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.
Highlights
Age-related macular degeneration (AMD) is the leading cause of visual impairment in the elderly in developed countries, most prominently in white populations [1,2]
We considered MerTK and its ligand Gas6 as candidate genes to play a role in AMD pathogenesis and searched for association between their polymorphisms and the disease
The p.Tyr402His polymorphisms of the complement factor H (CFH) gene, the rs11200638 polymorphism of the serine peptidase HTRA serine peptidase 1 (HTRA1) and the p.Ala69Ser polymorphism of the LOC387715 gene are unequivocally associated to AMD in different populations with robust risks
Summary
Age-related macular degeneration (AMD) is the leading cause of visual impairment in the elderly in developed countries, most prominently in white populations [1,2]. AMD is a multifactorial disease characterized by progressive degeneration of the central retina leading to visual deterioration. Two advanced forms of the disease are distinguished: extensive pigment epithelium atrophy referred to as geographic atrophy (GA) leading to irreversible and untreatable visual deterioration or subretinal neovascular membrane (SRNVM) formation characterized by intra- or subretinal invasion of new vessels arising from the choroid. The etiology of the disease is still largely unclear, several risk factors have been unequivocally linked to AMD, including advanced age, European origin and smoking. Cataract surgery has been shown to increase risk exclusively of dry late AMD, carriers of two complement factor H (CFH) risk alleles are prone to develop all types of AMD [7]
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