No associations appeared between HIF1A SNPs and AMD, which were studied here for the first time; however, polymorphism rs1061170 of the CFH gene is associated with AMD in our population.
Complement activation plays a significant role in age-related macular degeneration (AMD) pathogenesis, and polymorphisms interfering with factor H (fH) function, a complement alternative pathway (AP) inhibitor, are associated with increased AMD risk.
Here, we investigate the consequences of aHUS-linked mutations (R53H and R78G) within the FH N-terminal complement control protein module that also carries the I62V variation linked to dense-deposit disease and age-related macular degeneration.
In a similar study, we also failed to sustain an association between C4BP polymorphisms and predisposition to age-related macular degeneration, another disorder which is associated strongly with polymorphisms in factor H, and is thought to involve alternative pathway dysregulation.
We studied a single nucleotide polymorphism (SNP) in each patient for each of the genes associated with high susceptibility to developing AMD using Real-time PCR with TaqMan probes for CFH and ARMS2 polymorphisms and PCR-RFLP for HTRA1 polymorphism.
The epistatic interactions newly found by AprioriGWAS on AMD data are likely true interactions, since genes interacting with CFH are retinal genes, and GO term enrichment also verified that interaction between glycosaminoglycans (GAGs) and CFH plays an important role in disease pathology of AMD.
CFH and LOC387715/HTRA1 haplotypes and smoking status exerted large effects on AMD susceptibility, enabling risk scores to be generated with appropriate weighting of these three factors.
In addition to CFH (rs800292, P = 4.23 × 10(-15)) and ARMS2 (rs3750847, P = 8.67 × 10(-29)) loci, we identified two new susceptibility loci for exudative AMD: TNFRSF10A-LOC389641 on chromosome 8p21 (rs13278062, combined P = 1.03 × 10(-12), odds ratio = 0.73) and REST-C4orf14-POLR2B-IGFBP7 on chromosome 4q12 (rs1713985, combined P = 2.34 × 10(-8), odds ratio = 1.30).
Furthermore, an independent association of C2/CFB variants was found for both typical AMD and PCV with age, sex, smoking, and genetic background of ARMS2 A69S and CFHI62V (vs. typical AMD: P = 0.0073, odds ratio [OR] = 0.47; vs. PCV: P = 0.0083, OR = 0.53).
In addition, we identify the Factor H-like protein 1 (FHL-1), an alternative splice product of the CFH gene as an additional protein that includes the risk residue 402, and thus confers risk for AMD.
To evaluate the efficacy of using a CRISPR/Cas-mediated strategy to correct a common high-risk allele that is associated with age-related macular degeneration (AMD; rs1061170; NM_000186.3:c.1204T>C; NP_000177.2:p.His402Tyr) in the complement factor H <i>(CFH)</i> gene.
We analyzed the CFH duplication and deletion by multiplex ligation probe amplification (MLPA) and found no duplication and deletion in CFH gene in AMD patients.
After multivariate adjustment, CFHY402H and ARMS2 A69S polymorphisms were associated with very high risk for exudative AMD (OR = 6.21 and OR = 11.7, respectively, p < 0.0001).