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Human Molecular Genetics Advance Access originally published online on December 15, 2007
Human Molecular Genetics 2008 17(7):971-977; doi:10.1093/hmg/ddm369
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Deletion of CFHR3 and CFHR1 genes in age-related macular degeneration

Kylee L. Spencer1, Michael A. Hauser3, Lana M. Olson1, Silke Schmidt3, William K. Scott5, Paul Gallins5, Anita Agarwal2, Eric A. Postel4, Margaret A. Pericak-Vance5 and Jonathan L. Haines1,*

1 Center for Human Genetics Research and 2 Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, USA 3 Center for Human Genetics and 4 Duke University Eye Center and Department of Ophthalmology, Duke University Medical Center, Durham, NC, USA 5 Miami Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA

* To whom correspondence should be addressed at: Center for Human Genetics Research, 519 Light Hall, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Tel: +1 6153435851; Fax: +1 6153438619; Email: jonathan{at}chgr.mc.vanderbilt.edu

Received October 9, 2007; Accepted December 11, 2007


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 SUPPLEMENTARY MATERIAL
 FUNDING
 REFERENCES
 
Age-related macular degeneration (AMD) impairs vision for ~7.5 million Americans. Both susceptibility variants and protective haplotypes in the complement factor H (CFH) gene modulate risk for AMD. Recently, deletion of the ‘CFH-related’ genes CFHR1 and CFHR3 was found to be segregating with a particular CFH haplotype, which reduced the risk of AMD. We tested the deletion for association in a Caucasian population of 780 cases and 265 controls and examined its effect in the context of known AMD risk factors. The deletion did not segregate perfectly with any one SNP, as previously suggested. CFH haplotype P2 was the most frequent haplotype in deletion homozygotes (47%), and the majority (14/16) of these individuals were homozygous for the non-risk allele of Y402H. Overall, deletion homozygosity was significantly more frequent in controls than cases (2.6% controls, 0.8% cases, P = 0.025, OR = 0.29, 95% CI = 0.10–0.86). After controlling for age, Y402H, smoking and LOC387715 A69S, the protective effect of the deletion was no longer statistically significant (P = 0.27). However, using a CFH haplotype that all deletion homozygotes share as a surrogate for the deletion, this marker remained modestly associated with AMD after adjustment for known risk factors (OR = 0.63, 95% CI 0.39–1.04, P = 0.07). Therefore, deletion of CFHR1 and CFHR3 may account for a small portion of the protection from AMD associated with particular haplotypes in CFH. The presence of protective haplotypes in CFH that do not carry the deletion, suggests that other protective variants in this region have yet to be discovered.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 SUPPLEMENTARY MATERIAL
 FUNDING
 REFERENCES
 
The genetic etiology of age-related macular degeneration (AMD), the leading cause of blindness in the elderly, is beginning to be unraveled with the discovery of the associations with Y402H in complement factor H (CFH) on chromosome 1 and LOC387715 A69S on chromosome 10 (1–5). Taking into account known environmental/lifestyle risk factors for AMD has aided the search for pre-disposing genetic variants, as was the case when cigarette smoking was suggested to act synergistically with the LOC387715 variant to further increase susceptibility (6,7), though this was not confirmed by all studies (8,9). Furthermore, polymorphisms that reduce the risk of AMD are now being identified, including variants in factor B and complement component 2 on chromosome 6 (10,11).

The CFH gene resides within the region of complement activation (RCA) gene cluster, which also includes five ‘CFH-related’ genes (Fig. 1). While the function of the CFHR genes is largely unknown, the high degree of sequence similarity between these genes and the suggestion that they arose out of duplication events with CFH suggest an overlapping function of the CFHR genes in immune system function and/or regulation.


Figure 1
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  		Figure 1. The Region of Complement Activation Gene Cluster. Exons are represented by solid vertical lines under each gene. The deletion of the CFHR3 and CFHR1 genes is indicated by the solid blue box. SNP positions and the deletion position are approximate. Adapted by permission from Macmillan Publishers Ltd: Nature Genetics. Hughes et al. (14).

