Original Article

Genes and Immunity (2008) 9, 231–239; doi:10.1038/gene.2008.10; published online 13 March 2008

Complement factor H polymorphisms, renal phenotypes and age-related macular degeneration: the Blue Mountains Eye Study

C Xing1,2,3, T A Sivakumaran1, J J Wang4, E Rochtchina4, T Joshi1, W Smith5, P Mitchell4 and S K Iyengar1,6,7

  1. 1Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA
  2. 2Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA
  3. 3McDermott Center of Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA
  4. 4Department of Ophthalmology Westmead Millennium Institutes, Centre for Vision Research, University of Sydney, Sydney, Australia
  5. 5Centre for Clinical Epidemiology and Biostatistics, University of Newcastle, Newcastle, Australia
  6. 6Department of Genetics, Case Western Reserve University, Cleveland, OH, USA
  7. 7Department of Ophthalmology, Case Western Reserve University, Cleveland, OH, USA

Correspondence: Associate Professor SK Iyengar, Department of Epidemiology and Biostatistics, Case Western Reserve University, Wolstein Research Building, 1315, 10900 Euclid Avenue, Cleveland, OH 44106, USA. E-mail: ski@case.edu

Received 16 November 2007; Revised 3 January 2008; Accepted 8 January 2008; Published online 13 March 2008.

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Abstract

Complement factor H (CFH) is a key regulator of the alternative pathway of complement and its mutations have been associated with membranoproliferative glomerulonephritis type II, atypical hemolytic uremic syndrome and age-related macular degeneration (AMD), suggesting that alternative pathway dysregulation is a common pathogenetic feature of these ocular and renal conditions. In this study we tested the hypothesis that common CFH variants have a global role in renal function in the Australian population-based Blue Mountains Eye Study (BMES). We replicated the association of I62V with estimated glomerular filtration rate (GFR; P=0.017) and creatinine clearance (CRCL; P=0.015). The minor allele of I62V (G) was deleterious: adding one copy of the G allele decreased GFR/CRCL by ~0.98mlmin−1 per 1.73m2 (95% confidence interval (CI): 0.97, 0.99). We also replicated the association of Y402H with AMD and provided an unbiased estimate of population attributable risk (PAR). The minor allele of Y402H (C) was deleterious: the odds ratio estimate of CC genotype compared to TT was 1.87 (95% CI: 1.44, 2.45). The PAR of the C allele was estimated as 0.22 (95% CI: 0.15, 0.28). In summary, in the BMES population we confirmed the association between I62V and renal function, as measured by the estimated GFR, plus the association of Y402H with both early- and late-stage AMD.

Keywords:

CFH, AMD, GFR, creatinine clearance

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Introduction

The complement system is a crucial component in innate immunity, and the alternative pathway of complement is an ancient pathway to recognize and eliminate infectious pathogens. There is a cluster of genes constituting the regulator of complement activation on human chromosome 1q32. Complement factor H (CFH), encoded by one of the genes, is the predominant fluid-phase alternative pathway complement regulator. Mutations and variants in CFH have been associated with kidney diseases such as membranoproliferative glomerulonephritis (MPGN) type II, atypical hemolytic uremic syndrome (aHUS) and the eye disease age-related macular degeneration (AMD). Genetic, immunological and structural studies have been helping elucidate the molecular bases underlying different pathologies associated with CFH by delineating the functional domains responsible for regulatory activities in CFH. Two organ systems, the eye and the kidney, have been studied in this regard. Observations regarding malfunctioning of CFH have not only provided an understanding in the regulation of the alternative pathway of complement, but have also brought to our attention the connection between eye and kidney (dys)function (for reviews see, for example, references1, 2, 3).

It has been long recognized that MPGN II and AMD share common pathological characteristics in accumulating extracellular deposits in either eye or kidney, or both (for reviews see, for example, Zipfel et al.3). AMD is characterized by a progressive loss of central vision due to degenerative and neovascular changes. The hallmark of AMD is the formation of extracellular deposits called drusen in the macula area, within the basement membrane of the retinal pigment epithelial (RPE) cells. MPGN II is characterized by accumulation of dense deposits in the glomerular capillary wall. In most cases with MPGN II there is also a distinctive retinal phenotype, with drusen being evident ophthalmoscopically by the time renal failure develops. Not only are there histopathological similarities between the deposits under the ocular RPE and in the kidney in MPGN II cases,4, 5, 6 but also the composition of drusen in AMD is similar to the deposits associated with MPGN II,7, 8 although the exact pathophysiological mechanism leading to the deposit formation may not be the same. It has been shown that several of the same CFH risk alleles segregate in MPGN II and AMD patients,9, 10, 11 indicating that specific CFH haplotypes are a key factor in drusen formation.

