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1.  Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype 
Background Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case–control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking.
Methods To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, ‘Y402H’) with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26 494 individuals, including 14 174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene–smoking interaction; and 16 published studies from non-European ancestry.
Results In individuals of European ancestry, there was a significant association between Y402H and late-AMD with a per-allele odds ratio (OR) of 2.27 [95% confidence interval (CI) 2.10–2.45; P = 1.1 x 10−161]. There was no evidence of effect modification by smoking (P = 0.75). The frequency of Y402H varied by ancestral origin and the association with AMD in non-Europeans was less clear, limited by paucity of studies.
Conclusion The Y402H variant confers a 2-fold higher risk of late-AMD per copy in individuals of European descent. This was stable to stratification by study design and AMD classification and not modified by smoking. The lack of association in non-Europeans requires further verification. These findings are of direct relevance for disease prediction. New research is needed to ascertain if differences in circulating levels, expression or activity of factor H protein explain the genetic association.
doi:10.1093/ije/dyr204
PMCID: PMC3304526  PMID: 22253316
Age-related macular degeneration (AMD); Complement factor H gene; meta-ananlysis
2.  Complement Factor H 402H Variant and Reticular Macular Disease 
Archives of ophthalmology  2011;129(8):1061-1066.
Objective
To determine the association of high-risk alleles in the complement factor H (CFH; Y402H, rs1061170) and age-related maculopathy susceptibility (ARMS2; A69S, rs10490924) genes with reticular macular disease (RMD), a major clinical subphenotype of age-related macular degeneration (AMD).
Methods
Using retinal images from the Columbia Macular Genetics Study, we identified 67 subject individuals with RMD. A comparison group of 64 subjects with AMD without RMD was matched by ethnicity, age, sex, and AMD clinical stage.
Results
In the RMD group, 53 of 67 subjects (79.1%) were female, the mean age was 83 years, and 47 of 67 (70.1%) had late AMD, with closely matched values in the non-RMD group. The frequencies of the CFH 402H allele were 39.6% in the RMD group (53 of 134 individuals) and 58.6% in the non-RMD group (75 of 128 individuals) (χ2=8.8; P=.003; odds ratio, 0.46 [95% confidence interval, 0.28–0.76]). The corresponding frequencies of the risk allele for ARMS2 were 44.0% (40 of 128 individuals) and 31.3% (40 of 128 individuals), respectively (χ2=4.0; P=.045; odds ratio, 1.73 [95% confidence interval, 1.04–2.90]). Homozygosity for 402Hwas particularly associated with the absence of RMD, occurring in 8 of 67 subjects (11.9%) with RMD vs 24 of 64 subjects (37.5%) without RMD(P χ.001). Retinal macular disease also was associated with hypertension among male patients.
Conclusions
The AMD-associated CFH 402H risk variant is significantly associated with the absence of RMD but enhanced risk for RMD is conferred by the ARMS2 69S AMD risk allele. These results are consistent with the hypothesis that 402H may confer a survival benefit against certain infections, some of which may cause RMD.
Clinical Relevance
Reticular macular disease may be genetically distinct from the rest of AMD.
doi:10.1001/archophthalmol.2011.212
PMCID: PMC3767386  PMID: 21825189
3.  Polymorphism p.402Y>H in the complement factor H protein is a risk factor for age related macular degeneration in an Italian population 
The British Journal of Ophthalmology  2006;90(9):1142-1145.
Aims
To evaluate the complement factor H (CFH) p.402Y>H polymorphism as a risk factor in age related macular degeneration (AMD) in an Italian population.
Methods
104 unrelated Italian AMD patients and 131 unrelated controls were screened for the CFH polymorphism p.402Y>H (c.1277 T>C), which has been associated with AMD. Retinography was obtained for patients and controls; the AMD diagnosis was confirmed by fluorescein angiograms. The c.1277 T>C polymorphism was genotyped with the TaqMan real time polymerase chain reaction single nucleotide polymorphism assay.
Results
The frequency of c.1277C allele was higher in AMD patients than in controls (57.2% v 39.3%; p<0.001). The odds ratio (OR; logistic regression analysis) for AMD was 3.9 (95% confidence interval (CI): 1.9 to 8.2) for CC homozygotes. The CC genotype conferred a higher risk for sporadic (OR 4.6; CI: 2.0 to 10.5) than for familial AMD (OR 2.9; CI: 1.0 to 8.4). Genotypes were not related to either age at AMD diagnosis or to AMD phenotype. However, geographic atrophy and choroidal neovascularisation were more frequent in sporadic than in familial AMD (p = 0.027). Overall, the percentage of population attributable risk for the CC genotype was 28% (95% CI:18% to 33%).
Conclusion
The association between the p.402Y>H (c.1277T>C) polymorphism and AMD applies to the Italian population and the CC genotype is more frequent in sporadic than in familial AMD cases.
doi:10.1136/bjo.2006.096487
PMCID: PMC1857371  PMID: 16774956
age related macular degeneration; polymorphisms; complement factor H; Italy
4.  Variation in genetic admixture and population structure among Latinos: the Los Angeles Latino eye study (LALES) 
BMC Genetics  2009;10:71.
Background
Population structure and admixture have strong confounding effects on genetic association studies. Discordant frequencies for age-related macular degeneration (AMD) risk alleles and for AMD incidence and prevalence rates are reported across different ethnic groups. We examined the genomic ancestry characterizing 538 Latinos drawn from the Los Angeles Latino Eye Study [LALES] as part of an ongoing AMD-association study. To help assess the degree of Native American ancestry inherited by Latino populations we sampled 25 Mayans and 5 Mexican Indians collected through Coriell's Institute. Levels of European, Asian, and African descent in Latinos were inferred through the USC Multiethnic Panel (USC MEP), formed from a sample from the Multiethnic Cohort (MEC) study, the Yoruba African samples from HapMap II, the Singapore Chinese Health Study, and a prospective cohort from Shanghai, China. A total of 233 ancestry informative markers were genotyped for 538 LALES Latinos, 30 Native Americans, and 355 USC MEP individuals (African Americans, Japanese, Chinese, European Americans, Latinos, and Native Hawaiians). Sensitivity of ancestry estimates to relative sample size was considered.
Results
We detected strong evidence for recent population admixture in LALES Latinos. Gradients of increasing Native American background and of correspondingly decreasing European ancestry were observed as a function of birth origin from North to South. The strongest excess of homozygosity, a reflection of recent population admixture, was observed in non-US born Latinos that recently populated the US. A set of 42 SNPs especially informative for distinguishing between Native Americans and Europeans were identified.
Conclusion
These findings reflect the historic migration patterns of Native Americans and suggest that while the 'Latino' label is used to categorize the entire population, there exists a strong degree of heterogeneity within that population, and that it will be important to assess this heterogeneity within future association studies on Latino populations. Our study raises awareness of the diversity within "Latinos" and the necessity to assess appropriate risk and treatment management.
doi:10.1186/1471-2156-10-71
PMCID: PMC3087512  PMID: 19903357
5.  Three Major Loci Involved in Age-Related Macular Degeneration are also Associated with Polypoidal Choroidal Vasculopathy 
Ophthalmology  2010;117(8):1567-1570.
Purpose
To investigate the frequency of variants in three major age-related macular degeneration (AMD)-associated loci in patients with polypoidal choroidal vasculopathy (PCV) of European-American descent.
Design
Cross-sectional case-control association study.
Participants
Fifty-five patients with PCV, 368 patients with advanced AMD and 368 age- and ethnically-matched unaffected controls of European-American descent.
Methods
Association analysis of allele and genotype frequencies, determined by TaqMan assays, was performed for the following haplotype-tagging single nucleotide polymorphisms (htSNPs): risk alleles in the complement factor H (CFH) gene (Y402H and IVS14) in the ARMS2/HTRA1 locus on 10q26 (A69S) and protective alleles in CFH (IVS1 and IVS6) and in the complement factor B/complement component C2 (CFB/C2) locus (IVS10 and H9L).
Main Outcome Measures
Allele and genotype frequencies of the htSNPs in the CFH, CFB/C2, and ARMS2/HTRA1 loci.
Results
Four AMD-associated haplotype-tagging alleles (rs547154, rs1061170, rs1410996, rs10490924) in the three major loci, CFH, CFB/C2 and ARMS2/HTRA1, were statistically significantly associated also with the PCV phenotype (P<0.05). Three other alleles from the same loci (rs4151667, rs529825, rs3766404) showed a trend towards association (P<0.2), but did not reach statistical significance possibly because of the combined effects of a relatively small sample size and low minor allele frequency in the screened populations.
Conclusion
The PCV phenotype in Caucasian patients is associated with the major alleles/genotypes in the AMD-associated loci, suggesting that PCV and AMD are genetically similar in the tested loci.
doi:10.1016/j.ophtha.2009.12.018
PMCID: PMC2901561  PMID: 20378180
6.  The effect of genetic variants in SERPING1 on the risk of neovascular age-related macular degeneration 
Purpose
Genetic factors influence an individual’s risk for developing age-related macular degeneration (AMD), a leading cause of irreversible vision loss. Previous studies investigating the potential association between all AMD subtypes and the SERPING1 gene, which encodes a key regulator of the classical complement pathway, have yielded conflicting results. The purpose of this study was to determine whether variations in SERPING1 are associated with the neovascular form of AMD.
Methods
A total of 556 patients with neovascular AMD and 256 ethnically-matched controls were genotyped for polymorphisms in SERPING1. A tagging single nucleotide polymorphism (tSNP) approach was used to cover the SERPING1 gene plus 2 kilobases (kb) on each side, spanning the promoter and the 3′ untranslated regions. Ten SNPs with a minimum allele frequency of 0.10 were covered by three tSNPs (rs1005510, rs11603020, rs2511989).
Results
SERPING1 SNPs rs1005510 and rs2511989 were significantly associated with neovascular AMD in our cohort, with rs1005510 conferring an adverse risk effect (OR 1.49, 95% CI 1.18–1.88) and rs2511989 conferring a protective effect (OR 0.73, 95% CI 0.59–0.90). For both tSNPs, logistic regression of individual genotypes demonstrated statistically-significant stepwise changes in the risk of developing AMD. Combined analysis of rs1005510 with variants in CFH and HTRA1 confirmed an independent risk effect. The rs11603020 variant had no effect on AMD susceptibility in this study (OR 0.98, 95% CI 0.78–1.24).
