Evidence of association of APOE with age‐related macular degeneration ‐ a pooled analysis of 15 studies

Age‐related macular degeneration (AMD) is the most common cause of incurable visual impairment in high‐income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low‐density cholesterol modulation. Potential interaction between APOE and sex, and smoking status has been reported. We present a pooled analysis (n = 21,160) demonstrating associations between late AMD and APOε4 (odds ratio [OR] = 0.72 per haplotype; confidence interval [CI]: 0.65–0.74; P = 4.41×10−11) and APOε2 (OR = 1.83 for homozygote carriers; CI: 1.04–3.23; P = 0.04), following adjustment for age group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR = 1.54; CI: 1.38–1.72; P = 2.8×10−15) and atrophic (OR = 1.38; CI: 1.18–1.61; P = 3.37×10−5) AMD but not early AMD (OR = 0.94; CI: 0.86–1.03; P = 0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyond ε2 and ε4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low‐density cholesterol specifically, in AMD disease etiology. 32:1407–1416, 2011. ©2011 Wiley Periodicals, Inc.

Lars G Fritsche | Ammarin Thakkinstian | Wei Chen | Usha Chakravarthy | Gareth J McKay | Giuliana Silvestri | Johanna M Seddon | Valentina Cipriani | Daniel E Weeks | John Attia | Caroline Hayward | Johannes R Vingerling | Sarah Ennis | Michael B Gorin | Ian S Young | Inga Peter | Fotis Topouzis | Goncalo R Abecasis | Robyn H Guymer | Anand Swaroop | Reecha Sofat | Michael Dean | Peter J Francis | Bernhard H F Weber | Chia-Ling Kuo | Alan F Wright | Paul N Baird | G. Abecasis | D. Weeks | C. Klaver | A. Hingorani | Wei Chen | A. Swaroop | P. D. de Jong | A. Wright | C. Keilhauer | A. Fletcher | Wei Chen | C. Hayward | J. Attia | R. Guymer | J. Vingerling | G. Soubrane | L. Fritsche | M. Othman | B. Weber | M. Klein | J. Vioque | Chia-Ling Kuo | J. Seddon | M. Gorin | F. Topouzis | M. Dean | V. Cipriani | A. Webster | A. Moore | S. Ennis | J. Yates | C. Patterson | A. Kanda | M. Rahu | P. Francis | R. Sofat | G. Silvestri | D. Stambolian | A. Lotery | P. Baird | U. Chakravarthy | I. Peter | A. Orlin | G. McKay | L. Tomazzoli | A. Thakkinstian | Dwight Stambolian | Anthony T Moore | Aroon D Hingorani | Andrew R Webster | Mati Rahu | Paulus T V M de Jong | Astrid E Fletcher | Jesus Vioque | Johan H Seland | Gisele Soubrane | Laura Tomazzoli | S. Dasari | Lintje Ho | I. Young | J. Seland | Julie Sawitzke | Mohammad Othman | Atsuhiro Kanda | Anton Orlin | Andrew J Lotery | J. Attia | Michael L Klein | Chris C Patterson | Shilpa Dasari | Caroline C Klaver | Lintje Ho | Julie Sawitzke | John R W Yates | Claudia N Keilhauer | D. Stambolian | B. Weber | G. Mckay | Giuliana Silvestri | A. Wright | A. Moore | A. Wright | Johannes R. Vingerling | Chris C Patterson | J. R. Yates | Paulus T. V. M. de Jong | Caroline C. Klaver | Astrid E. Fletcher | Ian S. Young | Gisele Soubrane | Jesús Vioque | Michael Dean | Johanna M. Seddon | Inga Peter | Andrew R. Webster | Anthony T. Moore | John R.W. Yates | Bernhard H.F. Weber | Sarah Ennis | Peter J. Francis | Anton Orlin | Michael B. Gorin | Chia‐Ling Kuo | Anand Swaroop | Atsuhiro Kanda | Ian S. Young

[1]  R. T. Smith,et al.  Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration , 2006, Nature Genetics.