 
In Caucasians, haplotype analysis of CFH has revealed two common protective haplotypes (P1, P2) and a neutral haplotype, in addition to the common risk haplotype carrying the C allele of CFH Y402H (Fig. 2) (12–15). However, synthesis of these results has been complicated since not every study used the same variants to define the haplotypes in the region. Nevertheless, from the frequencies of each haplotype and from the SNPs that do overlap between studies, it appears that P1, P2 and the neutral haplotypes are the same across the four studies (Figs 2 and 4). Furthermore, if rs419137 is excluded from Hughes et al., then the risk 1 and risk 2 haplotypes merge into a single risk haplotype with a frequency of 61% in cases and 41% in controls, somewhat similar to the frequency of the risk haplotype in the other two Caucasian populations.


Figure 2
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  		Figure 2. Frequencies of protective, risk, and neutral haplotypes in various studies. Okamoto et al. (16) studied a Japanese population; all others are Caucasian. We assumed based on the frequencies and the SNPs that overlap, that the P1, P2, risk and neutral haplotypes are equivalent across the studies, but that is not certain. The alleles at rs2019724 and rs2274700 from Hughes et al. (14) were switched to the opposite strand, so that they match the strand genotyped in this study. CFH Y402H = rs1061170.

 


Figure 4
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  		Figure 4. Haplotype frequencies in the deletion homozygotes compared with the complete data set. Alleles shared between all haplotypes and alleles shared between most haplotypes in the deletion homozygotes are marked in red and blue boxes, respectively. Notice, the overall frequency of P2 is 6%, but this increases to 47% in deletion homozygotes. The P1, risk and neutral haplotypes are not found in the deletion homozygotes.

 
Interestingly, in the Japanese population the frequency of the risk haplotype is much lower than in Caucasians and is equal in cases and controls, suggesting that the C allele of CFH Y402H is not a major risk factor for AMD in the Japanese (16). This lack of association with CFH Y402H was later confirmed in other Japanese populations (17–20). Despite this, two haplotypes unique to the Japanese and not carrying the C allele at CFH Y402H, did significantly increase risk for AMD in this population (16), implying that while the risk associated with CFH Y402H does not translate across ethnic groups, variation in the CFH gene universally modulates susceptibility to AMD.

It has been suggested that a deletion of ~84 000 bp covering the CFHR1 and CFHR3 genes, which segregates with one of the protective CFH haplotypes, is the source of the protective effect on chromosome 1 (13,14). We screened our data set for deletion homozygotes and tested for association with decreased AMD susceptibility.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
DISCUSSION
 MATERIALS AND METHODS
 SUPPLEMENTARY MATERIAL
 FUNDING
 REFERENCES
 
Linkage disequilibrium and haplotype association of the pre-defined P1, P2, risk and neutral haplotypes
The 12 SNPs from the pre-defined haplotypes were in strong linkage disequilibrium (LD) with many r2 values exceeding 0.20 (Fig. 3). There are no universally accepted criteria for defining haplotype blocks, and though Haploview depicts two separate blocks of LD, we chose to include all 12 SNPs in one large haplotype across the region for ease of comparison with previous reports. When testing the combined 12-SNP haplotypes for association, the P1 and risk haplotypes were very strongly associated with AMD, as expected from prior studies (P < 0.001, Table 1). However, this set of SNPs did not capture the protective effect previously ascribed to P2 (P = 0.10, Table 1).


Figure 3
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  		Figure 3. LD in the complete data set. Numbers in each square are r2 values. Darker shading indicates higher r2.

 


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  		Table 1. Haplotype association analysis

 
Segregation of the deletion with CFH haplotypes
After screening 1045 samples, we identified 13 individuals who were homozygous for the deletion, six cases and seven controls. Though the deletion segregated perfectly with the A allele of rs6677604 in previous studies (14), this was not true in our data set. While all of the deletion homozygotes were also homozygous for the A allele of rs6677604, three individuals who were not homozygous for the deletion were homozygous for the A allele of rs6677604.