Recent progress in immunological and structural studies highlights the common characteristics shared by aHUS and AMD; both of them are associated with mutations and variants located in the polyanion recognition domains of CFH, which affect its binding capacity to anionic surfaces such as Bruch's membrane in the eye and the glomerular capillary wall in the kidney (for reviews see, for example, Saunders et al.12, 13). CFH consists of 20 homologous short complement regulator (SCR) domains, among which SCR 7 and 19 and 20 are most likely involved in interactions with C3b, heparin and C-reactive protein.14, 15, 16, 17 It is of interest to note that the majority of mutations associated with aHUS cluster at the C terminus, in particular, in SCR 19 and 20.12 Similarly, a polymorphism Y402H, which is postulated as a primary pathogenic variant that increases the risk of developing AMD,10, 18, 19, 20 is located in SCR 7. Thus, both aHUS and AMD have mutations in the polyanion-binding regions of CFH suggesting a similar underlying pathophysiological mechanism.

In addition to the knowledge that AMD, MPGN II and aHUS are all involved in the alternative pathway of complement, there are other renal and ocular diseases linked together genetically and pathophysiologically, which further justify the investigation of gene variants affecting the susceptibility of ocular and renal diseases and their interrelationship. From the genetic perspective, a series of renal abnormalities are also linked to chromosome 1q31–q32 such as MPGN III,21 focal segmental glomerulosclerosis,22 nephrotic syndrome23 and fibronectin glomerulopathy.24 Moreover, animal models of CFH deficiency also support the hypothesis that CFH variants are involved in renal function.11, 25, 26, 27

Creatinine clearance (CRCL) and glomerular filtration rate (GFR) are indicators of global renal function and may indicate a propensity for development of end-stage renal disease. Our group has observed strong association of chronic kidney disease, as measured by estimated CRCL, with risk of early AMD independent of age and other known risk factors in the population-based Blue Mountains Eye Study (BMES),28 suggesting shared pathophysiological mechanisms between the two conditions. Although linkage studies did not show evidence of GFR and CRCL linked to chromosome 1q32,29, 30 recently Thompson et al.31 detected moderate association of common CFH variants with estimated GFR in a large cohort study.

In this report, we aim to test the hypothesis proposed by Thompson et al.31 that there is an association between CFH variants and overall renal function as measured by estimated GFR and CRCL in the Australian BMES Caucasian population. In addition, we also aim to replicate the association of the common nonsynonymous variant Y402H with AMD in the BMES, and provide a reasonable population attributable risk (PAR) estimate.

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Results

CFH and renal phenotypes

Single nucleotide polymorphism (SNP) I62V showed moderate association with both the estimated GFR (PU=0.024, PA=0.017; PU and PA denote P-values before and after adjusting for AMD affection status by including it as a covariate, respectively) and CRCL (PU=0.024 and PA=0.015), and both measurements decreased by ~0.98mlmin−1 per 1.73m2 (95% confidence interval (CI): 0.97, 0.99) with addition of one copy of the minor allele; the other two SNPs were not associated with either trait (Table 1). Haplotype analysis was consistent with the observation of SNP I62V being associated with estimated GFR and CRCL. Among the four common haplotypes with frequency greater than 0.05 (A-C-G, A-T-G, G-T-G and A-T-T), only the haplotype G-T-G, that is, the one with G allele at I62V, showed a moderate association with estimated GFR (PU=0.032 and PA=0.024) and CRCL (PU=0.033 and PA=0.022), although the global haplotype tests were not significant. Neither of the renal traits was correlated with AMD after adjusting for age and sex (P=0.35 and 0.42 for estimated GFR and CRCL, respectively), however, there was a consistent indication of the association signal increasing between renal traits and I62V after adjusting for AMD status (Table 1).


CFH and AMD

For analysis of the AMD trait, incident data and the combined prevalent and incident data with correlated or uncorrelated individuals gave similar results in terms of parameter estimates. To maximize statistical power, we only present results for the combined prevalent and incident data for both sporadic and familial cases and controls. The mean age of people in the case groups was significantly greater than in the control group (P<1.0 × 10−4 for all three comparisons), and people with late AMD on average tended to be older than those with early AMD (P<1.0 × 10−4). There were more women than men in each AMD category and the female proportions tended to be greater in case categories than in the controls (Table 2).


The genotypic distributions of all three SNPs in each AMD category are summarized in Table 3 and the odds ratio (OR) estimates are presented in Table 4. There was no evidence of departure from Hardy–Weinberg equilibrium for all three SNPs in either a single category or the whole sample (results not shown). The minor allele (G, C and T for I62V, Y402H and E936D, respectively) frequencies were 0.25, 0.36 and 0.17, similar to the results estimated by the International HapMap project.32 For I62V, allele G was more frequent in controls than in cases (percent control:percent total cases=0.25:0.17). This comparison was most significant (P=7.8 × 10−7) when contrasting controls versus all cases in a codominant model, that is, comparing the genotype distribution instead of the allele distribution. The minor allele C of Y402H showed a deleterious effect by having a higher frequency in cases than in controls (percent total cases:percent control=0.48:0.36). Allele C showed a dosage effect by attaining the most significant association (P=6.6 × 10−9) when comparing controls to all cases in a codominant model. The OR of the CC genotype compared to the TT genotype was estimated to be 2.86 (95% CI: 1.98, 4.14) and the PAR of the C allele was estimated to be 0.18 (95% CI: 0.09, 0.25), 0.40 (95% CI: 0.26, 0.48) and 0.22 (95% CI: 0.15, 0.28) for early AMD, late AMD and all AMD cases, respectively. E936D did not show any evidence of association with AMD. Haplotype analysis confirmed the observation of Y402H being deleterious of and E936D not being associated with AMD. The distribution of AMD incident cases among the Y402H variant stratified by age group is summarized in Table 5.




We also investigated the modifying effect of renal traits on the association between Y402H and AMD, and found no additive or interactive effects (P>0.05).

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Discussion

The association between common CFH variants and renal phenotypes has been replicated in this older Australian population. In studying the global renal function, we confirmed the association between I62V and estimated GFR, as first reported by Thompson et al.31 Although each study showed only moderate evidence (P=0.029 and 0.017, respectively), the association is consistent. A simple meta-analysis of combining P-values from our and Thompson's studies using Fisher's method33 Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author attained a P-value of 0.0042. Note that the effect size of adding one copy of the I62V minor allele was estimated to be a decrease of ~0.98mlmin−1 per 1.73m2 of GFR/CRCL, which was close to the estimate of 0.90mlmin−1 per 1.73m2 by Thompson et al.31 Given only three representative CFH SNPs were examined in both studies, the moderate effect detected between I62V and renal traits may be due to I62V being only in linkage disequilibrium (LD) with causative SNPs. It is also worth noting that data were population based and ascertained without regard to renal failure, and thus the majority of individuals were with GFR/CRCLgreater than or equal to60mlmin−1 per 1.73m2 (Table 6). However, the formulae for estimating GFR/CRCL were designed for application in patients with GFR/CRCL <60mlmin−1 per 1.73m2,34, 35 and they tend to underestimate GFR in people with normal or near-normal renal function.36, 37 Therefore, the distribution of the estimated GFR/CRCL is condensed, and consequently the association between estimated GFR/CRCL and I62V can be attenuated. In addition, among the three CFH SNPs selected in this study, I62V and Y402H had been previously confirmed to be associated with MPGN II,9, 10, 11 and E936D had been confirmed to be associated with aHUS.11, 38, 39


In this prospective study we replicated the well-known association between the CFH Y402H variant and AMD with BMES prevalence and incidence data; moreover, we confirmed that this variant confers significant risk to both early- and late-stages of AMD.10, 40, 41, 42, 43 The P-values for association with late AMD were smaller than those with early AMD; however, it should be noted that the most significant results occurred in the larger sample size (number of affected=356) when grouping both AMD categories. Although the OR (3.51) for late AMD was much greater than that for either early AMD (OR=1.65) or total AMD (OR=1.87), its 95% CI (1.85, 6.66) was also much broader than for early AMD (1.24, 2.20) and total AMD (1.44, 2.45), indicating an unstable point estimate due to the smaller sample size. In our study, we were not able to further divide the late AMD cases into subgroups, choroidal neovascularization (CNV) or geographic atrophy (GA) due to small numbers.