Conclusions
This study comprehensively investigates the SERPING1 gene (using three tSNPs) and evaluates these genetic variants in the largest neovascular AMD cohort to date. Our results support the hypothesis that SERPING1 has a modest effect on the risk of neovascular AMD.
doi:10.1136/bjo.2009.172007
PMCID: PMC3655725  PMID: 20606025
SERPING1; Complement cascade; Age-Related Macular Degeneration; Choroidal Neovascularization
7.  Dissection of Chromosome 16p12 Linkage Peak Suggests a Possible Role for CACNG3 Variants in Age-Related Macular Degeneration Susceptibility 
Through extensive linkage and association analyses in multiple independent datasets, this study identified CACNG3 as the most likely AMD susceptibility gene on 16p12.
Purpose.
Age-related macular degeneration (AMD) is a complex disorder of the retina, characterized by drusen, geographic atrophy, and choroidal neovascularization. Cigarette smoking and the genetic variants CFH Y402H, ARMS2 A69S, CFB R32Q, and C3 R102G have been strongly and consistently associated with AMD. Multiple linkage studies have found evidence suggestive of another AMD locus on chromosome 16p12 but the gene responsible has yet to be identified.
Methods.
In the initial phase of the study, single-nucleotide polymorphisms (SNPs) across chromosome 16 were examined for linkage and/or association in 575 Caucasian individuals from 148 multiplex and 77 singleton families. Additional variants were tested in an independent dataset of unrelated cases and controls. According to these results, in combination with gene expression data and biological knowledge, five genes were selected for further study: CACNG3, HS3ST4, IL4R, Q7Z6F8, and ITGAM.
Results.
After genotyping additional tagging SNPs across each gene, the strongest evidence for linkage and association was found within CACNG3 (rs757200 nonparametric LOD* = 3.3, APL (association in the presence of linkage) P = 0.06, and rs2238498 MQLS (modified quasi-likelihood score) P = 0.006 in the families; rs2283550 P = 1.3 × 10−6, and rs4787924 P = 0.002 in the case–control dataset). After adjusting for known AMD risk factors, rs2283550 remained strongly associated (P = 2.4 × 10−4). Furthermore, the association signal at rs4787924 was replicated in an independent dataset (P = 0.035) and in a joint analysis of all the data (P = 0.001).
Conclusions.
These results suggest that CACNG3 is the best candidate for an AMD risk gene within the 16p12 linkage peak. More studies are needed to confirm this association and clarify the role of the gene in AMD pathogenesis.
doi:10.1167/iovs.09-5112
PMCID: PMC3101690  PMID: 21169531
8.  Association between complementary factor H Y402H polymorphisms and age-related macular degeneration in Chinese: Systematic review and meta-analysis 
AIM
Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world and complement factor H (CFH) polymorphism has been found to associate with the AMD. To investigate whether the Y402H variant in CFH is associated with AMD in Chinese populations, a systematic review and meta-analysis were performed to estimate the magnitude of the gene effect and the possible mode of action.
METHODS
A meta-analysis was performed using data available from ten case-control studies assessing association between the CFH Y402H polymorphism and AMD in Chinese populations involving 1538 AMD. Data extraction and study quality assessment were performed in duplicate. Summary odds ratios (ORs) and 95% confidence intervals (CIs) an allele contrast and genotype contrast were estimated using fixed- effects models. The Q-statistic test was used to assess heterogeneity, and Funnel plot was used to evaluate publication bias.
RESULTS
Seven of ten case-control studies were neovascular AMD, and few studies came from west and north of China. There was strong evidence for association between CFH and AMD in Chinese population, with those having risk allele C 2.35 times more likely to have AMD than subjects with T allele. Evidence of publication bias was not observed in our meta-analysis.
CONCLUTION
This meta-analysis summarizes the strong evidence for an association between CFH and AMD in Chinese and indicates each C allele increasing the odds of AMD by 2.33-fold.But more evidences about the relation between CFH polymorphism and different type of Chinese AMD from various district were needed.
doi:10.3980/j.issn.2222-3959.2012.02.25
PMCID: PMC3359047  PMID: 22762059
age-related macular degeneration; complement factor H polymorphism; meta-analysis; Chinese population
9.  Kidney function, albuminuria and age-related macular degeneration in NHANES III 
Nephrology Dialysis Transplantation  2011;26(10):3159-3165.
Background. Age-related macular degeneration (AMD) and kidney disease may have shared risk factors, including cardiovascular disease risk factors; additionally AMD and dense deposit disease share a common causal link, with both associated with polymorphisms in the complement pathway. Accordingly, we explored a population-based cohort of US adults to examine if markers of kidney disease identify a higher risk population for prevalent AMD.
Methods. A cross-sectional nested case–control study matching on age, sex and race was performed using data on adult participants in the Third National Health and Nutrition Examination Survey. Predictor variables included urine albumin-to-creatinine ratio and estimated glomerular filtration rate (eGFR). Study outcomes included late AMD, defined as neovascular disease or geographic atrophy (5:1 matching), and a composite of both early AMD, defined as soft drusen or pigment irregularities with or without any drusen, and late AMD (1:1 matching).
