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Ophthalmic Molecular Genetics |

Typing of ARMS2 and CFH in Age-Related Macular Degeneration Case-Control Study and Assessment of Frequency in the Italian Population FREE

Federico Ricci, MD; Stefania Zampatti, MD; Francesca D’Abbruzzi, MD; Filippo Missiroli, MD; Claudia Martone; Tiziana Lepre; Ilenia Pietrangeli; Cecilia Sinibaldi, PhD; Cristina Peconi; Giuseppe Novelli, PhD, MD; Emiliano Giardina, PhD
[+] Author Affiliations

Author Affiliations: Unità Operative Semplici Dipartimentali Patologia Retinica Fondazione PTV “Policlinico Tor Vergata” (Drs Ricci, D’Abbruzzi, and Missiroli), and Department of Biopathology, Centre of Excellence for Genomic Risk Assessment in Multifactorial and Complex Diseases, School of Medicine, University of Rome “Tor Vergata” and Fondazione PTV “Policlinico Tor Vergata” (Drs Zampatti, Martone, Lepre, Pietrangeli, Sinibaldi, Peconi, Novelli, and Giardina), Rome, Italy.


Section Editor: Janey L Wiggs, MD, PhD

More Author Information
Arch Ophthalmol. 2009;127(10):1368-1372. doi:10.1001/archophthalmol.2009.237.
Text Size: A A A
Published online

Objectives  To determine the effects of the polymorphisms CFHTyr402His and ARMS2del443ins54 on susceptibility to age-related macular degeneration (AMD) and to find the frequencies of these single-nucleotide polymorphisms in an Italian population that was not examined clinically.

Methods  A total of 286 control subjects (126 men and 160 women) and 159 white patients (73 men and 86 women) harboring exudative AMD in 1 eye were recruited. A third group of 182 DNA samples from blood donors of the same geographical areas were also typed to assess the frequency of CFHTyr402His and ARMS2del443ins54 polymorphisms in the general population. The data were analyzed statistically by a standard 2 × 2 table, Fisher exact tests, and odds ratios.

Results  The deletion-insertion at chromosome 10q26 (del443ins54) showed the strongest association with AMD in terms of both Pvalue and odds ratio (P = 2.7 × 10−15; odds ratio = 3.25), and a highly significant association was also confirmed for Tyr402His at the CFHlocus (P = 9.9 × 10−13; odds ratio = 2.86). We found no differences in allele and genotype association between classic and occult choroidal neovascularization. We also observed that 39% of the samples in the general Italian population were at least 5.4 times more likely than control subjects to develop AMD.

Conclusions  To our knowledge, this is the first confirmation of the association of del443ins54 in Italian patients with AMD, and we also confirmed the association of Tyr402His with CFH. Genetic analysis of the general population suggested that analysis of the ARMS2and CFHrisk alleles alone may be helpful in differentiating high- risk individuals (odds ratio > 5.00) from low-risk individuals (odds ratio < 0.45).

Clinical Relevance  Individuals at high risk for developing AMD could be identified and selected for specific prevention programs. In this context, the development of prevention programs based on dietary antioxidants or on close monitoring of at-risk individuals should be considered or suggested.

Age-related macular degeneration (AMD) is the most common irreversible cause of severe vision loss throughout the world in people aged 50 years or older.1Thirty percent of people older than 75 years show early signs of the disease.2,3Laser surgery, photodynamic therapy, and intraocular injections offer some chance of visual improvement, but they require invasive delivery methods and cannot always prevent the progress of the disease. Although several risk factors for AMD such as smoking, being white, and having a family history of AMD have been reported, the risk of developing advanced AMD is assessed on the basis of ocular findings in those who already have the early stages.2,46Accordingly, early identification of individuals at greatest risk for vision loss due to AMD prior to the development of any signs of the disease can be clinically important. In this respect, the identification and validation of genetic predisposing variants to be used as biomarkers would help to identify people at increased risk for more advanced stages of AMD. Hence, heredity is a primary contributor to AMD susceptibility as suggested by family and twin studies.7,8First-degree relatives of patients with AMD are at increased risk (odds ratio [OR] = 2.4) for the condition compared with first-degree relatives in families without the disorder. They are also affected at a younger age and have an increased lifetime risk of late AMD (risk ratio = 4.2).911In 2005, several groups1216independently reported that AMD is strongly associated with the polymorphism Tyr402His in the complement factor H gene (CFH) (GenBank NG_007259), located in chromosome 1q31. CFHis implicated in all stages of AMD from early hallmarks such as drusen to vision-disabling late AMD.11,17

The average ORs for the CFHTyr402His variant are 2- to 7-fold depending on the number of risk alleles. Also, it was calculated that individuals homozygous for the risk allele C at the CFHTyr402His polymorphism have a 48% risk of developing late AMD by age 95 years, whereas this risk does not exceed 22% for noncarriers.9A second polymorphism (Ala69Ser) in the age-related maculopathy susceptibility 2 gene (ARMS2,also known as LOC387715) (GenBank NG_011725) located on chromosome 10q26 was reported as another major locus contributing to the pathogenesis of AMD.1820Rivera et al19found the strongest association with LOC387715, reporting a 7.6-fold increased risk for individuals homozygous for the risk allele T of rs10490924. Association at chromosome 10q26 is located between 2 nearby genes, ARMS2and HTRA1(high-temperature requirement factor A1; GenBank NG_011554), suggesting 2 equally probable candidates. Recently it was reported that a deletion-insertion polymorphism in ARMS2(del443ins54) was strongly associated with AMD, directly affecting the transcript by removing the polyadenylation signal and inserting a 54–base pair (bp) element known to mediate rapid messenger RNA turnover.21As a consequence, ARMS2shows no detectable expression in homozygous carriers of the deletion-insertion variant. In this article, we present the first confirmation to our knowledge of a deletion-insertion at chromosome 10q26 (del443ins54) in the Italian population, we confirm the association of CFHsingle-nucleotide polymorphism rs1061170 (Tyr402His), we assess the joint effects of both variations on AMD, and we assess the frequencies of the single and complex genotypes in the general Italian population.

STUDY SUBJECTS

One hundred fifty-nine consecutive white patients (73 men and 86 women) harboring exudative AMD in 1 eye were prospectively recruited at the Medical Retina Centre (Table 1). All study subjects underwent a detailed eye examination including best-corrected visual acuity and slitlamp biomicroscopy of the fundus. Color fundus photography and fluorescein angiography were performed. Exudative AMD was diagnosed by the investigators (F.R., F.D., and F.M.) according to the international classification guidelines.22

Table Graphic Jump LocationTable 1. Clinical Characteristics of Patients With Age-Related Macular Degeneration and Control Subjects

Inclusion criteria were being older than 55 years and having unilateral or bilateral exudative AMD. Exclusion criteria were presence of other retinal disease (eg, diabetic retinopathy, high myopia, or retinal dystrophies), having the atrophic form of AMD, association of atrophic and exudative forms of AMD, and having fibrovascular scarring that did not allow the choroidal neovascularization (CNV) angiographic type to be precisely graded.

To classify the initial lesions before any treatment, exudative AMD was graded on the earliest fluorescein angiography examination results available. The grading was performed before the genetic testing and classified as either classic CNV (including prevalently classic) or occult CNV (including minimally classic). The CNV was classified by the type of fluorescein leakage based on guidelines from the Macular Photocoagulation Study and other studies.23,24

There were 286 control subjects (126 men and 160 women). They had no family history of AMD, signs of AMD, or any other major eye disease except mild senile cataracts and low refractive defects. In this group, fundus examination excluded the presence of drusen, focal atrophy, and abnormal retinal pigment epithelium change.

A third group of samples was also obtained from 182 blood donors from the same geographical areas as the patients and control subjects. All of the patients and control subjects were sex matched. The study was conducted according to the Declaration of Helsinki, and informed consent was obtained from the participating subjects after the nature of the study had been explained. The study protocol was approved by the ethics committee of the University of Rome “Tor Vergata,” Rome, Italy.