When calculating PAR it is important to consider the sample source for derivation of subjects who were exposed to risk factors. PAR can only be calculated appropriately if the controls are sampled agnostic to the disease status, and known confounding factors are adjusted for, with the use of adjusted relative risks. The PAR of CFH Y402H for AMD was estimated as approximately 50%. However, with only a couple of exceptions,31, 41, 44, 45 most of the literature is based on clinic ascertained case–control studies; moreover, in most studies PAR was estimated using Levin's formula46 and neglecting the existence of confounding factors such as age. The present study provided an opportunity to estimate PAR more accurately by using population-based prospective cohort data. In particular, we estimated the category-specific attributable risk47 to control for confounding factors, among which age was a major concern in the current study because people in the control group were significantly younger than those in the case groups (Table 2). To best investigate the causal relationship between CFH Y402H variant and AMD, we restricted our analysis to 10-year incident cases after adjusting for age and sex. The PAR in our sample was estimated to be 0.22 with 95% CI (0.15, 0.28), which was similar to that estimated from another population-based study,31 but much smaller than from most previous reports based on clinical case–control samples with cross-sectional designs. This small PAR estimate is supported by data from other epidemiological and genetic studies suggesting that the Y402H variant alone does not cause AMD but does in combination with other genetic and environmental factors.10, 48, 49, 50, 51, 52, 53, 54, 55

Although I62V is associated with both AMD and renal function as measured by estimated GFR and CRCL, these two correlations seem to be independent because there is no association between AMD and renal function (P=0.35 and 0.42 for estimated GFR and CRCL, respectively) after adjusting for age and sex. Furthermore, the association between I62V and renal function was revealed regardless of AMD adjustment. The slight decrease of P-values after adjusting for ADM affection status might be a purely statistical result of random noise reduction by adding one more covariate. Regression coefficient estimates suggest the minor allele G of I62V being deleterious to filtering capacity of the kidney, that is, correlated with worse estimated GFR and CRCL, but being protective against AMD susceptibility, and thus the role of I62V to these two conditions might suggest a negative correlation between the susceptibilities of renal and AMD phenotypes. However, Liew et al.28 observed a positive correlation between chronic kidney disease, defined using low CRCL, and the risk of early AMD. Therefore, I62V may not be the major genetic determinant underlying the connection between the renal and ocular traits, and the allelic architecture of causal variants for these two diseases may be fairly complex.

In summary, we confirmed the association between the CFH variant I62V and renal function as measured by estimated GFR, and the association between Y402H and AMD in the BMES population. Y402H conferred a significant risk to both early-stage and late-stage AMD, and its PAR was estimated to be 0.22 in our population-based sample. The current study provides further evidence that the alternative pathway of complement is involved in both ocular and renal functions, and further studies in this regard are warranted.

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Methods

Subjects

The BMES is a population-based survey of visual function and common eye diseases in an urban population-based cohort, 49 years or older, resident in two postcodes of the Blue Mountains region, west of Sydney, Australia. The survey methods and procedures were previously described.56 The design was a prospective cohort, with baseline eye examinations performed during 1992–1994 with 3654 participants 49 year or older (82.4% participation). Five-year follow-up eye examinations were conducted during 1997–1999 with 2335 participants (75.1% of survivors; 543 persons died), and the 10-year follow-up examination conducted during 2002–2004 with 1952 participants (76.5% of survivors; 1103 persons died). For studying renal traits we used the BMES II (1997–2000) survey data (3509 participants) including the 2335 5-year follow-up participants plus an additional 1174 participants who had become eligible by moving into the area or into the age bracket of the original survey; no renal traits were available at the baseline examination. All examinations were approved by the human ethics committee of the Western Sydney Area Health Service and University of Sydney. Signed informed consent was obtained from participants at each examination.

Phenotypic evaluation

Measures of renal function were obtained at the 5-year follow-up examination. Indirect measurements are typically used to assess filtering capacity of the kidney. In this study, we used the Cockcroft–Gault equation34 to calculate CRCL based on serum creatinine measured within 4h of blood collection. Because estimation of CRCL is subject to other factors such as age, race, gender, nutritional status and kidney diseases, we also calculated the estimated GFR using the Modification of Diet in Renal Disease equation35 because this method provides a more accurate measurement of GFR given confounding factors. Other potential confounders measured included body mass index, systolic blood pressure, diastolic blood pressure, fibrinogen level, triglyceride level, total serum cholesterol level and high-density lipoprotein cholesterol level. The distribution of renal phenotypes stratified by the chronic kidney disease stages according to the National Kidney Foundation guidelines57 is summarized in Table 6.