The deletion seemed to segregate completely with alleles ‘GCGAAG’ at SNPs rs529825, rs2019724, rs1831281, rs677604, rs3753396 and rs1065489 (red boxes, Fig. 4), though with only 13 total deletion homozygotes observed, this could be an artifact of sample size. If we do use this haplotype as a marker for the deletion, then the overall estimated frequency of the deletion is ~10% (14% in controls, 8% in cases), and it follows Hardy–Weinberg equilibrium (P = 0.42). CFH protective haplotype 2 (P2) was the most frequent pre-defined haplotype found in these individuals with a frequency of ~47% (Fig. 4), and the risk, neutral and P1 haplotypes of CFH were not observed in this group. Co-segregation of the deletion with the risk allele of CFH Y402H was very rare (1 CT CFH Y402H heterozygote of 13 total deletion homozygotes), consistent with previous reports (3 CT CFH Y402H heterozygotes and 3 CC homozygotes of 56 total, Hageman et al. 13).

Deletion association analyses
Overall, deletion homozygosity was significantly more frequent in controls than cases (2.6% controls, 0.8% cases, Fisher's exact P = 0.025, Table 2). Most of the deletion homozygotes were grade 1 controls (Table 3). Using the ‘GCGAAG’ haplotype that all deletion homozygotes share as a surrogate for the deletion, we can increase power to detect association by including both deletion homozygotes and potential heterozygotes in the estimate of deletion frequency. This haplotype marker was strongly associated with AMD (P < 0.0001, age-adjusted OR = 0.40, 95% confidence interval = 0.28–0.58).


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  		Table 2. Univariate association analysis of the deletion

 


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  		Table 3. Features of deletion homozygotes

 
Because most of the deletion carriers are also homozygous for the non-risk allele of CFH Y402H, one may ask whether the deletion itself is truly protective or if the decreased risk is caused by absence of the CFH Y402H risk allele. To test this statistically, we re-tested the deletion for association in the subset of Y402H TT homozygotes. Though the deletion was more than twice as frequent in controls compared with cases (9.9% controls, 4.3% cases), this difference was not statistically significant in the reduced sample of 188 CFH Y402H TT homozygotes (Fisher's exact P = 0.22, OR = 0.41, 95% CI = 0.12–1.34, Table 2).

After controlling for age, CFH Y402H, LOC387715 A69S and smoking, the protective effect of the deletion was no longer statistically significant (OR = 0.45, 95% CI 0.11–1.83, P = 0.27), though this is unsurprising given the low frequency of the deletion and the reduced sample size of 469 cases and 190 controls with complete covariate data (Table 4). However, the ‘GCGAAG’ CFH haplotype, which serves as a proxy for the deletion in our data set, trended towards significance after adjusting for the known AMD risk factors (OR = 0.63, 95% CI 0.39–1.04, P = 0.07).


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  		Table 4. Logistic regression analysis of the deletion with known AMD risk factors

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
MATERIALS AND METHODS
 SUPPLEMENTARY MATERIAL
 FUNDING
 REFERENCES
 
Homozygosity for deletion of the CFHR3 and CFHR1 genes was inversely associated with AMD risk. Because of its low frequency, much larger sample sizes will be needed to test whether the deletion is protective in individuals without the CFH Y402H risk allele. However, absence of the CFHR1 and CFHR3 proteins in the serum of deletion homozygotes and the hypothesis that CFHR1 and CFHR3 protein may compete with CFH for C3 binding and therefore interfere with normal regulation of the complement system by CFH argue against a purely statistical association (14).

P2 was the most commonly observed pre-defined haplotype in deletion homozygotes. The frequency for P2 of 47% in the deletion homozygotes was less than the 63% reported by Hageman et al. (13) Perhaps the perfect correspondence in the Hughes et al. (14) study was caused by a founder effect in their Irish study population.