GENETIC ANALYSIS

Genotyping of rs1061170 was performed by TaqMan assays (Applied Biosystems, Foster City, California). Reactions were run in an AB7500 (Applied Biosystems) and interpreted using Sequence Detection System 2.1 software (Applied Biosystems). Each plate contained 3 positive control samples (samples previously confirmed by direct sequencing as heterozygous and both homozygous) and 2 negative control samples. No departure from Hardy-Weinberg equilibrium was detected. Results from genotype assessment of rs1061170 and del443ins54 were confirmed by postgenotyping direct resequencing of 10 random samples. Typing of del443ins54 was performed by polymerase chain reaction and agarose gel electrophoresis. Polymerase chain reaction was performed in a 25-μL volume containing 5mM magnesium chloride, 2 μL of 10X buffer (Applied Biosystems), 1 U of Taq Gold polymerase (Applied Biosystems), 1.25mM deoxynucleoside triphosphate (Invitrogen Corp, Carlsbad, California), 80 ng of template DNA, and 10 pmol of each primer (forward: 5′-TCCTAACATCTGGATTCCTC-3′; reverse: 5′- TGAAGTCCAAGCTTCTTACC-3′). Polymerase chain reaction amplification included a 10-minute hot start at 94°C, 30 cycles of denaturation at 94°C for 1 minute, annealing at 58°C for 1 minute, extension at 72°C for 1 minute, and a final extension at 72°C for 10 minutes. Amplified polymerase chain reaction products were resolved by electrophoresis on 1.8% agarose (the size of the deleted allele is 239 bp, whereas the size of the nondeleted allele is 628 bp).

STATISTICAL ANALYSIS

Statistical analyses were performed by a standard 2 × 2 table and Fisher exact tests. Allele and genotype frequencies of rs1061170 and del443ins54 were compared with those of the clinically examined control subjects (n = 286) and then separately with those of the clinically unexamined control subjects (n = 186). Allele analysis in unrelated samples was performed using the software UNPHASED (http://www.litbio.org). The ORs were calculated using the online software “Calculator for Confidence Intervals of Odds Ratio in an Unmatched Case Control Study” (http://www.hutchon.net/ConfidOR.htm). Joint analyses of rs1061170 and del443ins54 were performed by comparing the frequencies of combined genotypes in the 3 groups (patients, clinically examined control subjects, and clinically unexamined control subjects).

Allele and genotype frequencies of rs1061170 and del443ins54 were characterized in a cohort of 159 patients with AMD and 286 healthy control subjects.

In our Italian case-control cohort consisting of patients and healthy control subjects who underwent clinical examinations, the deletion-insertion at chromosome 10q26 (del443ins54) showed the strongest association with AMD in terms of both Pvalue and OR (P = 2.7 × 10−15; OR = 3.25) (Table 2). Genotype association revealed OR values of 3.18 and 20.61 if 1 or 2 risk alleles were present, respectively, with 124 patients (78%) having at least 1 risk allele with respect to 130 control subjects (45%). A highly significant association was also confirmed for the risk allele C of rs1061170 at the CFHlocus, generating a Pvalue of 9.9 × 10−13and an OR of 2.86. Genotype association revealed OR values of 2.88 and 13.06 if 1 or 2 risk alleles were present, respectively, with 122 patients (77%) having at least 1 risk allele with respect to 144 control subjects (50%) (Table 2). We found no differences in allele and genotype association between classic CNV and occult CNV.

Table Graphic Jump LocationTable 2. Allele and Genotype Frequency of del443ins54 and rs1061170 in Italian Patients vs Control Subjects and vs the General Population

Table 3shows the joint OR for the ARMS2and CFHvariations. Joint analyses revealed 5 risk diplotype classes with ORs ranging from 5.46 (in samples homozygous for the T allele of rs1061170 and heterozygous for del443ins54) to 59.50 and 65.17 (in samples homozygous for both risk alleles and in samples homozygous for the C allele of rs1061170 and heterozygous for del443ins54, respectively). Diplotype analyses in control samples failed to observe samples homozygous for del443ins54 and heterozygous for rs1061170, making it unfeasible to assess the OR for this diplotype class. The only protective diplotype classes were observed for samples homozygous for the nondeleted allele of del443ins54 independently from the genotype of rs1061170. According to the genotype of rs1061170, we observed ORs ranging from 0.15 (for individuals homozygous for the nonrisk allele T of rs1061170) to 0.44 (for individuals homozygous for the risk allele C of rs1061170).