At each visit, 30° stereoscopic retinal photographs of the macula and other retinal fields of both eyes were taken using a Zeiss FF3 fundus camera (Carl Zeiss, Oberkochen, Germany). Details of the photographic grading for AMD lesions have been previously reported56 and it closely followed methods used in the Wisconsin AMD Grading System.58 Late-stage AMD was defined to include the two late AMD lesions, CNV and GA, as described in the International AMD classification;59 all late AMD cases were adjudicated by a retinal specialist (PM). Early-stage AMD was defined as the absence of late-stage AMD and presence of either (1) large (>125μm diameter) indistinct soft or reticular drusen or (2) both large distinct soft drusen and retinal pigmentary abnormalities (hyperpigmentation or hypopigmentation)59 within the superimposed grading grid.58 Incident late AMD was defined by the appearance at follow-up of CNV or GA in either eye of persons in whom no late AMD was present at baseline. Incident early AMD was defined by the appearance at follow-up of either indistinct soft or reticular drusen or the copresence of both distinct soft drusen and retinal pigmentary abnormalities in either eye of persons in whom no early or late AMD was present at baseline. All newly developed AMD lesions were confirmed in a side-by-side grading, performed after the initial grading. The population distribution for the CFH genetic study, which is based on the 10-year follow-up data, stratified by AMD status is summarized in Table 2.

Genotyping

We genotyped three common nonsynonymous CFH SNPs including rs800292 (I62V) in exon 2, rs1061170 (Y402H) in exon 9 and rs1065489 (E936D) in exon 18 to cover the main common coding variants in the gene. Genomic DNA (30ng) was subjected to PCR amplification in a volume of 5μl including 1 × TaqMan Universal PCR Master Mix (Applied Biosystems, Foster City, CA, USA), SNP Genotyping Assay Mix containing the two specific TaqMan MGB probes, forward and reverse primers (Applied Biosystems). The 384-well plate containing the reaction mixture was then run on the ABI 7900 Sequence Detection system. The overall genotyping error rate was estimated at less than 1% based on 136 replicates of all three SNPs, with similar error rates at each SNP. Genotyping completeness ranged from 99.1 to 100%.

Statistical analysis

Hardy–Weinberg equilibrium was tested by a goodness-of-fit test for each SNP. The degree of LD, as measured by the r2 metric, was estimated to be 0.18 between I62V and Y402H, 0.12 between Y402H and E936D, and 0.03 between I62V and E936D, which approximated the results obtained from the International HapMap project.32 Thus, there was little correlation between the SNPs genotyped for this gene and each represented a unique LD block and carried independent information. Therefore, analyses for renal and ocular traits were performed both by taking each SNP separately, and considering haplotypes formed by all three SNPs together.

Association between CFH SNPs and renal phenotypes (estimated GFR and CRCL) was assessed by linear models—the genotypic value was coded in an additive manner, that is, 0, 1 and 2 denote major allele homozygote, heterozygote and minor allele homozygote, respectively, and the estimated GFR and CRCL were log-transformed to obey the normality assumption in linear models. AMD affection status (control, early AMD and late AMD were coded as 0, 1 and 2, respectively) was either adjusted or not; the covariates age, sex and body mass index were selected by a forward step-wise selection procedure. Association between CFH SNPs and AMD was assessed by comparing frequencies (allele, genotype or haplotype) between cases and controls tested using likelihood ratio tests. OR and the corresponding 95% CI for allele and genotype risk were estimated using the logistic regression with the common allele (A, T and G for I62V, Y402H and E936D, respectively) and common genotype (AA, TT and GG for I62V, Y402H and E936D, respectively) as reference groups. All subsequent analyses pertinent to assessing significance level of association (P-values) or degree of risk (OR and PAR) were adjusted for age and sex. The PAR for presence of at least one Y402H C allele was estimated using the category-specific attributable risk, Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author,47 where pd denotes the proportion of cases with the C allele, and RR denotes relative risk, which can be approximated by the OR because controls representative of the population were used in the current study.

For the renal traits we used prevalent data as measured at BMES II (1997–2000), whereas for the ocular traits we used both incident and prevalent data. In each data set we used either the pooled data, that is, including both sporadic and familial data, or a subset of independent individuals by pooling sporadic data and one person randomly selected from each family. For the pooled sporadic and familial data, the correlation among individuals from the same family was accounted for by using the generalized estimating equation technique,60 except that for haplotype analyses a weighting technique based on probabilities of allele sharing identical-by-descent was used.61 Single SNP analysis was performed using the software SAS version 9.1.362 and haplotype analysis was performed using the softwares Haploview,63 CCREL64 and Haplo.stats.65 Note that we only used the subset of independent individuals when analyzing the renal traits because of software (Haplo.stats) limitations.

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Notes

Statement of competing financial interests

The authors have no competing conflicts of interests, financial or otherwise, to declare.

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Acknowledgements

We thank the two anonymous reviewers for their insightful comments that led to great improvements in this article. This study was supported, in part, by US Public Health Service research grants GM28356, from the National Institute of General Medical Sciences, grant EY015810 from the National Eye Institute, and grants 974159 and 211069 from NHMRC.

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