each examinee. In addition, for each examinee we defined a personal genetic history (PGH) based on genealogical records. The association between PGH and MLH and fibrinogen, D-dimer (Dd), von Willebrand factor (vWF), tissue plasminogen activator (tPA), and C-reactive protein (CRP) was performed with a mixed model, controlling for possible confounding effects. PGH was a significant predictor only for tPA (P < 0.001), whereas neither of the two MLH measures exhibited significant association with any of the investigated traits. The effects of individual genome-wide heterozygosity are most likely expressed in highly polygenically determined traits or in traits that are mediated by rare and recessive genetic variants. Weak associations between PGH and MLH and markers of hemostasis and inflammation suggest that their genetic control may not be highly polygenic and that they could be promising targets for genetic association studies.

High prevalence of glaucoma in Veli Brgud, Croatia, is caused by a dominantly inherited T377M mutation in the MYOC gene

An unusually high prevalence of early-onset open-angle glaucoma (OAG) in the population of Veli Brgud, Croatia, has been reported in previous studies.1 The most recent population census conducted in this isolated village in the mountains of Istrian peninsula (fig 1) reported a total of 550 inhabitants. Community-based ophthalmological examination was conducted during the 1990s among 536 inhabitants (97.5% of the total population) by the team of ophthalmologists from the University of Rijeka Medical School.1 OAG was diagnosed in 74 persons, and the population prevalence was found to be 13.8%. However, 67 (90%) of the affected individuals were linked to a single, large, nine-generation pedigree, while for the remaining seven persons with OAG, no link to the pedigree could be established. Although the village is isolated with high levels of inbreeding (proportion of consanguineous marriages is 22%), which usually favours the expression of recessive …

Acute bilateral cataract with phacomorphic glaucoma in a girl with newly diagnosed type 1 diabetes mellitus.

The authors present a rare case of acute bilateral cataract with phacomorphic glaucoma in a girl with newly diagnosed type 1 diabetes mellitus without a known history of ocular problems. Within 3 months after the diagnosis of diabetes mellitus, she presented with high intraocular pressure. Her visual acuity was limited to hand motions. The patient required immediate surgical intervention. Postoperatively, the intraocular pressure normalized and bilateral visual acuity was 6/6.

Cataract as Early Ocular Complication in Children and Adolescents with Type 1 Diabetes Mellitus

Cataract is a rare manifestation of ocular complication at an early phase of T1DM in the pediatric population. The pathophysiological mechanism of early diabetic cataract has not been fully understood; however, there are many theories about the possible etiology including osmotic damage, polyol pathway, and oxidative stress. The prevalence of early diabetic cataract in the population varies between 0.7 and 3.4% of children and adolescents with T1DM. The occurrence of diabetic cataract in most pediatric patients is the first sign of T1DM or occurs within 6 months of diagnosis of T1DM. Today, there are many experimental therapies for the treatment of diabetic cataract, but cataract surgery continues to be a gold standard in the treatment of diabetic cataract. Since the cataract is the leading cause of visual impairment in patients with T1DM, diabetic cataract requires an initial screening as well as continuous surveillance as a measure of prevention and this should be included in the guidelines of pediatric diabetes societies.

Epidemiology of ocular trauma in children requiring hospital admission: a 16–year retrospective cohort study

Background To study the epidemiology of ocular trauma requiring hospital admission in children under 18 years in age. Methods This retrospective cohort study included pediatric patients with ocular injuries at the Ophthalmology Department of the Clinical Hospital Centre, Split, Croatia, from 2000 to 2015, classified according to the Birmingham Eye Trauma Terminology. Results There were 353 children hospitalized, 82% of boys (mean age 11 years) and 18% of girls (mean age 10 years). The majority of traumas occurred in the outside environment (70%, nu2009=u2009249), followed by occurrences at home (17%, nu2009=u200960), and at a school/nursery (8%, nu2009=u200928). Final visual acuity was 6/18 or better in 286 (96%) patients with closed globe injury and in 26 (49%) patients with open globe injury. Severe impairment of vision was found in 12 (4.4%) patients in the closed globe injury group and 26 (49%) patients in the open globe injury group. A statistically significant difference was found between final visual acuity and initial visual acuity in all patients (χ2u2009=u200912.8; Pu2009<u20090.001). Conclusion The majority of pediatric eye injuries are happening in the outside environment and are preventable. Implementation of well–established safety precautions would greatly reduce this source of visual disability in children.

