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Stuart Cantsilieris, Stefan J. White, Maria Schache, Robyn H. Guymer, Paul N. Baird; Assessment Of Structural And Genetic Variation At The Complement Factor H Related 1-5 Gene Cluster In Age Related Macular Degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2011;52(14):5256.
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© ARVO (1962-2015); The Authors (2016-present)
The CFHR1-5 gene region on chromosome 1q32 has been shown to contain both risk and protective genetic variants for AMD. We conducted a comprehensive study of genetic variation across the CFHR1-5 region through the combined analysis of structural variation as assessed by copy number variants (CNVs) and through the use of single nucleotide polymorphisms (SNPs) in an Australian cohort.
Multiplex Ligation-dependant Probe Amplification (MLPA) was used to measure gene copy number variation across this region. Two MLPA probes were designed in each of the five CFHR genes. We used a tag SNP (tSNPs) approach, genotyping 21 tSNPs which defined 3 linkage disequilibrium (LD) blocks. tSNPs were genotyped on the Sequenom Massarray platform.
100 cases and 100 controls were analyzed for gene copy number variation in CFHR1-5. The common CFHR1 and CFHR3 deletion was present in 20% controls and 7.9% cases, consistent with previous reports. We also found a novel rare deletion encompassing CFHR1 and CFHR4 in 1 case and a rare duplication of CFHR1 and CFHR3 in two controls. An additional 402 cases and 119 controls were analyzed using 21 t SNPs. We indentified 9 SNPs significantly associated with AMD risk, within LD block 1 and 2. Of these, the most statistically significant SNP in LD block 1 was rs16840639 2.7x10-9 (OR 3.58, 95% CI= 2.37-5.40) and in LD block 2, rs6667243 1.9x10-4(OR 1.85, 95% CI= 1.34-2.56).
Using both SNP and copy number analysis we have identified novel rare copy number variants within the CFHR1-5 region and in addition, replicated the association of the protective CFHR1 and CFHR3 deletion in an Australian cohort. Furthermore, the identification of risk associated SNPs further illustrates the importance of the CFHR1-5 gene cluster in AMD
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