Association of HLA Class I and Class II Polymorphisms with Age-Related Macular Degeneration

Goverdhan, Srini; Howell, Martin W.; Mullins, Robert F.; Osmond, Clive; Hodgkins, P R; Self, James; Avery, K.; Lotery, Andrew

doi:10.1167/iovs.04-0928

Cited by 67 publications

(59 citation statements)

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“…13 For these reasons, HLA polymorphisms have been hypothesized to modulate susceptibility to AMD. 14,15 Drusen formation and AMD progression could result from an inflammatory response to RPE injury that involves HLA and the complement systems. 11,31,32 Our finding is the first to implicate the association of an HLA class II polymorphism with AMD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Drusen, a pathologic hallmark of AMD, contain HLA class II antigens, 12 and increased HLA class II immunoreactivity has been associated with drusen formation, 13 suggesting that HLA may influence the development of AMD. Although a few small candidate gene studies found that certain HLA class I and class II polymorphisms were associated with a predisposition to AMD, 14,15 the largest genome-wide association study (GWAS) meta-analysis conducted by the AMD Gene Consortium, which included more than 77 000 subjects, did not identify any HLA polymorphisms that were independently associated with the risk of AMD. 16 The AMD Consortium meta-analysis, although well powered to detect common variants of small effect, included a number of studies that utilized genotyping arrays, with array density ranging from 165 770 to 668 238 genotyped SNPs after QC, with incomplete coverage of genetic variants in the HLA region.…”

Section: Introductionmentioning

confidence: 99%

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Common coding variants in the HLA-DQB1 region confer susceptibility to age-related macular degeneration

et al. 2016

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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. European Journal of Human Genetics (2016) 24, 1049-1055; doi:10.1038/ejhg.2015.247; published online 6 January 2016 INTRODUCTION Age-related macular degeneration (AMD) is a complex, late-onset vision disorder, which is the leading cause of blindness among the elderly in developed countries. [1][2][3][4] Immune response and inflammation play a causal role in the pathogenesis and progression of AMD. [5][6][7][8][9][10][11] The human leukocyte antigen (HLA) region on chromosome 6p21.31 encodes gene products that regulate immune response. Drusen, a pathologic hallmark of AMD, contain HLA class II antigens, 12 and increased HLA class II immunoreactivity has been associated with drusen formation, 13 suggesting that HLA may influence the development of AMD. Although a few small candidate gene studies found that certain HLA class I and class II polymorphisms were associated with a predisposition to AMD, 14,15 the largest genome-wide association study (GWAS) meta-analysis conducted by the AMD Gene Consortium, which included more than 77 000 subjects, did not identify any HLA polymorphisms that were independently associated with the risk of AMD. 16 The AMD Consortium meta-analysis, although well powered to detect common variants of small effect, included a number of studies that utilized genotyping arrays, with array density ranging from 165 770 ...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Common coding variants in the HLA-DQB1 region confer susceptibility to age-related macular degeneration

et al. 2016

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“…and B.G., unpublished data). Finally, the single published study on MHC in AMD demonstrates modest protection for the class I locus B*4001 (P = 0.027) and the class II locus DRB1*1301 (P = 0.009) 25 . Because the protective alleles identified in this study are associated with AMD at a substantially higher statistical significance, it is very unlikely that the C2/BF association is due to LD with these and/or other loci in the MHC.…”