Genetic Background of a Recurrent Unusual Combined Form of Retinal Vein Occlusion: A Case Report

The authors report a rare case of nonischemic branch retinal vein occlusion and nonischemic hemiretinal vein occlusion in a patient with impaired fibrinolysis. A 61-year-old woman presented to the Department of Ophthalmology, Clinical Hospital Center Split, Croatia, with acute blurring of vision in the right eye (RE) due to branch retinal vein occlusion. Ophthalmologic evaluation revealed a best corrected visual acuity (BCVA) of 0.02 in the RE and of 1.0 in the left eye. Ophthalmoscopy and fluorescein angiography of the RE demonstrated signs of nonischemic branch retinal vein occlusion. She was otherwise healthy and had no other ocular and systemic diseases. She was treated with 3 consecutive intravitreal applications of anti-vascular endothelial growth factor (anti-VEGF; bevacizumab) due to cystoid macular edema with full resolution of the intraretinal fluid and improvement of the BCVA to 0.9. After 8 months, she presented again with acute blurring of vision in the same (right) eye with a BCVA of 0.5. Ophthalmoscopy and fluorescein angiography of the RE indicated nonischemic hemiretinal vein occlusion. She was treated with a single intravitreal application of anti-VEGF (ranibizumab) due to macular edema. Full resolution of the intraretinal fluid and improvement of the BCVA to 0.9 were achieved. A laboratory workup was performed to rule out all known causes of retinal venous occlusive disease, which showed negative results. A molecular analysis showed the gen of thrombophilia – plasminogen activator inhibitor (PAI)-1 4G/5G polymorphism genotype – as the only risk factor for retinal venous occlusive disease in our patient.

Cauterisation versus fibrin glue for conjunctival autografting in primary pterygium surgery (CAGE CUP): study protocol of a randomised controlled trial

Introduction Pterygium is a non-cancerous growth of the conjunctival tissue over the cornea that may lead to visual impairment in advanced stages, restriction of ocular motility, chronic inflammation and cosmetic concerns. Surgical removal is the treatment of choice, but recurrence of pterygium is a frequent problem. It has been previously shown that fibrin glue may result in less recurrence and may take less time than sutures for fixing the conjunctival graft in place during pterygium surgery. However, fibrin glue is a biological material and it carries the risk of transmitting infectious agents from pooled and single-donor blood donors and anaphylaxis in susceptible individuals. Cauterisation is another surgical option, and it would be advantageous to know whether cauterisation may be superior surgical option compared with fibrin glue. This protocol describes the rationale and design of the randomised controlled trial (RCT) in which we will compare cauterisation versus fibrin glue for conjunctival autografting in primary pterygium surgery. Methods and analyses This will be a parallel group RCT comparing cauterisation versus fibrin glue for conjunctival autografting in primary pterygium surgery. Computer-generated randomisation will be used, and allocation concealment will be conducted using sequentially numbered opaque sealed envelopes. Surgeons will not be blinded to the procedures, but participants, other investigators and outcome assessors will be blinded. Adult participants with primary pterygium operated in a tertiary hospital in Split, Croatia, will be included. Primary outcome will be recurrence of pterygium, defined as any regrowth of tissue from the area of excision across the limbus onto the cornea after 180 days. Ethics and dissemination The trial was approved by the ethics review board of the University Hospital Split (500-03/17-01/68). Results will be disseminated at conferences and through peer-reviewed publications. Trial registration number NCT03321201; Pre-results.