[2]  R. Klein,et al.  Hormone therapy and age-related macular degeneration: the Women's Health Initiative Sight Exam Study. , 2006, Archives of ophthalmology.

[3]  A. Munnich,et al.  The γ e4 allele of the apolipoprotein E gene as a potential protective factor for exudative age-related macular degeneration , 1998 .

[4]  J. Thompson,et al.  The choice of a genetic model in the meta-analysis of molecular association studies. , 2005, International journal of epidemiology.

[5]  P. Mitchell,et al.  Smoking and age-related maculopathy. The Blue Mountains Eye Study. , 1996, Archives of ophthalmology.

[6]  A. Hofman,et al.  Age-related macular degeneration and smoking. The Rotterdam Study. , 1996 .

[7]  M. Smith-Wheelock,et al.  Association of apolipoprotein E alleles with susceptibility to age-related macular degeneration in a large cohort from a single center. , 2004, Investigative ophthalmology & visual science.

[8]  Aaron Y. Lee,et al.  Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC) , 2010, Proceedings of the National Academy of Sciences.

[9]  S. Fisher,et al.  Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA , 2008, Nature Genetics.

[10]  A. Goate,et al.  Risk for Alzheimer's disease correlates with transcriptional activity of the APOE gene. , 1998, Human molecular genetics.

[11]  Prevalence of visual impairment and selected eye diseases among persons aged >/=50 years with and without diabetes--United States, 2002. , 2004, MMWR. Morbidity and mortality weekly report.

[12]  J. Haines,et al.  A pooled case-control study of the apolipoprotein E (APOE) gene in age-related maculopathy , 2002, Ophthalmic genetics.

[13]  Margaret A. Pericak-Vance,et al.  Genetic variants near TIMP3 and high-density lipoprotein–associated loci influence susceptibility to age-related macular degeneration , 2010, Proceedings of the National Academy of Sciences.

[14]  P. Duell,et al.  The prime role of HDL to transport lutein into the retina: evidence from HDL-deficient WHAM chicks having a mutant ABCA1 transporter. , 2007, Investigative ophthalmology & visual science.

[15]  S. Ennis,et al.  Association between the SERPING1 gene and age-related macular degeneration: a two-stage case–control study , 2008, The Lancet.

[16]  B. Fridley,et al.  Complement component 3 (C3) haplotypes and risk of advanced age-related macular degeneration. , 2009, Investigative ophthalmology & visual science.

[17]  G. Abecasis,et al.  Genetic susceptibility to age-related macular degeneration: a paradigm for dissecting complex disease traits. , 2007, Human molecular genetics.

[18]  R. Corbo,et al.  Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a ‘thrifty’ allele? , 1999, Annals of human genetics.

[19]  J. Attia,et al.  Association between apolipoprotein E polymorphisms and age-related macular degeneration: A HuGE review and meta-analysis. , 2006, American journal of epidemiology.

[20]  R. Hogg,et al.  Further assessment of the complement component 2 and factor B region associated with age-related macular degeneration. , 2009, Investigative ophthalmology & visual science.

[21]  J. Ott,et al.  Complement Factor H Polymorphism in Age-Related Macular Degeneration , 2005, Science.

[22]  M. Daly,et al.  Variation near complement factor I is associated with risk of advanced AMD , 2009, European Journal of Human Genetics.

[23]  I. Suñer,et al.  Nicotine increases size and severity of experimental choroidal neovascularization. , 2004, Investigative ophthalmology & visual science.

[24]  C. Patterson,et al.  Complement Component 3: an assessment of association with AMD and analysis of gene-gene and gene-environment interactions in a Northern Irish cohort , 2010, Molecular vision.

[25]  Johanna M Seddon,et al.  Variation in complement factor 3 is associated with risk of age-related macular degeneration , 2007, Nature Genetics.