Table Graphic Jump LocationTable 3. Joint Odds Ratios for the ARMS2and CFHVariations in the Patient Populationa

After this determination of contributing genetic factors in Italian patients with AMD, we decided to assess the frequency of combined genotypes at the CFHand ARMS2loci in the general population, ie, samples that were not clinically examined. We typed 182 DNA samples from blood donors of the same geographical areas as the patients and control subjects. We observed risk allele frequencies of 36% and 20% for rs1061170 (risk allele C) and del443ins54, respectively (Table 2). The risk allele frequency of rs1061170 differed somewhat from that reported in the HapMap database of white individuals (28%), but the frequency of del443ins54 did not differ from that reported in the HapMap database calculated using a marker of complete linkage disequilibrium (rs3750848) (22%). Table 4shows the frequency of diplotypes at the CFHand ARMS2loci in this general population. Interestingly, 39% of the blood donors are at least 5.4 times more likely than control subjects to develop AMD.

Table Graphic Jump LocationTable 4. Frequency of Diplotypes at the CFHand ARMS2Loci in the Italian General Populationa

In particular, on the basis of our screening, 18% and 6% of the population have risks 13 and 60 times greater than control subjects, respectively, for developing the disease. On the other hand, 61% of people do not have increased risks for AMD related to the rs1061170 and del443ins54 genotypes, with most of them showing reduced risk with respect to the general population.

To our knowledge, this is the first confirmation of the association of del443ins54 with AMD in the Italian population. We also confirmed the association with rs1061170 in CFHand assessed the frequency of these 2 variations in a control Italian population. With respect to the allele frequency of rs1061170 (C allele) previously reported in the Italian population,25we observed similar frequencies in the cohort of patients (57% vs 54%, respectively), whereas lower frequencies were observed in the healthy control samples (39% vs 29%, respectively). As a consequence, we observed higher ORs with respect to those previously reported (13.06 vs 3.90, respectively).25We believe that such discrepancies may be due to the selection of healthy control subjects and/or to the size of the case-control cohort analyzed. Similarly, we observed higher frequencies for the risk allele of del443ins54 in Italian patients with respect to German patients.21These 2 variations appear to independently contribute to the susceptibility to AMD in the Italian patients. Such highly penetrant genetic susceptibility factors in AMD might be used as diagnostic or prognostic molecular markers and/or for drug response. While genetic screening has become a routine practice for many mendelian diseases, population screening for risk assessment for a complex disease is still unexploited. The reason for this is that susceptibility to common diseases results from complex and unpredictable interactions of environment and genes, limiting the possibility of assessing individual risks. However, unlike most common diseases in which many susceptibility genes each have a small effect on the phenotype, AMD shows highly penetrant variations that are quite common in the population. Genetic analysis of the general population suggests that the analysis of the ARMS2and CFHrisk alleles alone may be used to differentiate high- risk individuals (OR > 5.00) from low-risk individuals (OR < 0.45).

Most people with early signs of AMD have little or no decrease in visual acuity or other aspects of vision. Independent studies have demonstrated that persons with early-stage AMD are more likely to have a stroke incident than persons without AMD.2628The association is independent of age, sex, ethnicity, history of diabetes, blood pressure, cigarette smoking, and other stroke risk factors.26Our findings, demonstrating the possibility of differentiating between high-risk individuals (OR > 5.00) and low-risk individuals (OR < 0.45) in the general population, have potential clinical implications. Recently, it was suggested that specific proteomic biomarkers can be useful for predicting AMD susceptibility in combination with genomic markers.29In particular, plasma carboxyethylpyrrole marker levels in combination with genomic markers discriminate between patients with AMD and control subjects with up to approximately 80% accuracy. On this basis, a prevention program could be suggested or developed for people at high risk for developing AMD (and/or stroke), ie, based on dietary antioxidants30or on close monitoring of at-risk individuals. In this perspective, the availability of a true predictive genetic screening for AMD may represent a bold step toward personalized and/or preventive medicine for the disease.