Results. There were 51 participants with late AMD and 865 with any AMD. In conditional logistic regression adjusting for diabetes, hypertension and total cholesterol, lower eGFR was independently associated with late AMD [odds ratio (OR) = 3.05, 95% confidence interval (CI): 1.51–6.13], while albuminuria was not significant. For any AMD, neither albuminuria nor eGFR were significant in adjusted models. In sensitivity analyses excluding diabetics, albuminuria was associated with any AMD (OR = 1.56, 95% CI: 1.11–1.29 and 1.57, 95% CI: 0.61–3.69 for micro- and macroalbuminuria, respectively, P = 0.03).
Conclusions. Late AMD is more common among individuals with reduced kidney function. Whether this association reflects a common causal pathway or shared risk factors such as hypertension requires additional investigation.
doi:10.1093/ndt/gfr022
PMCID: PMC3247860  PMID: 21339308
age-related macular degeneration; albuminuria; chronic kidney disease; dense deposit disease; glomerular filtration rate
10.  Complement Factor H Polymorphism in Age-Related Macular Degeneration 
Science (New York, N.Y.)  2005;308(5720):385-389.
Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. We report a genome-wide screen of 96 cases and 50 controls for polymorphisms associated with AMD. Among 116,204 single-nucleotide polymorphisms genotyped, an intronic and common variant in the complement factor H gene (CFH) is strongly associated with AMD (nominal P value <10−7). In individuals homozygous for the risk allele, the likelihood of AMD is increased by a factor of 7.4 (95% confidence interval 2.9 to 19). Resequencing revealed a polymorphism in linkage disequilibrium with the risk allele representing a tyrosine-histidine change at amino acid 402. This polymorphism is in a region of CFH that binds heparin and C-reactive protein. The CFH gene is located on chromosome 1 in a region repeatedly linked to AMD in family-based studies.
doi:10.1126/science.1109557
PMCID: PMC1512523  PMID: 15761122
11.  Insights into the Genetic Architecture of Early Stage Age-Related Macular Degeneration: A Genome-Wide Association Study Meta-Analysis 
PLoS ONE  2013;8(1):e53830.
Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10−31) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10−24) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10−6) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10−6) and upstream of GLI2 (rs6721654; P = 6.5×10−6), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10−6), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.
doi:10.1371/journal.pone.0053830
PMCID: PMC3543264  PMID: 23326517
12.  Assessment of the contribution of CFH and chromosome 10q26 AMD susceptibility loci in a Russian population isolate 
Background/aims
A strong association has been confirmed between age‐related macular degeneration (AMD) and variants at two independent loci including Tyr402His in the complement factor H (CFH) on 1q32 and Ser69Ala at LOC387715, a hypothetical gene on chromosome 10q26. The contribution of both loci to AMD was investigated in an isolated north‐west Russian population.
Methods
Together with a PLEKHA1 variant at 10q26, the CFH Tyr402His and LOC387715 Ser69Ala polymorphisms were genotyped in 155 patients with AMD and 151 age‐matched controls. χ2 and Mantel–Haenszel (M–H) score tests were used to test for association. Sex‐adjusted ORs were calculated.
Results
The frequency of the Tyr402His C allele was significantly higher in patients with AMD compared with controls (pM–H = 0.0035). The increased risk observed in patients homozygous for the C allele (ORHOM = 2.71, 95% CI 1.25 to 5.90) in this indigenous Russian population was considerably lower than that observed in previous western Caucasian populations. A significant increase in the frequency of the LOC387715 variant was observed in patients with late‐stage AMD compared with controls (pM–H = 0.007), with a homozygous OR of 3.47 (95% CI 1.01 to 11.9), although this association was not seen with early‐stage AMD.
Conclusion
The CFH gene contributes to AMD in this Russian population, although the risk conferred is considerably lower in this population than that found in other Western populations. A contribution of LOC387715 to disease in this population is also likely to be of weak effect.
doi:10.1136/bjo.2006.105577
PMCID: PMC1954757  PMID: 17050575
13.  Rapid and Sensitive Method for Detection of Y402, H402, I62, and V62 Variants of Complement Factor H in Human Plasma Samples Using Mass Spectrometry 
Purpose
Variations in the complement factor H (CFH) gene are tightly associated with age-related macular degeneration (AMD) across diverse populations. Of the many nonsynonymous coding variants in CFH, two are most strongly associated with increased risk of AMD: isoleucine 62 to valine (I62V) and tyrosine 402 to histidine (Y402H). Detection of these variations in a patient’s blood is important for a risk assessment of AMD and disease prognosis. However, traditional methods of genetic analysis cannot be used for measuring CFH allotypes in some sources of human plasma and other biological fluids not containing DNA. The purpose was to develop a protein-based method of detecting CFH allotypes.
Methods
A combination of a single-step affinity enrichment of CFH, gel separation, and mass spectrometry identification of the CFH peptides spanning amino acids at positions 62 and 402 was used to identify individual CFH allotypes.
Results
The CFH isoforms V62, I62, H402, and Y402 were reliably detected based on identification of tryptic peptides with masses of 1148.59 Da, 1162.60 Da, 2031.88 Da, and 2057.88 Da, respectively, using MALDI-TOF-TOF. The presence or absence pattern of these peptides in mass spectra of different CFH samples robustly correlated with all nine genotypes of CFH, as a result of variations at positions 62 and 402.
