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Published on: July 14, 2016
A rare penetrant mutation in CFH confers high risk of age-related macular degeneration
Soumya Raychaudhuri1, Oleg Iartchouk, Kimberly Chin
1Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA. soumya@broadinstitute.org
Insights
Researchers identified a rare, high-risk mutation in the complement factor H (CFH) gene. This discovery provides mechanistic insights into how CFH gene variants contribute to age-related macular degeneration (AMD) risk.
Area of Science:
- Genetics
- Ophthalmology
- Molecular Biology
Background:
- Common variants in the complement factor H (CFH) gene, specifically Y402H and rs1410996, are associated with age-related macular degeneration (AMD) risk.
- The precise role of CFH and the mechanism of susceptibility alleles in AMD remain unclear.
Purpose of the Study:
- To investigate rare functional variants in the CFH gene for mechanistic insights into AMD susceptibility.
- To identify and characterize high-risk mutations within the CFH gene.
Main Methods:
- Utilized genotype data and high-throughput sequencing to discover rare CFH variants.
- Genotyped a specific CFH mutation (R1210C) in a cohort of 2,423 AMD cases and 1,122 controls.
Main Results:
- Discovered a rare, high-risk CFH haplotype with a c.3628C>T mutation (R1210C substitution).
- This R1210C allele, previously linked to atypical hemolytic uremic syndrome, abrogates C-terminal ligand binding.
- The R1210C mutation showed high penetrance in AMD cases (40 cases vs. 1 control) and was associated with an earlier disease onset (6 years sooner).
Conclusions:
- Loss-of-function alleles in the CFH gene are strongly implicated as a driver of AMD risk.
- This study exemplifies how investigating common disease variants can lead to the discovery of rare, highly penetrant mutations with significant mechanistic implications.
Abstract:
Two common variants in the gene encoding complement factor H (CFH), the Y402H substitution (rs1061170, c.1204C>T)(1-4) and the intronic rs1410996 SNP(5,6), explain 17% of age-related macular degeneration (AMD) liability. However, proof for the involvement of CFH, as opposed to a neighboring transcript, and knowledge of the potential mechanism of susceptibility alleles are lacking. Assuming that rare functional variants might provide mechanistic insights, we used genotype data and high-throughput sequencing to discover a rare, high-risk CFH haplotype with a c.3628C>T mutation that resulted in an R1210C substitution. This allele has been implicated previously in atypical hemolytic uremic syndrome, and it abrogates C-terminal ligand binding(7,8). Genotyping R1210C in 2,423 AMD cases and 1,122 controls demonstrated high penetrance (present in 40 cases versus 1 control, P = 7.0 × 10(-6)) and an association with a 6-year-earlier onset of disease (P = 2.3 × 10(-6)). This result suggests that loss-of-function alleles at CFH are likely to drive AMD risk. This finding represents one of the first instances in which a common complex disease variant has led to the discovery of a rare penetrant mutation.
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