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confidence: 89%

Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration

et al. 2006

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Age-related macular degeneration (AMD) is the most common form of irreversible blindness in developed countries 1,2 . Variants in the factor H gene (CFH, also known as HF1), which encodes a major inhibitor of the alternative complement pathway, are associated with the risk for developing AMD [3][4][5][6][7][8] . Here we test the hypothesis that variation in genes encoding other regulatory proteins of the same pathway is associated with AMD. We screened factor B (BF) and complement component 2 (C2) genes, located in the major histo-compatibility complex class III region, for genetic variation in two independent cohorts comprising ~900 individuals with AMD and ~400 matched controls. Haplotype analyses identify a statistically significant common risk haplotype (H1) and two protective haplotypes. The L9H variant of BF and the E318D variant of C2 (H10), as well as a variant in intron 10 of C2 and the R32Q variant of BF (H7), confer a significantly reduced risk of AMD (odds ratio = 0. 45 and 0.36, respectively). Combined analysis of the C2 and BF haplotypes and CFH variants shows that variation in the two loci can predict the clinical outcome in 74% of the affected individuals and 56% of the controls. These data expand and refine our understanding of the genetic risk for AMD.Correspondence should be addressed to R.A. (rla22@columbia.edu) or M.D. (dean@ncifcrf.gov). Note: Supplementary information is available on the Nature Genetics website. AUTHOR CONTRIBUTION STATEMENTThe AMD Genetics Clinical Study Group includes Stanley Chang, Lawrence A. Yannuzzi, John C. Merriam and Irene Barbazetto (Department of Ophthalmology, Columbia University, New York); Leonid E. Lerner (F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia) and Stephen Russell, Jamal Hoballah, Jill Hageman and Heather Stockman (Department of Ophthalmology and Visual Sciences, Center for Macular Degeneration, University of Iowa, Iowa City, Iowa, USA). COMPETING INTERESTS STATEMENTThe authors declare competing financial interests (see the Nature Genetics website for details).Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/ NIH Public Access Inflammation has a central role in the pathobiology of AMD 9-14 . Dysfunction of the complement pathway is proposed to induce significant damage to macular cells, leading to atrophy, degeneration and the elaboration of choroidal neovascular membranes 3,[15][16][17] . Activation of the alternative pathway is initiated by cleavage of C3b-bound factor B (BF), resulting in the formation of the C3Bb complex (C3 convertase). This complex is stabilized by properdin, whereas its dissociation is accelerated by regulatory proteins, including complement factor H (CFH), the major inhibitor of the alternative complement pathway. As CFH haplotypes are associated with AMD 3 , we hypothesized that the same may be true for activators of the same pathway, such as complement factor B (BF). BF and compl...

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“…These works present differences with ours. Thus, Goverdham studies the existing relation between ARMD and the HLA, including 100 patients with ARMD and 92 controls (12). In that work they established 4 groups of patients according to age-related eye disease study (AREDS study) of which only a part of the fourth group (N = 62) includes patients with choroidal neovascularization (less than us and not describe what kind of wet ARMD-treatable, non treatable) (23).…”

Section: Discussionmentioning

confidence: 99%

“…It is also known that the immune system is involved in the development of ARMD (8)(9)(10). On the other hand, it is also known that certain genetic basis exists in this pathology (11,12).…”

Section: Introductionmentioning

confidence: 99%

HLA B27 as Predisposition Factor to Suffer Age Related Macular Degeneration

et al. 2009

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To research whether specific alleles HLA class I (HLA-A and HLA-B) and class II (HLA-DR) are risk factors for the development of exudative type of Age Related Macular Degeneration (ARMD), HLA antigens are expressed both in normal and affected eyes with ARMD. We designed a prospective case-controlled study. We recruited 75 patients with choroidal neovascularization predominantly classic or occult, secondary to ARMD, and treated with photodynamic therapy. Two hundred and fifty patients over 55 years old, without ophthalmologic pathology who went to hospital for an analytical routine check were used as control. The analysis of the data shows a significant difference between two groups. Allele HLA-B27 correlated positively with ARMD (p < 0.0113). However, we didn't find alleles negatively associated. Thus HLA-B27 is an allele predisposed to suffer ARMD. Cellular & Molecular Immunology. 2009;6(4):303-307.

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Association of HLA Class I and Class II Polymorphisms with Age-Related Macular Degeneration

Abstract: Significant positive and negative associations exist between HLA alleles and AMD. HLA polymorphisms influence the development of AMD, possibly via modulating choroidal immune function.

Cited by 67 publications

References 51 publications

Common coding variants in the HLA-DQB1 region confer susceptibility to age-related macular degeneration

Common coding variants in the HLA-DQB1 region confer susceptibility to age-related macular degeneration

Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration

HLA B27 as Predisposition Factor to Suffer Age Related Macular Degeneration

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