Mutation in KERA Identified by Linkage Analysis and Targeted Resequencing in a Pedigree with Premature Atherosclerosis
PLOS ONE
Authors: Maiwald, Stephanie; Sivapalaratnam, Suthesh; Motazacker, Mahdi M.; van Capelleveen, Julian C.; Bot, Ilze; de Jager, Saskia C.; van Eck, Miranda; Jolley, Jennifer; Kuiper, Johan; Stephens, Jonathon; Albers, Cornelius A.; Vosmeer, C. Ruben; Kruize, Heleen; Geerke, Daan P.; van der Wal, Allard C.; van der Loos, Chris M.; Kastelein, John J. P.; Trip, Mieke D.; Ouwehand, Willem H.; Dallinga-Thie, Geesje M.; Hovingh, G. Kees
Abstract
Aims: Genetic factors explain a proportion of the inter-individual variation in the risk for atherosclerotic events, but the genetic basis of atherosclerosis and atherothrombosis in families with Mendelian forms of premature atherosclerosis is incompletely understood. We set out to unravel the molecular pathology in a large kindred with an autosomal dominant inherited form of premature atherosclerosis. Methods and Results: Parametric linkage analysis was performed in a pedigree comprising 4 generations, of which a total of 11 members suffered from premature vascular events. A parametric LOD-score of 3.31 was observed for a 4.4 Mb interval on chromosome 12. Upon sequencing, a non-synonymous variant in KERA (c. 920C. G; p. Ser307Cys) was identified. The variant was absent from nearly 28,000 individuals, including 2,571 patients with premature atherosclerosis. KERA, a proteoglycan protein, was expressed in lipid-rich areas of human atherosclerotic lesions, but not in healthy arterial specimens. Moreover, KERA expression in plaques was significantly associated with plaque size in a carotid-collar Apoe 2/2 mice (r(2) = 0.69; p, 0.0001). Conclusion: A rare variant in KERA was identified in a large kindred with premature atherosclerosis. The identification of KERA in atherosclerotic plaque specimen in humans and mice lends support to its potential role in atherosclerosis.
Determinants of bleb morphology in minimally invasive, clear-cornea micropenetrating glaucoma surgery with mitomycin C
JOURNAL OF GLAUCOMA
Authors: Kessing, SV; Flesner, P; Jensen, PK
Abstract
Purpose: Antimetabolites, especially mitomycin C (MMC), increase the incidence of late bleb-related endophthalmitis in trabeculectomy. This is related to a higher incidence of avascular, thin, cystic, translucent blebs, which may be caused by a toxic effect on conjunctival tissue. An MMC dose-response study was carried out focusing on bleb morphology and function. Patients and Methods: In a retrospective, comparative case series study, 2 successive groups of patients with complicated glaucoma were compared 2 years after a special, minimally invasive, filtering procedure (intrastromal holmium laser kera-tostomy). Preoperative local subconjunctival injections of a fixed MMC dose (4 mu g) were used in group A, and lower M MC doses, calculated individually (1 or 2 mu g), were used in group B. Bleb vascularity and morphology were evaluated by masked grading of photomicrographs. Bleb function was evaluated by intraocular pressure (IOP). Results: Total bleb avascularity occurred in 63% of the blebs in group A and 0% in group B (P < 0.01). In eyes with IOP <= 20mm Hg without medical treatment, the mean TOP was significantly lower in group 1 (8 vs 15mm Hg, P < 0.002). A translucent cystic bleb without conjunctival stroma was observed in only 1 eye in group A. An optimal spongy stromal bleb was observed in all other eyes (96%) despite the different MMC doses. The numbers of complications in the 2 groups were nearly equal. Conclusions: Bleb avascularity after 4 mu g MMC could be avoided by the use of 1 or 2 mu g MMC on the basis of preoperative prognosticators for failure, but at the expense of some of IOP-lowering effect. This indicates that the therapeutic index (clinical safety margin) of MMC seems to be narrow. An MMC dose-response relation was not observed for the thin, cystic, and translucent bleb. The low incidence of this bleb (4%) indicates that the operative technique, apart from the vascularity, may be the most essential determinant of bleb morphology.