Molecular Genetics of Age-related Macular Degeneration

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Title: Molecular Genetics of Age-related Macular Degeneration
Author: Seitsonen, Sanna
Contributor: University of Helsinki, Faculty of Medicine, Institute of Clinical Medicine
Thesis level: Doctoral dissertation (article-based)
Abstract: Age-related macular degeneration (AMD; OMIM # 603075) is an eye disease of the elderly, signs of which appear after the age of 50. In the Western world it is a leading cause of permanent visual loss with a prevalence of 8.5% in persons under 54 years of age and of 37% in persons over 75 years of age. Early forms of AMD may be asymptomatic, but in the late forms usually a central scotoma in the visual field follows severely complicating daily tasks. Smoking, age, and genetic predisposition are known risk factors for AMD. Until recently no true susceptibility genes had been identified though the composition of drusen deposits, the hallmarks of AMD, has suggested that the complement system might play a role in the pathogenesis of AMD. When four groups reported in March 2005, that, on chromosome 1q32, a Y402H variant in the complement factor H (CFH) gene confers risk for AMD in independent Caucasian samples, a new period in the field of genetic research of AMD started. CFH is a key regulator of the complement system. Thus, it is logical to speculate, that it plays a role in the pathogenesis of AMD. We performed a case-control association study to analyse whether the CFH Y402H variant contain a risk for AMD in the Finnish population. Although the population of Finland represents a genetic isolate, the CFH Y402H polymorphism was associated with AMD also in our patient sample with similar risk allele frequencies as in the other Caucasian populations. We further evaluated the effects of this variant, but no association between lesion subtype (predominantly classic, minimally classic or occult lesion) or lesion size of neovascular AMD and the CFH Y402H variant was detected. Neither did the variant have an effect on the photodynamic therapy (PDT) outcome. The patients that respond to PDT carried the risk genotype as frequently as those who did not respond, and no difference was found in the number of PDT sessions needed in patients with or without the risk genotypes of CFH Y402H. Functional analyses, however, showed that the binding of C-reactive protein (CRP) to CFH was significantly reduced in patients with the risk genotype of Y402H. In the past two years, the LOC387715/ high-temperature requirement factor A1 (HTRA1) locus on 10q26 has also been repeatedly associated with AMD in several populations. The recent discovery of the LOC387715 protein on the mitochondrial outer membrane suggests that the LOC387715 gene, not HTRA1, is the true predisposing gene in this region, although its biological function is still unknown. In our Finnish patient material, patients with AMD carried the A69S risk genotype of LOC387715 more frequently than the controls. Also, for the first time, an interaction between the CFH Y402H and the LOC387715 A69S variants was found. The most recently detected susceptibilty gene of AMD, the complement component 3 (C3) gene, encodes the central component of the complement system, C3. In our Finnish sample, an additive gene effect for the C3 locus was detected, though weaker than the effects for the two main loci, CFH and LOC387715. Instead, the hemicentin-1 or the elongation of very long chain fatty acids-like 4 genes that have also been suggested as candidate genes for AMD did not carry a risk for AMD in the Finnish population. This was the first series of molecular genetic study of AMD in Finland. We showed that two common risk variants, CFH Y402H and LOC387715 A69S, represent a high risk of AMD also in the isolated Finnish population, and furthermore, that they had a statistical interaction. It was demonstrated that the CFH Y402H risk genotype affects the binding of CFH to CRP thus suggesting that complement indeed plays an important role in the pathogenesis of AMD.Silmänpohjan ikärappeuma on yleisin näkövammaisuutta aiheuttava sairaus länsimaissa. Suomessa sitä esiintyy noin 40%.lla yli 70-vuotiaista. Se on silmän verkkokalvon tarkan näkemisen alueen sairaus, joka voi aiheuttaa näkökentän keskeiseen osaan laajan puutosalueen, ja voi siten heikentää näkökykyä oleellisesti. Silmänpohjan ikärappeuman kiistattomia riskitekijöitä ovat ikä, perintötekijät ja tupakointi. Molekyyligeneettisten tutkimusten avulla on voitu viime vuosina osoittaa, että silmänpohjan ikärappeumalla on vahva immunologinen tausta. Kaksi ikärappeumaan liittyvistä alttiusgeeneistä komplementtifaktori H ja C3 vaikuttavat ihmisen immuunipuolustukseen. HTRA1 ja LOC387715-geenit ovat uusia geenejä, joiden toiminnasta on vielä vähän tietoa. Näistä LOC3817715 on uusi mitokondrion ulkokalvon proteiini, joka ilmentyy verkkokalvon soluissa ja vaikuttaa todennäköiseltä alttiusgeeniltä. Tässä väitöskirjatyössä on tutkittu edellä mainittuja silmän ikärappeuman alttiusgeenejä 300 suomalaisen potilaan aineistossa. Kyseisten alttiusgeenien variantit assosioituvat ikärappeumaan myös suomalaisilla potilailla ja riskialleelien frekvenssit olivat samaa tasoa kuin muissa kaukasialaisissa populaatioissa. Väitöskirjassa selvitettiin tarkemmin CFH Y402H polymorfismin merkitystä ikärappeuman synnyssä. CFH Y402H genotyypin ei todettu vaikuttavan siihen, minkälainen pitkälle edenneen ikärappeuman muoto (predominantly classic, minimally classic tai occult) potilaalla oli tai siihen, miten ikärappeumapotilas reagoi fotodynamiseen hoitoon, joka on viime vuosiin asti ollut pääasiallinen kostean ikärappeuman hoitomuoto. Väitöskirjassa osoitettiin myös, että tekijä H:n Y402H:n genotyyppi vaikutti tulehdusta ilmentävän C-reaktiivisen proteiinin sitoutumiseen. Silmän ikärappeumaa voidaan pitää oligogeenisenä tautina eli sen syntyyn vaikuttavat vain harvat suuren riskin sisältämät geenit. Niiden löytyminen auttaa osaltaan uusien hoitomuotojen kehittämisessä.
URI: URN:ISBN:978-952-10-4641-4
Date: 2008-04-18
Subject: lääketiede, silmätautioppi
medicine, ophthalmology
Rights: This publication is copyrighted. You may download, display and print it for Your own personal use. Commercial use is prohibited.

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