Correspondence: Emiliano Giardina, PhD, Department of Biopathology, University of Rome “Tor Vergata,” Via Montpellier 1, 00133 Rome, Italy (emiliano.giardina@uniroma2.it).

Submitted for Publication: January 30, 2009; final revision received May 29, 2009; accepted June 6, 2009.

Author Contributions: Dr Giardina had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: None reported.

Congdon  NO'Colmain  BKlaver  CC  et al. Eye Diseases Prevalence Research Group, Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol 2004;122 (4) 477- 485
PubMed Link to Article
Jager  RDMieler  WFMiller  JW Age-related macular degeneration. N Engl J Med 2008;358 (24) 2606- 2617
PubMed Link to Article
Thakkinstian  AHan  PMcEvoy  M  et al.  Systematic review and meta-analysis of the association between complement factor H Y402H polymorphisms and age-related macular degeneration. Hum Mol Genet 2006;15 (18) 2784- 2790
PubMed Link to Article
Klein  R Overview of progress in the epidemiology of age-related macular degeneration. Ophthalmic Epidemiol 2007;14 (4) 184- 187
PubMed Link to Article
DeAngelis  MMJi  FKim  IK  et al.  Cigarette smoking, CFH, APOE, ELOVL4, and risk of neovascular age-related macular degeneration. Arch Ophthalmol 2007;125 (1) 49- 54
PubMed Link to Article
Zhang  HMorrison  MADewan  A  et al.  The NEI/NCBI dbGAP database: genotypes and haplotypes that may specifically predispose to risk of neovascular age-related macular degeneration. BMC Med Genet 2008;951
PubMed Link to Article
Seddon  JMCote  JPage  WFAggen  SHNeale  MC The US twin study of age-related macular degeneration: relative roles of genetic and environmental influences. Arch Ophthalmol 2005;123 (3) 321- 327
PubMed Link to Article
Hammond  CJWebster  ARSnieder  HBird  ACGilbert  CESpector  TD Genetic influence on early age-related maculopathy: a twin study. Ophthalmology 2002;109 (4) 730- 736
PubMed Link to Article
Scholl  HPFleckenstein  MCharbel Issa  PKeilhauer  CHolz  FGWeber  BH An update on the genetics of age-related macular degeneration. Mol Vis 2007;13196- 205
PubMed
Klaver  CCAssink  JJvan Leeuwen  R  et al.  Incidence and progression rates of age-related maculopathy: the Rotterdam Study. Invest Ophthalmol Vis Sci 2001;42 (10) 2237- 2241
PubMed
Swaroop  ABranham  KEChen  WAbecasis  G Genetic susceptibility to age-related macular degeneration: a paradigm for dissecting complex disease traits. Hum Mol Genet 2007;16 (spec No. 2) R174- R182
PubMed Link to Article
Klein  RJZeiss  CChew  EY  et al.  Complement factor H polymorphism in age-related macular degeneration. Science 2005;308 (5720) 385- 389
PubMed Link to Article
Edwards  AORitter  R  IIIAbel  KJManning  APanhuysen  CFarrer  LA Complement factor H polymorphism and age-related macular degeneration. Science 2005;308 (5720) 421- 424
PubMed Link to Article
Haines  JLHauser  MASchmidt  S  et al.  Complement factor H variant increases the risk of age-related macular degeneration. Science 2005;308 (5720) 419- 421
PubMed Link to Article
Hageman  GSAnderson  DHJohnson  LV  et al.  A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A 2005;102 (20) 7227- 7232
PubMed Link to Article
Zareparsi  SBranham  KELi  M  et al.  Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration. Am J Hum Genet 2005;77 (1) 149- 153
PubMed Link to Article