[26]  D. Weeks,et al.  Candidate gene analysis suggests a role for fatty acid biosynthesis and regulation of the complement system in the etiology of age-related maculopathy. , 2005, Human molecular genetics.

[27]  Christine A. Curcio,et al.  Aging, age-related macular degeneration, and the response-to-retention of apolipoprotein B-containing lipoproteins , 2009, Progress in Retinal and Eye Research.

[28]  Liang Xu,et al.  Associated factors for age related maculopathy in the adult population in China: the Beijing eye study , 2006, British Journal of Ophthalmology.

[29]  S. Beatty,et al.  Apolipoprotein E genotype is associated with macular pigment optical density. , 2010, Investigative ophthalmology & visual science.

[30]  M. Campillos,et al.  Specific interaction of heterogeneous nuclear ribonucleoprotein A1 with the -219T allelic form modulates APOE promoter activity. , 2003, Nucleic acids research.

[31]  A. Hofman,et al.  Cholesterol and age-related macular degeneration: is there a link? , 2004, American journal of ophthalmology.

[32]  Lawrence A. Yannuzzi,et al.  Dietary Carotenoids, Vitamins A, C, and E, and Advanced Age-Related Macular Degeneration , 1994 .

[33]  W. Willett,et al.  The relation of diet, cigarette smoking, and alcohol consumption to plasma beta-carotene and alpha-tocopherol levels. , 1988, American journal of epidemiology.

[34]  R. Klein,et al.  Prevalence of age-related maculopathy. The Beaver Dam Eye Study. , 1992, Ophthalmology.

[35]  Johanna M Seddon,et al.  Risk factors for the incidence of Advanced Age-Related Macular Degeneration in the Age-Related Eye Disease Study (AREDS) AREDS report no. 19. , 2003, Ophthalmology.

[36]  I. Deary,et al.  Complement C3 variant and the risk of age-related macular degeneration. , 2007, The New England journal of medicine.

[37]  A. Edwards,et al.  Complement Factor H Polymorphism and Age-Related Macular Degeneration , 2005, Science.

[38]  N. Camp,et al.  A Variant of the HTRA1 Gene Increases Susceptibility to Age-Related Macular Degeneration , 2006, Science.

[39]  S. Fisher,et al.  Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk , 2005 .

[40]  Bernard Keavney,et al.  Association of apolipoprotein E genotypes with lipid levels and coronary risk. , 2007, JAMA.

[41]  R Hiller,et al.  Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group. , 1994, JAMA.

[42]  P. Mitchell,et al.  Mitochondrial DNA Variants of Respiratory Complex I that Uniquely Characterize Haplogroup T2 Are Associated with Increased Risk of Age-Related Macular Degeneration , 2009, PloS one.

[43]  M. Bullido,et al.  Neuronal specific regulatory elements in apolipoprotein E gene proximal promoter , 2005, Neuroreport.

[44]  T. Meitinger,et al.  Age‐related macular degeneration and functional promoter and coding variants of the apolipoprotein E gene , 2009, Human mutation.

[45]  J. Neitz,et al.  Local cellular sources of apolipoprotein E in the human retina and retinal pigmented epithelium: implications for the process of drusen formation. , 2001, American journal of ophthalmology.

[46]  J. Gilbert,et al.  Complement Factor H Variant Increases the Risk of Age-Related Macular Degeneration , 2005, Science.

[47]  J. Gilbert,et al.  Joint effects of smoking history and APOE genotypes in age-related macular degeneration. , 2005, Molecular vision.

[48]  B. Ning,et al.  An apolipoprotein E variant may protect against age‐related macular degeneration through cytokine regulation , 2006, Environmental and molecular mutagenesis.

[49]  Johannes R. Vingerling,et al.  The prevalence of age-related maculopathy in the Rotterdam Study. , 1995, Ophthalmology.

[50]  R. Wormald,et al.  Is the incidence of registrable age-related macular degeneration increasing? , 1996, The British journal of ophthalmology.