All deletion homozygotes were also homozygous for alleles ‘GCGAAG’ at rs529825, rs2019724 rs1831281, rs6677604, rs3753396 and rs1065489 (red boxes, Fig. 4). However, this combination of alleles should not be considered a complete surrogate for the deletion until a much larger screening of the population has confirmed that this is the case. Additionally, the risk, P1 and neutral haplotypes were not found in any of the deletion homozygotes.

Unfortunately, due to the nature of our genotyping assay and the very high sequence similarity between the homologous CFH and CFH-related genes, we were unable to distinguish between individuals with two copies of the CFHR1 and CFHR3 genes and deletion heterozygotes. We can overcome this limitation by using the ‘GCGAAG’ haplotype as a marker for the deletion, though we do not know for certain that this haplotype completely marks the deletion in the population at large. Nevertheless, under this assumption, the deletion allele frequency can be estimated at ~14% in controls and 8% in cases (HWE P-value = 0.42), and it was strongly associated with decreased risk for AMD (P < 0.0001).

We have assumed that the breakpoints of the deletion we observed match those reported by Hughes et al. (14), but this has yet to be confirmed. Because of the high homology throughout this region, there are many opportunities for non-allelic homologous recombination to occur. In fact, a new fusion protein made from a CFH/CFHR1 hybrid gene has recently been described (exons 1–21 are derived from CFH and exons 22 and 23 from CFHR1) (21). Therefore, this region is ripe for more detailed analyses, and other deletions, duplications or hybrids may still be found.

In conclusion, deletion of CFHR1 and CFHR3 may account for a small portion of the protection from AMD associated with particular haplotypes in CFH. The presence of another common protective haplotype that does not carry the deletion (P1, Table 1), suggests that other protective variants in this region have yet to be discovered.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
SUPPLEMENTARY MATERIAL
 FUNDING
 REFERENCES
 
Study populations
Our study population of 780 cases and 265 unrelated controls, all of Caucasian, non-Hispanic descent, was ascertained at Vanderbilt University Medical Center (VUMC) and Duke University Medical Center (DUMC) (Table 5). All patients and controls received an eye exam and had stereoscopic fundus photographs graded according to a modified version of the Age-Related Eye Disease Study (AREDS) grading system as described elsewhere (22,23). Grade 1 controls have no evidence of drusen or small non-extensive drusen without pigmentary abnormalities, while grade 2 controls may show signs of either extensive small drusen or non-extensive intermediate drusen and/or pigmentary abnormalities. Grade 3 AMD cases have extensive intermediate drusen or large, soft drusen with or without drusenoid retinal pigment epithelial detachment. Grade 4 AMD cases exhibit geographic atrophy and grade 5 individuals have exudative AMD, which includes non-drusenoid retinal pigment epithelial detachment, choroidal neovascularization and subretinal haemorrhage or disciform scarring. Individuals were classified according to status in the more severely affected eye. Approval for the study was obtained from the appropriate institutional review boards at VUMC and DUMC, all study participants gave informed consent, and this research adhered to the tenets of the Declaration of Helsinki.


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  		Table 5. Characteristics of the deletion screening data set

 
SNP genotyping
Five SNPs used to define the deletion haplotype from Hughes et al. (14) (rs2019724, rs1831281, rs2274700, rs6677604 and rs3753396) and seven additional SNPs that make up the protective haplotypes identified by Hageman et al. (13) (rs3753394, rs529825, rs800292, rs3766404, rs1061170, rs203674 and rs1065489) were genotyped according to the manufacturer's instructions using Taqman Assays on Demand from Applied Biosystems. Assays by Design were used when no pre-designed assay was available. Probe and primer sequences for the designed assays are available upon request.