Conclusions
A rapid and sensitive method has been developed for detection of V62, I62, H402, and Y402 variants of CFH in human plasma samples using mass spectrometry. This method can be used in clinical laboratories equipped with a basic inexpensive mass spectrometer capable of performing peptide fingerprinting.
doi:10.1167/iovs.08-2782
PMCID: PMC2808136  PMID: 19029036
14.  Association of complement factor H Y402H polymorphism with phenotype of neovascular age related macular degeneration in Israel 
Molecular Vision  2008;14:1829-1834.
Purpose
The Tyr402His variant of complement factor H (CFH) is associated with age-related macular degeneration (AMD) in several populations. Our aim was to evaluate if this single nucleotide polymorphism (SNP) is associated with AMD in the Israeli population and see if it underlies heterogeneity in clinical manifestation and responses to photodynamic therapy (PDT), which characterize neovascular AMD (NVAMD).
Methods
Genotyping for the Tyr402His variant was performed in 240 NVAMD patients (78.1±7 age range) and 118 controls (70.8±8.2 age range). Genotyping was correlated with clinical characteristics and treatment parameters in sequential 131 NVAMD patients who underwent PDT.
Results
TheTyr402His coding allele was associated with NVAMD in the Israeli population: odds ratio (OR)=1.9; 95% confidence interval (CI)=1.3–2.6; p=0.0002. Homozygosity for this variant was associated with an OR of 3.4 (95% CI: 1.7–6.8) for having AMD. There was no association among this SNP and age of onset of NVAMD, gender, neovascular lesion size, initial or final visual acuity, and number of PDT sessions required.
Conclusions
In accordance with findings from the majority of previous study populations, the Tyr402His variant of CFH is associated with NVAMD in Israel. However, heterogeneity in clinical manifestations of NVAMD and in its response to PDT is not underlined by this CFH variant and may be accounted for by other genetic and environmental factors.
PMCID: PMC2566586  PMID: 18852870
15.  Genetic profile for five common variants associated with age-related macular degeneration in densely affected families: a novel analytic approach 
About 40% of the genetic variance of age-related macular degeneration (AMD) can be explained by a common variation at five common single-nucleotide polymorphisms (SNPs). We evaluated the degree to which these known variants explain the clustering of AMD in a group of densely affected families. We sought to determine whether the actual number of risk alleles at the five variants in densely affected families matched the expected number. Using data from 322 families with AMD, we used a simulation strategy to generate comparison groups of families and determined whether their genetic profile at the known AMD risk loci differed from the observed genetic profile, given the density of disease observed. Overall, the genotypic loads for the five SNPs in the families did not deviate significantly from the genotypic loads predicted by the simulation. However, for a subset of densely affected families, the mean genotypic load in the families was significantly lower than the expected load determined from the simulation. Given that these densely affected families may harbor rare, more penetrant variants for AMD, linkage analyses and resequencing targeting these families may be an effective approach to finding additional implicated genes.
doi:10.1038/ejhg.2009.185
PMCID: PMC2911949  PMID: 19844262
AMD; complex trait; simulation; SNPs; liability threshold model
16.  The Complement Component 5 gene and Age-related Macular Degeneration 
Ophthalmology  2009;117(3):500-511.
Objective
To investigate the association between variants in the complement component 5 (C5) gene and age-related macular degeneration (AMD).
Design
Separate and combined data from three large AMD case-control studies and a prospective population-based study (The Rotterdam Study).
Participants
A total of 2599 AMD cases and 3458 ethnically matched controls.
Methods
Fifteen single nucleotide polymorphisms (SNPs) spanning the C5 gene were initially genotyped in 375 cases and 199 controls from the Netherlands (The AMRO-NL study population). Replication testing of selected SNPs was performed in the Rotterdam Study (NL) and study populations from Southampton, United Kingdom (UK) and New York, United States (US).
Main Outcome Measures
Early and late stages of prevalent and incident AMD, graded according to (a modification of) the international grading and classification system of AMD.
Results
Significant allelic or genotypic associations between eight C5 SNPs and AMD were found in the AMRO-NL study and this risk appeared independently of CFH Y402H, LOC387715 A69S, age and gender. None of these findings could be confirmed consistently in three replication populations.
Conclusions
Although the complement pathway, including C5, plays a crucial role in AMD, and the C5 protein is present in drusen, no consistent significant associations between C5 SNPs and AMD were found in all studies. The implications for genetic screening of AMD are discussed.
doi:10.1016/j.ophtha.2009.08.032
PMCID: PMC2830367  PMID: 20022638
17.  Rates of Nonexudative and Exudative Age-Related Macular Degeneration among Asian American Ethnic Groups 
Significant differences in rates of nonexudative AMD were noted among persons of different Asian ethnicities. Chinese Americans had a 63% increased risk for nonexudative AMD, whereas Japanese Americans had a 29% reduced risk for nonexudative AMD.
Purpose.
To determine whether the risk for nonexudative and exudative age-related macular degeneration (AMD) varies for Americans of different Asian ethnicities.
Methods.
