title: Common coding variants in the HLA-DQB1 region confer susceptibility to age-related macular degeneration.
abstract: Age-related macular degeneration (AMD) risk variants in the complement system point to the important role of immune response and inflammation in the pathogenesis of AMD. Although the human leukocyte antigen (HLA) region has a central role in regulating immune response, previous studies of genetic variation in HLA genes and AMD have been limited by sample size or incomplete coverage of the HLA region by first-generation genotyping arrays and imputation panels. Here, we conducted a large-scale HLA fine-mapping study with 4841 AMD cases and 23 790 controls of non-Hispanic white ancestry from the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohort. Genotyping was conducted using custom Affymetrix Axiom arrays, with dense coverage of the HLA region. Classic HLA polymorphisms were imputed using SNP2HLA, which utilizes a large reference panel to provide improved imputation accuracy of variants in this region. We examined a total of 6937 SNPs and 172 classical HLA alleles, conditioning on established AMD risk variants, which revealed novel associations with two non-synonymous SNPs in perfect linkage disequilibrium, rs9274390 and rs41563814 (odds ratio (OR)=1.21; P=1.4 × 10(-11)) corresponding to amino-acid changes at position 66 and 67 in HLA-DQB1, respectively, and the DQB1*02 classical HLA allele (OR=1.22; P=3.9 × 10(-10)) with the risk of AMD. We confirmed these association signals, again conditioning on established risk variants, in the MMAP data set of subjects with advanced AMD (rs9274390/rs41563814: OR=1.28; P=1.30 × 10(-3), DQB1*02: OR=1.32; P=9.00 × 10(-4)). These findings support a role of HLA class II alleles in the risk of AMD.
authors.affiliation: Kaiser Permanente Northern California Division of Research, Oakland, CA, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Jorgenson
authors.affiliation: Department of Ophthalmology, Kaiser Permanente Northern California Redwood City Medical Center, Redwood City, CA, USA.
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Melles
authors.affiliation: Institute for Human Genetics, University of California-San Francisco, San Francisco, CA, USA.|Department of Epidemiology and Biostatistics, University of California-San Francisco, San Francisco, CA, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hoffmann
authors.affiliation: Department of Neurology, University of California-San Francisco, San Francisco, CA, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Jia
authors.affiliation: Kaiser Permanente Northern California Division of Research, Oakland, CA, USA.
authors.forename: Lori C
authors.initials: LC
authors.lastname: Sakoda
authors.affiliation: Institute for Human Genetics, University of California-San Francisco, San Francisco, CA, USA.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Kvale
authors.affiliation: Institute for Human Genetics, University of California-San Francisco, San Francisco, CA, USA.
authors.forename: Yambazi
authors.initials: Y
authors.lastname: Banda
authors.affiliation: Kaiser Permanente Northern California Division of Research, Oakland, CA, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Schaefer
authors.affiliation: Kaiser Permanente Northern California Division of Research, Oakland, CA, USA.|Institute for Human Genetics, University of California-San Francisco, San Francisco, CA, USA.|Department of Epidemiology and Biostatistics, University of California-San Francisco, San Francisco, CA, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Risch
authors.affiliation: Kaiser Permanente Northern California Division of Research, Oakland, CA, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Shen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D005260:Female; D059866:HLA-DQ beta-Chains / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology; D008297:Male; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
chemical_list: D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen