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Paul N Baird, Andrea J Richardson, Robyn H Guymer; Identification of independent associations involving HLA Class II loci and Age-Related Macular Degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2014;55(13):2218. doi: https://doi.org/.
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Multiple studies have implicated immune related genes as associated with age related macular degeneration (AMD) including Complement Factor H (CFH), Complement Component 2 (C2), Complement Component 3 (C3), and Complement Factor B (CBF). Immune background of an individual may also therefore play an important role in the aetiology of AMD. We wished to assess loci from the Class II region of the major histocompatibility complex (MHC) and investigate possible associations with AMD.
DNAs from a total of 495 individuals from Melbourne consisting of 250 advanced stage AMD cases and 245 controls (no observable clinical signs of AMD) were PCR amplified and underwent sequence based typing for the HLA-DRB1 and HLA-DQB1 loci. Data were analysed using Assign™ SBT sequence analysis software. Genotyping of amplified DNAs was also undertaken for the SNP rs641153 (R32Q) in the CFB gene using the MassArray platform.
A total of 16 HLA-DRB1 alleles were tested in this cohort. Of these, HLA-DRB1*02/*05 and *06 alleles were not present and HLA-DRB1*11 was not in Hardy Weinberg equilibrium. Following Bonferroni correction, only the HLA-DRB1*15 allele remained significant (OR 0.6, 95%CI 0.42, 0.85), p=4x10-3. In terms of the HLA-DQB1 locus, a total of 6 alleles were tested with HLA-DQB*1 not being present. Following Bonferroni correction, only the HLA-DQB1*6 allele remained significant (OR 0.56, 95%CI 0.41, 0.75), p=6x10-4. As SNPs in the C2/CFB genes in this region are known to be strongly associated with AMD, conditional analysis was undertaken on rs641153 in the CFB gene to establish whether the HLA loci represented independent associations. Following conditional analysis and adjustment for the covariates of age and sex, both the HLA-DRB1*15 allele (p=2x10-2) and the HLA-DQB1*6 allele (p=9.8x10-4) remained significantly associated with AMD.
This work provides evidence that independent associations exist in the MHC region aside from those of the C2/CFB genes. Further dissection of this region is required to better establish haplotypes, how far these haplotypes extend and what implications this has on disease.
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