title: Effect of the Gas6 c.834+7G>A polymorphism and the interaction of known risk factors on AMD pathogenesis in Hungarian patients.
abstract: Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the developed world. Numerous genetic factors contribute to the development of the multifactorial disease. We performed a case-control study to assess the risk conferred by known and candidate genetic polymorphisms on the development of AMD. We searched for genetic interactions and for differences in dry and wet AMD etiology. We enrolled 213 patients with exudative, 67 patients with dry AMD and 106 age and ethnically matched controls. Altogether 12 polymorphisms in Apolipoprotein E, complement factor H, complement factor I, complement component 3, blood coagulation factor XIII, HTRA1, LOC387715, Gas6 and MerTK genes were tested. No association was found between either the exudative or the dry form and the polymorphisms in the Apolipoprotein E, complement factor I, FXIII and MerTK genes. Gas6 c.834+7G>A polymorphism was found to be significantly protective irrespective of other genotypes, reducing the odds of wet type AMD by a half (OR = 0.50, 95%CI: 0.26-0.97, p = 0.04). Multiple regression models revealed an interesting genetic interaction in the dry AMD subgroup. In the absence of C3 risk allele, mutant genotypes of both CFH and HTRA1 behaved as strongly significant risk factors (OR = 7.96, 95%CI: 2.39 = 26.50, p = 0.0007, and OR = 36.02, 95%CI: 3.30-393.02, p = 0.0033, respectively), but reduced to neutrality otherwise. The risk allele of C3 was observed to carry a significant risk in the simultaneous absence of homozygous CFH and HTRA1 polymorphisms only, in which case it was associated with a near-five-fold relative increase in the odds of dry type AMD (OR = 4.93, 95%CI: 1.98-12.25, p = 0.0006). Our results suggest a protective role of Gas6 c.834+7G>A polymorphism in exudative AMD development. In addition, novel genetic interactions were revealed between CFH, HTRA1 and C3 polymorphisms that might contribute to the pathogenesis of dry AMD.
authors.affiliation: Department of Ophthalmology, University of Debrecen, Debrecen, Hungary. losigeri@gmail.com
authors.forename: Gergely
authors.initials: G
authors.lastname: Losonczy
authors.forename: Attila
authors.initials: A
authors.lastname: Vajas
authors.forename: Lili
authors.initials: L
authors.lastname: Takács
authors.forename: Erika
authors.initials: E
authors.lastname: Dzsudzsák
authors.forename: Agnes
authors.initials: A
authors.lastname: Fekete
authors.forename: Eva
authors.initials: E
authors.lastname: Márhoffer
authors.forename: László
authors.initials: L
authors.lastname: Kardos
authors.forename: Eva
authors.initials: E
authors.lastname: Ajzner
authors.forename: Begoña
authors.initials: B
authors.lastname: Hurtado
authors.forename: Pablo Garcia
authors.initials: PG
authors.lastname: de Frutos
authors.forename: András
authors.initials: A
authors.lastname: Berta
authors.forename: István
authors.initials: I
authors.lastname: Balogh
mesh_terms: D000368:Aged; D000483:Alleles; D001057:Apolipoproteins E / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D006814:Hungary; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D008967:Molecular Biology; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012044:Regression Analysis; D012306:Risk; D012307:Risk Factors; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D001057:Apolipoproteins E; D036341:Intercellular Signaling Peptides and Proteins; D000099255:Growth Arrest-Specific Protein 6