Haplotypes of HTRA1 rs1120638, TIMP3 rs9621532, VEGFA rs833068, CFI rs10033900, ERCC6 rs3793784, and KCTD10 rs56209061 Gene Polymorphisms in Age-Related Macular Degeneration

Abstract

Background. To determine the impact of HTRA1 rs1120638, TIMP3 rs9621532, VEGFA rs833068, CFI rs10033900, ERCC6 rs3793784, and KCTD10 rs56209061 genotypes on the development of age-related macular degeneration (AMD) in the Lithuanian population. Methods. A total of 916 subjects were examined: 309 patients with early AMD, 301 patients with exudative AMD, and 306 healthy controls. The genotyping of HTRA1 rs11200638, TIMP3 rs9621532, VEGFA rs833068, CFI rs10033900, ERCC6 rs3793784, and KCTD10 rs56209061 was carried out using the RT-PCR method. Results. Our study showed that single-nucleotide polymorphisms rs3793784 and rs11200638 were associated with increased odds of early and exudative AMD, and the variant in KCTD10 (rs56209061) was found to be associated with decreased odds of early and exudative AMD development after adjustments for age and gender in early AMD analysis and after adjustments only for age in exudative AMD. The haplotype containing two minor alleles C-A and the G-A haplotype in rs3793784-rs11200638 were statistically significantly associated with an increased risk of exudative AMD development after adjustment for age, while the G-G haplotype showed a protective role against early and exudative AMD and the haplotype C-G in rs3793784-rs11200638 was associated with a decreased risk only of exudative AMD development. Conclusions. Our study identified two markers, rs11200638 and rs3793784, as risk factors for early and exudative AMD, and one marker, rs56209061, as a protective factor for early and exudative AMD development. The haplotypes constructed of rs3793784-rs11200638 were found to be associated with AMD development, as well.

Molecular Genetic Mechanisms in Age-Related Macular Degeneration

“…The rs5754227 [ 51 ], rs713685 [ 174 ], rs743751 [ 174 ], and rs5749482 [ 175 ] TIMP-3 intron variants have been particularly associated with an increased risk of AMD. Conversely, the rs9621532 TIMP-3 variant has been found to have a slight to moderate protective effect against AMD in some studies [ 47 , 49 , 165 , 176 ], as well as a protective effect against the development of MNV [ 177 ]—although other studies have found no association with AMD risk [ 178 , 179 ]. Finally, TIMP-3 variants rs6518799, rs756481, rs5749498, rs12170368, and rs1427385 have not been found to be associated with AMD [ 174 , 180 ].…”

“…Patients with AMD have been found to have decreased retinal ERCC6 expression [ 286 ]. Mutations in the ERCC6 gene have been inconsistently associated with increased AMD risk [ 179 , 284 , 286 , 287 , 288 ] and may have a synergic effect with CFH mutations [ 284 ].…”

Learning from Fifteen Years of Genome-Wide Association Studies in Age-Related Macular Degeneration

“…Vice versa, the clinical ophthalmologist may not be aware of the implications of a specific GWAS result for further recruitment needs. Often genetic studies deal exclusively with haplotype structures and allele frequencies but may not consider subtleties in phenotypic features [ 13 , 35 , 36 ]. Finally, clinical studies often bear the risk to leave out crucial knowledge of genetics in their interpretations and considerations [ 37 , 38 , 39 ].…”

Matrix Metalloproteinases in Age-Related Macular Degeneration (AMD)

“…Studies on the TIMP-3 rs9621532 polymorphism, which is also an intron variant, found contradictory results. Three of the reports found no statistical association between the polymorphism and the disease, while four reported that the C allele of TIMP-3 rs9621532 polymorphism was associated with a decreased risk of AMD [125,[194][195][196][197][198][199]. TIMP-3 rs9621532 polymorphism, being an intron variant, could be responsible for alteration in the gene expression.…”