Gareth J. MckayChris C. PattersonUsha ChakravarthyShilpa DasariCaroline C. KlaverJohannes R. VingerlingLintje HoPaulus T.V.M. de JongAstrid E. FletcherIan S. YoungJohan H. SelandMati RahuGisele SoubraneLaura TomazzoliFotis TopouzisJesus VioqueAroon D. HingoraniReecha SofatMichael DeanJulie SawitzkeJohanna M. SeddonInga PeterAndrew R. WebsterAnthony T. MooreJohn R.W. YatesValentina CiprianiLars G. FritscheBernhard H.F. WeberClaudia N. KeilhauerAndrew J. LoterySarah EnnisMichael L. KleinPeter J. FrancisDwight StambolianAnton OrlinMichael B. GorinDaniel E. WeeksChia Ling KuoAnand SwaroopMohammad OthmanAtsuhiro KandaWei ChenGoncalo R. AbecasisAlan F. WrightCaroline HaywardPaul N. BairdRobyn H. GuymerJohn AttiaAmmarin ThakkinstianGiuliana SilvestriQueen's University BelfastErasmus University Medical CenterNetherlands Institute for Neuroscience NIN - KNAWAcademic Medical Centre, University of AmsterdamLondon School of Hygiene & Tropical MedicineStavanger University HospitalTervise Arengu InstituutUniversitaire de CreteilClinica OculisticaAristotle University of ThessalonikiUniversidad Miguel Hernandez de ElcheCIBERESPUCLNational Cancer Institute at FrederickTufts University School of MedicineTufts Medical CenterIcahn School of Medicine at Mount SinaiUCL Institute of OphthalmologyMoorfields Eye Hospital NHS Foundation TrustUniversity of CambridgeUniversitat RegensburgUniversitatsklinikum WurzburgUniversity of SouthamptonSouthampton General HospitalOHSU School of MedicineUniversity of PennsylvaniaDavid Geffen School of Medicine at UCLAUniversity of Pittsburgh Graduate School of Public HealthThe University of the Michigan Kellogg Eye CenterNational Eye InstituteUniversity of Michigan School of Public HealthWestern General HospitalUniversity of MelbourneUniversity of Newcastle, AustraliaJohn Hunter HospitalMahidol University2018-05-032018-05-032011-12-01Human Mutation. Vol.32, No.12 (2011), 1407-141610981004105977942-s2.0-81255168210https://repository.li.mahidol.ac.th/handle/20.500.14594/11425Age-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. © 2011 Wiley Periodicals, Inc.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyMedicineArticleSCOPUS10.1002/humu.21577