[51]  Frank Dudbridge,et al.  Likelihood-Based Association Analysis for Nuclear Families and Unrelated Subjects with Missing Genotype Data , 2008, Human Heredity.

[52]  J. Haines,et al.  Mitochondrial DNA Polymorphism A4917G Is Independently Associated with Age-Related Macular Degeneration , 2008, PloS one.

[53]  G. Tikellis,et al.  Apolipoprotein (APOE) gene is associated with progression of age‐related macular degeneration (AMD) , 2006, Human mutation.

[54]  Gonçalo R. Abecasis,et al.  A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration , 2007, Proceedings of the National Academy of Sciences.

[55]  R. T. Smith,et al.  A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[56]  J. Seddon,et al.  Do age-related macular degeneration and cardiovascular disease share common antecedents? , 1999, Ophthalmic epidemiology.

[57]  D. Granville,et al.  Apolipoprotein E, an important player in longevity and age-related diseases , 2008, Experimental Gerontology.

[58]  G. Siest,et al.  Apolipoprotein E: an important gene and protein to follow in laboratory medicine. , 1995, Clinical chemistry.

[59]  M. Boulton,et al.  The role of oxidative stress in the pathogenesis of age-related macular degeneration. , 2000, Survey of ophthalmology.

[60]  Marco A Zarbin,et al.  Current concepts in the pathogenesis of age-related macular degeneration. , 2004, Archives of ophthalmology.

[61]  D. Snodderly,et al.  Cigarette Smoking and Retinal Carotenoids: Implications for Age-related Macular Degeneration , 1996, Vision Research.

[62]  G. Abecasis,et al.  Variations in apolipoprotein E frequency with age in a pooled analysis of a large group of older people. , 2011, American journal of epidemiology.

[63]  Chi Pui Pang,et al.  HTRA1 promoter polymorphism in wet age-related macular degeneration. , 2007, Science.

[64]  J. Ott,et al.  Polymorphisms in C2, CFB and C3 are associated with progression to advanced age related macular degeneration associated with visual loss , 2008, Journal of Medical Genetics.

[65]  Lars G Fritsche,et al.  Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. , 2005, Human molecular genetics.

[66]  B. Gold,et al.  Multilocus analysis of age-related macular degeneration , 2009, European Journal of Human Genetics.

[67]  D. Weeks,et al.  Susceptibility genes for age-related maculopathy on chromosome 10q26. , 2005, American journal of human genetics.

[68]  A. Munnich,et al.  The epsilon4 allele of the apolipoprotein E gene as a potential protective factor for exudative age-related macular degeneration. , 1998, American journal of ophthalmology.

[69]  Masaru Miyagi,et al.  Drusen proteome analysis: An approach to the etiology of age-related macular degeneration , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[70]  A. Fletcher,et al.  Methods for a population-based study of the prevalence of and risk factors for age-related maculopathy and macular degeneration in elderly European populations: the EUREYE study , 2004, Ophthalmic epidemiology.

[71]  R. Klein,et al.  Further observations on the association between smoking and the long-term incidence and progression of age-related macular degeneration: the Beaver Dam Eye Study. , 2008, Archives of ophthalmology.

[72]  N. Orr,et al.  A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration , 2006, Nature Genetics.

[73]  Robyn H Guymer,et al.  The epsilon2 and epsilon4 alleles of the apolipoprotein gene are associated with age-related macular degeneration. , 2004, Investigative ophthalmology & visual science.

[74]  A. Hofman,et al.  Genetic association of apolipoprotein E with age-related macular degeneration. , 1998, American journal of human genetics.

[75]  Gary C. Brown,et al.  Analysis of six genetic risk factors highly associated with AMD in the region surrounding ARMS2 and HTRA1 on chromosome 10, region q26. , 2010, Investigative ophthalmology & visual science.

[76]  T. Peto,et al.  Does smoking influence the type of age related macular degeneration causing visual impairment? , 2006, British Journal of Ophthalmology.