Claims data from a large national United States managed care network were reviewed to identify Asian Americans age 40 and older who had ≥1 eye care visits from 2001 to 2007. International Classification of Disease (ICD-9CM) billing codes were used to identify enrollees with nonexudative and exudative AMD. Incidence and prevalence rates were calculated for nonexudative and exudative AMD and were stratified by Asian ethnicity. Cox regression analyses were performed to determine the relative risk for developing nonexudative and exudative AMD for persons of different Asian ethnicities, with adjustment for sociodemographic factors and ocular and medical conditions.
Results.
Of the 44,103 Asian Americans who met the inclusion criteria, 2221 (5.04%) had nonexudative AMD and 217 (0.49%) had exudative AMD. Chinese Americans (adjusted hazard ratio [HR], 1.63; 95% confidence interval [CI], 1.50–1.77) and Pakistani Americans (HR, 1.97, 95% CI, 1.40–2.77) had a significantly increased risk for nonexudative AMD compared with non-Hispanic white Americans. By contrast, Japanese Americans had a 29% decreased risk for nonexudative AMD compared with non-Hispanic white Americans (HR, 0.71; 95% CI, 0.59–0.85). There were no significant differences in risk for exudative AMD for any of the Asian ethnicities compared with white Americans.
Conclusions.
Asian Americans are the second fastest growing racial group in the United States. Eye care providers must be aware of the overall disease burden of AMD within this group and appreciate how disease rates can vary substantially among different Asian ethnicities.
doi:10.1167/iovs.11-7179
PMCID: PMC3176030  PMID: 21778274
18.  CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD 
PLoS Medicine  2005;3(1):e5.
Background
Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the developed world. The two forms of advanced AMD, geographic atrophy and neovascular AMD, represent different pathological processes in the macula that lead to loss of central vision. Soft drusen, characterized by deposits in the macula without visual loss, are considered to be a precursor of advanced AMD. Recently, it has been proposed that a common missense variant, Y402H, in the Complement Factor H (CFH) gene increases the risk for advanced AMD. However, its impact on soft drusen, GA, or neovascular AMD—or the relationship between them—is unclear.
Methods and Findings
We genotyped 581 Icelandic patients with advanced AMD (278 neovascular AMD, 203 GA, and 100 with mixed neovascular AMD/GA), and 435 with early AMD (of whom 220 had soft drusen). A second cohort of 431 US patients from Utah, 322 with advanced AMD (244 neovascular AMD and 78 GA) and 109 early-AMD cases with soft drusen, were analyzed. We confirmed that the CFH Y402H variant shows significant association to advanced AMD, with odds ratio of 2.39 in Icelandic patients (p = 5.9 × 10−12) and odds ratio of 2.14 in US patients from Utah (p = 2.0 × 10−9) with advanced AMD. Furthermore, we show that the Y402H variant confers similar risk of soft drusen and both forms of advanced AMD (GA or neovascular AMD).
Conclusion
Soft drusen occur prior to progression to advanced AMD and represent a histological feature shared by neovascular AMD and GA. Our results suggest that CFH is a major risk factor of soft drusen, and additional genetic factors and/or environmental factors may be required for progression to advanced AMD.
A common missense variant, Y402H, in the Complement Factor H gene is associated strongly with soft drusen, a precursor of advanced age-related macular degeneration
doi:10.1371/journal.pmed.0030005
PMCID: PMC1288033  PMID: 16300415
19.  ARMS2/HTRA1 Locus Can Confer Differential Susceptibility to the Advanced Subtypes of Age-Related Macular Degeneration 
American journal of ophthalmology  2010;151(2):345-52.e3.
Purpose
To determine if genetic variants that have been associated with age-related macular degeneration (AMD) have a differential effect on the risk of choroidal neovascularization (CNV) and geographic atrophy.
Design
Genetic association study.
Methods
Setting
Multicenter study.
Study Population
Seven hundred forty-nine participants with geographic atrophy and 3209 participants with CNV were derived from 4 AMD studies with similar procedures from Tufts Medical Center, the Age-Related Eye Disease Study, University of Utah, and Hopital Intercommunal de Creteil.
Procedures
AMD grade was assigned based on fundus photography and examination using the clinical age-related maculopathy staging system. All samples were genotyped for single nucleotide polymorphisms (SNPs) previously associated with AMD. Allele frequencies were compared between participants with CNV and geographic atrophy using PLINK within each cohort and Mantel-Haenszel meta-analysis was performed to combine odds ratios (OR).
Main Outcome Measures
Differences in allele frequencies between participants with geographic atrophy and CNV.
Results
The frequency of the T allele of ARMS2/HTRA1 rs10490924 was significantly higher in participants with CNV than in those with geographic atrophy (OR, 1.37; 95% confidence interval, 1.21–1.54; P value = 4.2 × 10−7). This result remained statistically significant when excluding individuals who had geographic atrophy in 1 eye and CNV in the contralateral eye (P = 2.2 × 10−4). None of the other SNPs showed a significant differential effect for CNV vs geographic atrophy, including CFH, C2/CFB, C3, CFI, LIPC, and TIMP3.