Despriet  DDKlaver  CCWitteman  JC  et al.  Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration. JAMA 2006;296 (3) 301- 309
PubMed Link to Article
Jakobsdottir  JConley  YPWeeks  DEMah  TSFerrell  REGorin  MB Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet 2005;77 (3) 389- 407
PubMed Link to Article
Rivera  AFisher  SAFritsche  LG  et al.  Hypothetical LOC387715is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet 2005;14 (21) 3227- 3236
PubMed Link to Article
Schmidt  SHauser  MAScott  WK  et al.  Cigarette smoking strongly modifies the association of LOC387715and age-related macular degeneration. Am J Hum Genet 2006;78 (5) 852- 864
PubMed Link to Article
Fritsche  LGLoenhardt  TJanssen  A  et al.  Age-related macular degeneration is associated with an unstable ARMS2(LOC387715) mRNA. Nat Genet 2008;40 (7) 892- 896
PubMed Link to Article
Bird  ACBressler  NMBressler  SB  et al. International ARM Epidemiological Study Group, An international classification and grading system for age-related maculopathy and age-related macular degeneration. Surv Ophthalmol 1995;39 (5) 367- 374
PubMed Link to Article
Macular Photocoagulation Study Group, Subfoveal neovascular lesions in age-related macular degeneration: guidelines for evaluation and treatment in the Macular Photocoagulation Study. Arch Ophthalmol 1991;109 (9) 1242- 1257
PubMed Link to Article
Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study Group, Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials: TAP report 1. Arch Ophthalmol 1999;117 (10) 1329- 1345
PubMed Link to Article
Simonelli  FFrisso  GTesta  F  et al.  Polymorphism p.402Y>H in the complement factor H protein is a risk factor for age related macular degeneration in an Italian population. Br J Ophthalmol 2006;90 (9) 1142- 1145
PubMed Link to Article
Wong  TYKlein  RSun  C  et al. Atherosclerosis Risk in Communities Study, Age-related macular degeneration and risk for stroke. Ann Intern Med 2006;145 (2) 98- 106
PubMed Link to Article
Tan  JSWang  JJLiew  GRochtchina  EMitchell  P Age-related macular degeneration and mortality from cardiovascular disease or stroke. Br J Ophthalmol 2008;92 (4) 509- 512
PubMed Link to Article
Cackett  PCheung  NWong  TY Age-related macular degeneration and mortality from cardiovascular disease or stroke. Br J Ophthalmol 2008;92 (11) 1564
PubMed Link to Article
Gu  JPaeur  GJYue  X  et al. Clinical Genomic and Proteomic AMD Study Group, Assessing susceptibility to age-related macular degeneration with proteomic and genomic biomarkers. Mol Cell Proteomics 2009;8 (6) 1338- 1349
PubMed Link to Article
Vokó  ZHollander  MHofman  AKoudstaal  PJBreteler  MM Dietary antioxidants and the risk of ischemic stroke: the Rotterdam Study. Neurology 2003;61 (9) 1273- 1275
PubMed Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Clinical Characteristics of Patients With Age-Related Macular Degeneration and Control Subjects
Table Graphic Jump LocationTable 4. Frequency of Diplotypes at the CFHand ARMS2Loci in the Italian General Populationa
Table Graphic Jump LocationTable 3. Joint Odds Ratios for the ARMS2and CFHVariations in the Patient Populationa
Table Graphic Jump LocationTable 2. Allele and Genotype Frequency of del443ins54 and rs1061170 in Italian Patients vs Control Subjects and vs the General Population

