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Published on: July 14, 2016
Genetic analysis of complement factor H related 5, CFHR5, in patients with age-related macular degeneration
Umadevi Narendra1, Gayle J T Pauer, Stephanie A Hagstrom
1Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Insights
Genetic variations in the CFHR5 gene are not a major cause of age-related macular degeneration (AMD). However, the Asp169Asp variant may offer some protection against AMD.
Area of Science:
- Genetics
- Ophthalmology
- Molecular Biology
Background:
- Age-related macular degeneration (AMD) is a leading cause of vision loss.
- The complement system, including complement factor H (CFH) and its related proteins, plays a role in AMD pathogenesis.
- The complement factor H related 5 (CFHR5) gene is a potential candidate for AMD association studies.
Purpose of the Study:
- To investigate the complement factor H related 5 (CFHR5) gene for genetic polymorphisms or mutations linked to age-related macular degeneration (AMD).
Main Methods:
- Direct genomic sequencing of the ten coding exons and flanking intronic DNA of CFHR5 in 639 AMD patients and 663 controls.
- Computational analysis using PolyPhen and PMut algorithms to assess the pathologic impact of identified sequence variants.
Main Results:
- Five heterozygous sequence changes were identified in CFHR5.
- The Asp169Asp variant showed a significantly lower frequency in AMD patients compared to controls (p<0.0001).
- Met514Arg was predicted to be damaging to CFHR5 protein function, while other variants were deemed neutral or benign.
Conclusions:
- No definitive pathogenic CFHR5 mutations were found in AMD patients, suggesting CFHR5 variations are not a major determinant of AMD susceptibility.
- The Asp169Asp variant may have a protective role against AMD, warranting further investigation in larger populations.
- Sequence variations in CFHR5 do not appear to be a primary cause of AMD.
Purpose:
To investigate the complement factor H related 5 (CFHR5) gene, encoding a member of the complement factor H family, for the presence of genetic polymorphisms or mutations associated with age-related macular degeneration (AMD).
Methods:
We screened 639 unrelated patients with AMD and 663 age-matched normal controls using direct genomic sequencing of the ten coding exons, along with the immediately flanking intronic DNA. The pathologic impact of the identified sequence variants were analyzed by computational methods using PolyPhen and PMut algorithms.
Results:
We identified five heterozygous sequence changes in CFHR5. Asp169Asp had a minor allele frequency of 0.001% in patients and 0.014% in controls (p<0.0001), while Arg356His had a minor allele frequency of 0.016% in patients and 0.007% in controls. Val379Leu, Met514Arg, and Cys568Ter were found only in normal controls. In silico analysis predicted Arg356His and Val379Leu to be neutral and benign. Met514Arg was predicted to be pathological and damaging to the function of the CFHR5 protein.
Conclusions:
No definitive pathogenic CFHR5 mutations have been found in any of 639 unrelated patients with AMD, indicating that sequence variations in CFHR5 do not play a major role in determining AMD susceptibility. However, our findings suggest a possible protective role for Asp169Asp. Further studies of different and larger populations of patient and control samples will be required to address this observation.
