René Hoehn

Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus

Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10−8). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4–1.88, P = 2.7 × 10−10, and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29–1.68, P = 4.9 × 10−9). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10−4; tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.

Distribution of Intraocular Pressure and Its Association with Ocular Features and Cardiovascular Risk Factors: The Gutenberg Health Study

PURPOSE To describe the distribution of intraocular pressure (IOP) and its association with ocular features and cardiovascular risk factors in an adult European cohort. DESIGN Population-based, cross-sectional study. PARTICIPANTS This analysis was based on a Gutenberg Health Study (GHS) cohort that included 4335 eligible enrollees from among 5000 subjects who participated in the survey from 2007 through 2008. The age range was 35 to 74 years at enrollment. METHODS Participants underwent a standardized protocol with a comprehensive questionnaire; ophthalmic examination including slit-lamp biomicroscopy, noncontact tonometry, fundus photography, central corneal thickness measurement, and visual field testing; and a thorough general examination focused on cardiovascular parameters, psychological evaluation, and laboratory tests, including genetic analysis. MAIN OUTCOME MEASURES Mean and reference interval of IOP stratified by age, gender, and eye. RESULTS Mean ± standard deviation (SD) IOP was 14.0 ± 2.6 mmHg in both eyes, 13.9 ± 2.7 mmHg in right eyes, and 14.0 ± 2.7 mmHg in left eyes. Mean ± SD IOP in men (n = 2216) and in women (n = 2119) was 14.1 ± 2.7 mmHg and 13.9 ± 2.5 mmHg with an intersex difference (P = 0.009). Positive univariate associations with higher IOP were detected for brown iris color, central corneal thickness, hypertension, diabetes, smoking, obesity, dyslipidemia, body mass index, weight, hip size (women only), waist circumference, and waist-to-hip ratio. Multivariate testing revealed male gender, central corneal thickness, brown iris color, hypertension, smoking, and waist-to-hip ratio to be correlated with higher IOP. In women, age correlated negatively with IOP in the multivariate analysis. CONCLUSIONS Intraocular pressure distribution in this cohort yielded a lower mean IOP than in similar white study populations. Increasing age in women correlated with lower IOP. Association analyses with several systemic characteristics revealed that cardiovascular risk factors correlated with higher IOP. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Prevalence and Cardiovascular Associations of Diabetic Retinopathy and Maculopathy: Results from the Gutenberg Health Study

Objective Diabetic retinopathy (DR) is the leading cause of blindness in people of working age. The purpose of this paper is to report the prevalence and cardiovascular associations of diabetic retinopathy and maculopathy (DMac) in Germany. Research Design and Methods The Gutenberg Health Study (GHS) is a population-based study with 15,010 participants aged between 35 at 74 years from the city of Mainz and the district of Mainz-Bingen. We determined the weighted prevalence of DR and DMac by assessing fundus photographs of persons with diabetes from the GHS data base. Diabetes was defined as HbA1c ≥ 6.5%, known diagnosis diabetes mellitus or known diabetes medication. Furthermore, we analysed the association between DR and cardiovascular risk factors and diseases. Results Overall, 7.5% (1,124/15,010) of the GHS cohort had diabetes. Of these, 27.7% were unaware of their disease and thus were newly diagnosed by their participation in the GHS. The prevalence of DR and DMac was 21.7% and 2.3%, respectively among patients with diabetes. Vision-threatening disease was present in 5% of the diabetic cohort. In the multivariable analysis DR (all types) was associated with age (Odds Ratio [95% confidence interval]: 0.97 [0.955–0.992]; p = 0.006) arterial hypertension (1.90 [1.190–3.044]; p = 0.0072) and vision-threatening DR with obesity (3.29 [1.504–7.206]; p = 0.0029). DR (all stages) and vision-threatening DR were associated with duration of diabetes (1.09 [1.068–1.114]; p<0.0001 and 1.18 [1.137–1.222]; p<0.0001, respectively). Conclusions Our calculations suggest that more than a quarter-million persons have vision-threatening diabetic retinal disease in Germany. Prevalence of DR was lower in the GHS compared to East-Asian studies. Associations were found with age, arterial hypertension, obesity, and duration of diabetes mellitus.