References

Congdon  NO'Colmain  BKlaver  CC  et al. Eye Diseases Prevalence Research Group, Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol 2004;122 (4) 477- 485
PubMed Link to Article
Jager  RDMieler  WFMiller  JW Age-related macular degeneration. N Engl J Med 2008;358 (24) 2606- 2617
PubMed Link to Article
Thakkinstian  AHan  PMcEvoy  M  et al.  Systematic review and meta-analysis of the association between complement factor H Y402H polymorphisms and age-related macular degeneration. Hum Mol Genet 2006;15 (18) 2784- 2790
PubMed Link to Article
Klein  R Overview of progress in the epidemiology of age-related macular degeneration. Ophthalmic Epidemiol 2007;14 (4) 184- 187
PubMed Link to Article
DeAngelis  MMJi  FKim  IK  et al.  Cigarette smoking, CFH, APOE, ELOVL4, and risk of neovascular age-related macular degeneration. Arch Ophthalmol 2007;125 (1) 49- 54
PubMed Link to Article
Zhang  HMorrison  MADewan  A  et al.  The NEI/NCBI dbGAP database: genotypes and haplotypes that may specifically predispose to risk of neovascular age-related macular degeneration. BMC Med Genet 2008;951
PubMed Link to Article
Seddon  JMCote  JPage  WFAggen  SHNeale  MC The US twin study of age-related macular degeneration: relative roles of genetic and environmental influences. Arch Ophthalmol 2005;123 (3) 321- 327
PubMed Link to Article
Hammond  CJWebster  ARSnieder  HBird  ACGilbert  CESpector  TD Genetic influence on early age-related maculopathy: a twin study. Ophthalmology 2002;109 (4) 730- 736
PubMed Link to Article
Scholl  HPFleckenstein  MCharbel Issa  PKeilhauer  CHolz  FGWeber  BH An update on the genetics of age-related macular degeneration. Mol Vis 2007;13196- 205
PubMed
Klaver  CCAssink  JJvan Leeuwen  R  et al.  Incidence and progression rates of age-related maculopathy: the Rotterdam Study. Invest Ophthalmol Vis Sci 2001;42 (10) 2237- 2241
PubMed
Swaroop  ABranham  KEChen  WAbecasis  G Genetic susceptibility to age-related macular degeneration: a paradigm for dissecting complex disease traits. Hum Mol Genet 2007;16 (spec No. 2) R174- R182
PubMed Link to Article
Klein  RJZeiss  CChew  EY  et al.  Complement factor H polymorphism in age-related macular degeneration. Science 2005;308 (5720) 385- 389
PubMed Link to Article
Edwards  AORitter  R  IIIAbel  KJManning  APanhuysen  CFarrer  LA Complement factor H polymorphism and age-related macular degeneration. Science 2005;308 (5720) 421- 424
PubMed Link to Article
Haines  JLHauser  MASchmidt  S  et al.  Complement factor H variant increases the risk of age-related macular degeneration. Science 2005;308 (5720) 419- 421
PubMed Link to Article
Hageman  GSAnderson  DHJohnson  LV  et al.  A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A 2005;102 (20) 7227- 7232
PubMed Link to Article
Zareparsi  SBranham  KELi  M  et al.  Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration. Am J Hum Genet 2005;77 (1) 149- 153
PubMed Link to Article
Despriet  DDKlaver  CCWitteman  JC  et al.  Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration. JAMA 2006;296 (3) 301- 309
PubMed Link to Article
Jakobsdottir  JConley  YPWeeks  DEMah  TSFerrell  REGorin  MB Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet 2005;77 (3) 389- 407
PubMed Link to Article
Rivera  AFisher  SAFritsche  LG  et al.  Hypothetical LOC387715is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet 2005;14 (21) 3227- 3236
PubMed Link to Article
Schmidt  SHauser  MAScott  WK  et al.  Cigarette smoking strongly modifies the association of LOC387715and age-related macular degeneration. Am J Hum Genet 2006;78 (5) 852- 864
PubMed Link to Article
Fritsche  LGLoenhardt  TJanssen  A  et al.  Age-related macular degeneration is associated with an unstable ARMS2(LOC387715) mRNA. Nat Genet 2008;40 (7) 892- 896
PubMed Link to Article
Bird  ACBressler  NMBressler  SB  et al. International ARM Epidemiological Study Group, An international classification and grading system for age-related maculopathy and age-related macular degeneration. Surv Ophthalmol 1995;39 (5) 367- 374
PubMed Link to Article
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