Abstract
The two most common genetic contributors to age-related macular degeneration (AMD), a leading cause of irreversible vision loss worldwide, are variants associated with CFH-CFHR5 on chromosome 1 (Chr1) and ARMS2/HTRA1 on chromosome 10 (Chr10). We sought to determine if risk and protective variants associated with these two loci drive differences in macular retinal thickness prior and subsequent to the onset of clinically observable signs of AMD. We considered 299 individuals (547 eyes) homozygous for risk variants or haplotypes on Chr1 or Chr10 exclusively (Chr1-risk and Chr10-risk, respectively) or homozygous for a neutral haplotype (Chr1-neu), for the protective I62 tagged haplotype (Chr1-prot-I62) or for the protection conferring CFHR3/1 deletion haplotype (Chr1-prot-del) on Chr1 without any risk alleles on Chr10. Among eyes with no clinically observable signs of AMD, the deletion of CFHR3/1, which is strongly protective against this disease, is associated with significantly thicker retinas in the perifovea. When controlling for age, Chr10-risk eyes with early or intermediate AMD have thinner retinas as compared to eyes from the Chr1-risk group with similar disease severity. Our analysis indicates that this difference likely results from distinct biological and disease initiation and progression events associated with Chr1- and Chr10-directed AMD.
Highlights
The two most common genetic contributors to age-related macular degeneration (AMD), a leading cause of irreversible vision loss worldwide, are variants associated with CFH-CFHR5 on chromosome 1 (Chr1) and age-related maculopathy susceptibility 2 (ARMS2)/high-temperature requirement factor A1 (HTRA1) on chromosome 10 (Chr[10])
The two most common genetic contributors to AMD are variants associated with a cluster of genes (complement factor H (CFH) – complement factor H-related (CFHR) 1 to 5) located on chromosome 1 (Chr1) and variants associated with age-related maculopathy susceptibility 2 (ARMS2) and high-temperature requirement factor A1 (HTRA1), two tightly-linked genes located on chromosome 10 (Chr10)[6,7,8]
The Steele Center for Translational Medicine (SCTM) cohort, which consisted of 3473 individuals, was stratified into genetic groups based on diplotypes on Chr[1] and Chr[10]
Summary
The two most common genetic contributors to age-related macular degeneration (AMD), a leading cause of irreversible vision loss worldwide, are variants associated with CFH-CFHR5 on chromosome 1 (Chr1) and ARMS2/HTRA1 on chromosome 10 (Chr[10]). Many aspects of the natural history of AMD including conversion to late stage disease11–13, prognoses[14,15] and response to existing therapies for neovascular A MD16 differ between individuals with genetic risk on Chr[1] or Chr[10] This suggest that risk variants and haplotypes associated with the CFH-CFHR5 locus and with ARMS2/HTRA1 drive distinct biological and disease initiation and progression events. Haplotype analyses have shown that more than 90% of the genetic variability at the CFH-CFHR5 locus could be explained by four common haplotypes that include the two SNPs rs1061170, rs800292 and the deletion of CFHR3/129 One of these haplotypes confers an increased risk for AMD, two of them confer a protection against the development of disease, and one of them is present with similar frequencies in cases and controls, it is neutral[26,29]. The study identified an association between late AMD, risk haplotypes and elevated levels of circulating factor H-related protein 4
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