Distribution of central corneal thickness and its association with ocular parameters in a large central European cohort: the Gutenberg health study.

Main objective To evaluate the distribution of central corneal thickness (CCT) in a large German cohort and to analyse its relationship with intraocular pressure and further ocular factors. Design Population-based, prospective, cohort study. Methods The Gutenberg Health Study (GHS) cohort included 4,698 eligible enrollees of 5,000 subjects (age range 35–74 years) who participated in the survey from 2007 to 2008. All participants underwent an ophthalmological examination including slitlamp biomicroscopy, intraocular pressure measurement, central corneal thickness measurement, fundus examination, and were given a questionnaire regarding glaucoma history. Furthermore, all subjects underwent fundus photography and visual field testing using frequency doubling perimetry. Results Mean CCT was 557.3±34.3 µm (male) and 551.6±35.2 µm in female subjects (Mean CCT from right and left eyes). Younger male participants (35–44 years) presented slightly thicker CCT than those older. We noted a significant CCT difference of 4 µm between right and left eyes, but a high correlation between eyes (Wilcoxon test for related samples: p<0.0001). Univariable linear regression stratified by gender showed that IOP was correlated with CCT (p<0.0001). A 10 µm increase in CCT led to an increase in IOP between 0.35–0.38 mm Hg, depending on the eye and gender. Multivariable linear regression analysis revealed correlations between gender, spherical equivalent (right eyes), and CCT (p<.0001 and p = 0.03, respectively). Conclusions We observed positive correlations between CCT and IOP and gender. CCT was not correlated with age, contact lens wear, positive family history for glaucoma, lens status, or iris colour.

Correlations between central corneal thickness and general anthropometric characteristics and cardiovascular parameters in a large European cohort from the Gutenberg Health Study.

Purpose: The aim of this study was to evaluate the correlations between general anthropometric features and cardiovascular parameters and central corneal thickness (CCT) in an adult European cohort. Methods: Analysis was based on a Gutenberg Health Study cohort that included 5000 subjects (2540 male, 2460 female), aged 35 to 74 years at enrollment. The participants underwent a standardized protocol with a comprehensive questionnaire; ophthalmic examination (slit-lamp biomicroscopy; autorefractometry; noncontact tonometry; fundus photography; CCT measurements (optical pachymetry); visual field testing; and a thorough general examination focused on cardiovascular parameters, psychosomatic evaluation, and laboratory tests including genetic analysis. Results: Reliable CCT measurements were available for 4708 right eyes (OD, 94.2%), 4721 left eyes (OS, 94.4%), and both eyes (OU) in 4698 subjects (94.0%). The mean CCT was 555 ± 35 &mgr;m in men and 549 ± 35 &mgr;m in women. In multiple linear regression analysis, the CCT was associated with gender [P < 0.001 for OU], body height [in men, P = 0.007 for OD, P = 0.04 for OS; in women P < 0.001 for OU], and body mass index (P < 0.001 for OD, P = 0.001 for OS). In men only, the CCT correlated with the body weight [P = 0.024 (OD), P = 0.048 (OS)] and smoking [P = 0.006 (OD), P < 0.001 (OS)]. No correlations were found between the CCT and dyslipidemia, diabetes, or hypertension. Conclusions: The CCT was associated with male gender, body height, and body mass index in an adult white cohort. It correlated with body weight and nicotine abuse in men only. No associations were found between the CCT and dyslipidemia, diabetes, or hypertension.

Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility

Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1, that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically diverse population of mice with known sequence variants, we are able to determine that the intraocular pressure-lowering effect of pregabalin is dependent on the Cacna2d1 haplotype. Using human genome-wide association study (GWAS) data, evidence for association of a CACNA2D1 single-nucleotide polymorphism and primary open angle glaucoma is found. Importantly, these results demonstrate that our systems genetics approach represents an efficient method to identify genetic variation that can guide the selection of therapeutic targets.Elevated intraocular pressure (IOP) is a heritable risk factor for primary open angle glaucoma. Using forward mouse genetics, cell biology, pharmacology and human genetic data, the authors identify CACNA2D1 as an IOP risk gene that can be therapeutically targeted by the drug pregabalin in animal models.

Seizures following subconjunctival 5-FU therapy

Dear Editor, Antiproliferative treatment following glaucoma surgery includes subconjunctival 5-fluorouracil (5-FU) injections as a routine procedure. Cumulative dosage during the postoperative period is adjusted to individual needs ranging from 5 to 75 mg. We report the case of a 68-year-old male Caucasian patient who underwent uneventful trabeculectomy for advanced primary open-angle glaucoma with intraoperative application of Mitomycin C. Under topical anesthesia with tetracaine eye drops, a subconjunctival injection of 5 mg 5-FU was administered on postoperative day 4. A few minutes later, a generalized tonic and clonic seizure occurred lasting for 3 min that ended spontaneously. A second episode of seizures happened 3 h later. The patient did not retain any memory of the episode and amnesia was observed for the immediate postictal period. However, epilepsy was hitherto unknown in this patient nor did his medical history give any hints as to such a condition. Known systemic conditions included arterial hypertension, coronary heart disease, congenital aortic coarctation, hyperlipidemia, and prostate hyperplasia. Neurologic examination including electroencephalography and cranial imaging revealed spike wave complexes, but no specific focus. Thirteen days later, two more subconjunctival injections of 5 mg 5-FU were applied without complications under anticonvulsive therapy with Valproic acid 300 mg twice a day. No more seizures occurred in the domestic environment. When trabeculectomy was performed on the fellow eye 4 months later, 5 mg 5-FU was again applied to prevent bleb scarring without obvious complications. Upon a 5-h interval after the second injection, two more grand-mal convulsions occurred despite permanent therapy with gabapentin 300 mg three times a day and acute therapy with lorazepam 1 mg after the first seizure. Afterwards, the therapy was modified to Valproic acid 600 mg twice a day. 5-fluorouracil is a pyrimidine antimetabolite that prevents DNA synthesis and inhibits RNA processing and function. It quickly penetrates the blood–brain barrier and achieves significant concentrations within the cerebrospinal fluid. Observed neurotoxicity of 5-FU as a commonly used, systemic chemotherapy agent is estimated <1% [1–3], but also up to 5.7% [4, 5] in high-dose chemotherapy. Acute neurotoxicity is dose-related and generally reversible [6]. It typically manifests as encephalopathy with somnolence and confusion or cerebellar syndrome. However, seizures are described in a few cases [3, 6], and in only one case as isolated generalized tonic-clonic seizures [7]. The exact pathways of neurotoxicity are not completely understood. The most plausible pathogenetic mechanism for developing seizures or paresis-like symptoms may be the Krebs cycle blockade by fluoroacetate and fluorocitrate, which results in a reduction of high-energy adenosine triphosphate [2, 8, 9]. Other proposed mechanisms are thiamine deficiency and inherited deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD), which metaboPresentation at a conference Parts of this case report were presented at the 107th Congress of the Deutschen Ophthalmologischen Gesellschaft (DOG), Leipzig

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = −0.62, P = 5.30 × 10−5) but not between CCT and primary open-angle glaucoma (r = −0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.Reduced central corneal thickness (CCT) is observed in common eye diseases as well as in rare Mendelian disorders. Here, in a cross-ancestry GWAS, the authors identify 19 novel genetic loci associated with CCT, a subset of which is involved in rare corneal or connective tissue disorders.