Conclusions
Genetic variation at the ARMS2/HTRA1 locus confers a differential risk for CNV vs geographic atrophy in a well-powered sample.
doi:10.1016/j.ajo.2010.08.015
PMCID: PMC3763907  PMID: 21122828
20.  Elevated Membrane Attack Complex in Human Choroid With High Risk Complement Factor H Genotypes 
Experimental eye research  2011;93(4):565-567.
Data from human genetics, histopathology, and animal models reveal a major role for the complement system in the development of age-related macular degeneration (AMD). Genetic variations in the complement factor H (CFH) gene are associated with an elevated risk of AMD. In this study we sought to determine whether eyes from donors with a high risk genotype (homozygosity for the histidine allele at codon 402) exhibit altered levels of membrane attack complex (MAC) in the choroid, compared to eyes with a low risk genotype (homozygosity for tyrosine). Proteins were extracted from the RPE/choroid of 18 donors (10 low risk and 8 high risk) and levels of MAC were assessed using an ELISA assay. Eyes from donors homozygous for the histidine allele showed 69% higher levels of MAC than those homozygous for the tyrosine allele (p<0.05), independent of whether the eyes showed signs of early AMD. Our results provide evidence that high-risk CFH genotypes may affect AMD risk by increased deposition of MAC around the aging choriocapillaris.
doi:10.1016/j.exer.2011.06.015
PMCID: PMC3206185  PMID: 21729696
21.  Evaluation of Clustering and Genotype Distribution for Replication in Genome Wide Association Studies: The Age-Related Eye Disease Study 
PLoS ONE  2008;3(11):e3813.
Genome-wide association studies (GWASs) assess correlation between traits and DNA sequence variation using large numbers of genetic variants such as single nucleotide polymorphisms (SNPs) distributed across the genome. A GWAS produces many trait-SNP associations with low p-values, but few are replicated in subsequent studies. We sought to determine if characteristics of the genomic loci associated with a trait could be used to identify initial associations with a higher chance of replication in a second cohort. Data from the age-related eye disease study (AREDS) of 100,000 SNPs on 395 subjects with and 198 without age-related macular degeneration (AMD) were employed. Loci highly associated with AMD were characterized based on the distribution of genotypes, level of significance, and clustering of adjacent SNPs also associated with AMD suggesting linkage disequilibrium or multiple effects. Forty nine loci were highly associated with AMD, including 3 loci (CFH, C2/BF, LOC387715/HTRA1) already known to contain important genetic risks for AMD. One additional locus (C3) reported during the course of this study was identified and replicated in an additional study group. Tag-SNPs and haplotypes for each locus were evaluated for association with AMD in additional cohorts to account for population differences between discovery and replication subjects, but no additional clearly significant associations were identified. Relying on a significant genotype tests using a log-additive model would have excluded 57% of the non-replicated and none of the replicated loci, while use of other SNP features and clustering might have missed true associations.
doi:10.1371/journal.pone.0003813
PMCID: PMC2583911  PMID: 19043567
22.  Do Nutritional Supplements Have a Role in Age Macular Degeneration Prevention? 
Journal of Ophthalmology  2014;2014:901686.
Purpose. To review the proposed pathogenic mechanisms of age macular degeneration (AMD), as well as the role of antioxidants (AOX) and omega-3 fatty acids (ω-3) supplements in AMD prevention. Materials and Methods. Current knowledge on the cellular/molecular mechanisms of AMD and the epidemiologic/experimental studies on the effects of AOX and ω-3 were addressed all together with the scientific evidence and the personal opinion of professionals involved in the Retina Group of the OFTARED (Spain). Results. High dietary intakes of ω-3 and macular pigments lutein/zeaxanthin are associated with lower risk of prevalence and incidence in AMD. The Age-Related Eye Disease study (AREDS) showed a beneficial effect of high doses of vitamins C, E, beta-carotene, and zinc/copper in reducing the rate of progression to advanced AMD in patients with intermediate AMD or with one-sided late AMD. The AREDS-2 study has shown that lutein and zeaxanthin may substitute beta-carotene because of its potential relationship with increased lung cancer incidence. Conclusion. Research has proved that elder people with poor diets, especially with low AOX and ω-3 micronutrients intake and subsequently having low plasmatic levels, are more prone to developing AMD. Micronutrient supplementation enhances antioxidant defense and healthy eyes and might prevent/retard/modify AMD.
doi:10.1155/2014/901686
PMCID: PMC3941929  PMID: 24672708
23.  Inflammation, Complement Factor H, and Age-Related Macular Degeneration: The Multi-Ethnic Study of Atherosclerosis 
Ophthalmology  2008;115(10):1742-1749.
Objective
To describe the relationship of systemic inflammatory disease, complement factor H (CFH) Y402H (1277T→C) genotype status and age-related macular degeneration (AMD) prevalence in a multiethnic population of whites, blacks, Hispanics, and Chinese.
Design
Population-based, cross-sectional study.
Participants
We included 5887 persons aged 45 to 84 years with gradable AMD.
Methods
Digital fundus photographs were used to measure AMD. Two years earlier, biomarkers of inflammation were measured and history of inflammatory disease and use of antiinflammatory agents obtained.
Main Outcome Measure
Prevalence of AMD.