Deletion screening by PCR and agarose gel electrophoresis
We genotyped the deletion by PCR amplification with primers that amplify both a 325 bp product of CFH and a 381 bp product of CFHR1. Individuals with visible bands for both amplicons by agarose gel electrophoresis were scored as not homozygous for the deletion. Individuals with the 325 bp band for CFH, but lacking the 381 bp band for CFHR1, were scored as being homozygous for the deletion (Supplementary Material, Fig. S1). The primer sequences were 5'-CTCTTCTTTTTCTGCATCTGC-3' and 5'-ATTGCTGCTTATGGTAGATCAGG-3'. For each 10 µl reaction, 9.15 ul of Platinum PCR Supermix and 0.5 µl of each primer diluted with Puregene DNA Hydration Solution to a concentration of 0.1 µg/µl was added to 20 ng of genomic DNA. The PCR conditions were as follows: 1 cycle 96°C 15 min; 10 cycles 95°C 1 min, 55°C 1.5 min, 71°C 1 min; 30 cycles 95°C 1 min, 53°C 1.5 min, 71°C 1 min; 4°C hold. Agarose gel electrophoresis was used to visualize the resulting product(s) on a 2% agarose gel with ethidium bromide. A mix of all PCR reagents without a DNA sample added served as a negative control.

Statistical analysis
Haploview software (24) was used to examine LD patterns in the complete data set. Haplo.stats (25) was used to estimate haplotype frequencies and generate score statistics for tests of association for the 12-SNP haplotype composed of a blend of SNPs genotyped from the previous studies. We also used Haplo.stats to test association of the deletion marker ‘GCGAAG’ haplotype. This analysis included both haplotype homozygotes and heterozygotes, unlike the test of deletion association which could not distinguish deletion heterozygotes. Fisher's exact test was used to test for a significant difference in deletion homozygosity between all 780 cases and 265 controls and in a smaller group of 188 CFH Y402H TT homozygotes (Intercooled Stata 9.1 software, StataCorp LP, College Station, TX). Logistic regression was used to examine the effect of the deletion in the context of known AMD risk factors (SAS v9.1 software, SAS Institute, Cary, NC). The sample size for this analysis was reduced to 469 cases and 190 controls with complete age, CFH Y402H, LOC387715 A69S, deletion and smoking data. Age was included in the model as a continuous covariate measured in years. CFH Y402H and LOC387715 A69S genotypes were coded as ‘1’ for heterozygotes or homozygotes of the risk allele (CFH Y402H risk allele=C, LOC387715 A69S risk allele=T) and ‘0’ for the non-risk allele homozygotes. We chose to model the genetic effects this way rather than using a ‘0/1/2’ coding system for each genotype to avoid further stratification of the data set. Deletion homozygotes were coded as ‘1’ and all others were coded as ‘0’. Smokers (those who had smoked at least 100 cigarettes) were coded as ‘1’ and non-smokers (those who had smoked fewer than 100 cigarettes over their lifetime) were coded as ‘0’.


   SUPPLEMENTARY MATERIAL
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 SUPPLEMENTARY MATERIAL
FUNDING
 REFERENCES
 
Supplementary Material is available at HMG Online.


   FUNDING
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 SUPPLEMENTARY MATERIAL
 FUNDING
REFERENCES
 
Supported by grants EY12118 (to M.A.P.-V. and J.L.H.) and EY015216 (to S.S.) from the NIH/National Eye Institute, and grant M01 RR-00095 from the NIH/National Center for Research Resources (to Vanderbilt University).


   ACKNOWLEDGEMENTS
 
Special thanks to the patients, their families and the controls who participated in the study.

Conflict of Interest statement. None declared.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 SUPPLEMENTARY MATERIAL
 FUNDING
 REFERENCES
 

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T. Montes, A. Tortajada, B. P. Morgan, S. Rodriguez de Cordoba, and C. L. Harris
Functional basis of protection against age-related macular degeneration conferred by a common polymorphism in complement factor B
PNAS, March 17, 2009; 106(11): 4366 - 4371.
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