Results
While controlling for age, gender, race/ethnicity, and study site, there were no associations between systemic inflammatory factors and AMD severity. Higher levels of high-sensitivity C-reactive protein (odds ratio [OR] per standard deviation [SD] increase in natural log [ln] units, 2.34; 95% confidence interval [CI], 1.33–4.13) and interleukin-6 (OR per SD in ln, 2.06; 95% CI, 1.21–3.49) were associated with geographic atrophy but not other AMD end points. History of periodontal disease (OR, 1.68; 95% CI, 1.14–2.47) was related to increased retinal pigment. A history of arthritis was associated with soft distinct drusen (OR, 1.24; 95% CI, 1.06–1.46). A history of oral steroid use was related to large drusen (OR, 2.13; 95% CI, 1.14–3.97) and soft distinct drusen (OR, 1.76; 95% CI, 1.00–3.10) and history of cyclooxygenase 2 inhibitor use were associated with large drusen (OR, 1.50; 95% CI, 1.10–2.04), soft indistinct drusen (OR, 1.84; 95% CI, 1.09–3.10), and large drusen area (OR, 1.66; 95% CI, 1.02–2.71). Whites, blacks, and Hispanics with CFH Y402H CC variant genotype had the highest frequency of early AMD compared with those with wild TT genotype. The frequency of CFH did explain some of the difference in AMD prevalence between Chinese and Hispanics compared with whites, but did not explain the difference in prevalence between whites and blacks.
Conclusions
This study confirmed associations of the Y402H CFH gene variant with AMD in nonwhite populations, but neither explained the lack of association between inflammatory factors and AMD in the cohort nor the basis for the observed differences in AMD prevalence across ethnic groups.
doi:10.1016/j.ophtha.2008.03.021
PMCID: PMC2936447  PMID: 18538409
24.  A Prospective Assessment of the Y402H Variant in Complement Factor H, Genetic Variants in C-reactive Protein, and Risk of Age-Related Macular Degeneration in Men 
Background:
Two biologically related factors, complement factor H (CFH) and C-reactive protein (CRP) have been associated with age-related macular degeneration (AMD). The Y402H variant of CFH is located within the binding site of CFH for CRP. Although plasma CRP levels have been related to AMD, and plasma CRP levels are partly determined by genetic variation, there is no information on whether genetic variants in CRP are associated with AMD.
Methods:
We performed a prospective analysis among 111 men who eventually developed AMD and 401 men who remained free of AMD, all participants in the Physicians’ Health Study. We determined genotypes for the common T>C single nucleotide polymorphism (SNP) in exon 9 of CFH (rs1061170; protein Y402H) as well as seven previously described CRP SNPs (rs3093059, rs2794521, rs3091244, rs1417938, rs1800947, rs1130864, rs1205). We used logistic regression analysis to evaluate individual SNPs as well as six CRP haplotypes for association with AMD.
Results:
The high-risk C allele of CFH was present in 45% of cases and 34% of controls. We observed an odds ratio for AMD of 1.46 (95% CI=1.05-2.04) for TC heterozygotes and 2.13 (95% CI=1.10-4.16) for CC homozygotes assuming a multiplicative (log-additive) model, and calculated an attributable fraction of 25% (95% CI=1% to 44%). For CRP, single-marker or haplotype-based analysis failed to reveal any significant associations with risk of AMD.
Conclusion:
These prospective data confirm an association between the Y402H variant of CFH and risk of AMD. In contrast, although biologically plausible, genetic variation in CRP does not appear to be associated with risk of AMD. Further prospective study of larger numbers of subjects is needed to substantiate available information on the genetic epidemiology of AMD.
doi:10.1167/iovs.05-1456
PMCID: PMC1828123  PMID: 16723442
25.  Complement factor B polymorphism 32W protects against age-related macular degeneration 
Molecular Vision  2011;17:983-988.
Purpose
The 32Q (rs641153; A) and 32W (rs12614; T) variants of complement factor B (CFB) cause less efficient complement activation in vitro than the common 32R variant. This is thought to be the reason that the 32Q variant is associated with decreased risk of age-related macular degeneration (AMD). We investigated whether the 32W variant was also associated with decreased risk of AMD.
Methods
We genotyped 367 cases with neovascular AMD and 251 disease-free controls. Association with the disease phenotype was assessed by logistic regression for polymorphisms of CFB alone and in combination with smoking status and genetic risk markers of complement factor H (CFH) and HtrA serine peptidase 1 (HTRA1). We performed meta-analysis of all previously published reports of 32W allele frequency in AMD cases and controls.
Results
The CFB variant 32W was associated with protection against neovascular AMD, compared to the common 32R variant (odds ratio 0.64, p<0.05, in logistic regression with CFB variants; odds ratio 0.53, p<0.05, in logistic regression with CFB variants, CFH haplotypes, HTRA1 rs10490924 genotype, and smoking status). Meta-analysis (n=1,795) including this study and two others of neovascular AMD showed a combined odds ratio of 0.75 (p<0.05) for 32W, compared to 32R. Meta-analysis (n=2,600) of all reported studies of all types of AMD showed a combined odds ratio of 0.79 (p<0.01).
Conclusions
Our study shows that the 32W variant of CFB is associated with protection against AMD, in keeping with evidence of its functional effect on the complement system. The protective effect is less strong than that associated with 32Q.
PMCID: PMC3084221  PMID: 21541267

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