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Abstract
IntroductionThe presence of the HLA-B*27 allele is a major risk factor for the development of ankylosing spondylitis (AS), which causes chronic inflammation of the spine and other sites. We investigated residual effects outside HLA-B within the major histocompatibility complex (MHC) region in the Korean population.MethodsUsing the Korean HLA reference panel, we inferred the classic HLA alleles and amino-acid residues of the six HLA genes (HLA-A, -B, -C,-DPB1, -DQB1, and -DRB1) and MHC single-nucleotide polymorphisms in 3820 Korean subjects, including 654 Korean cases of AS and 3166 controls, who were genotyped by using Immunochip. Logistic regression and log-likelihood ratio tests were used in AS association tests for imputed markers.ResultsThe most significant associations were identified at amino-acid positions in the epitope-binding site of HLA-B (P = 1.71 × 10−481 at position 70, P = 7.20 × 10−479 at position 97, and P = 2.54 × 10−484 at positions 114), highlighting the risk effect of the HLA-B*27 allele and the protective effects of other classic alleles. A secondary effect was located at the leucine at amino-acid position 116 in the epitope-binding site of HLA-C (P = 1.69 × 10−14), completely tagging the HLA-C*15:02 allele. This residue had a large effect in HLA-B*27-negative patients (odds ratio = 6.6, 95 % confidence interval = 3.8 to 11.4).ConclusionsThe four amino-acid positions of HLA-B and -C account for most of the associations between AS and MHC in the Korean population. This finding updates the list of AS susceptibility loci and provides new insight into AS pathogenesis mediated by MHC class I molecules.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0855-3) contains supplementary material, which is available to authorized users.
Highlights
The presence of the human leukocyte antigen (HLA)-B*27 allele is a major risk factor for the development of ankylosing spondylitis (AS), which causes chronic inflammation of the spine and other sites
Imputing variants in major histocompatibility complex (MHC) To dissect the associations between various MHC variants and AS, we analyzed high-density Singlenucleotide polymorphism (SNP) data from 654 Korean cases of AS and 3166 controls
We note that the Korean HLA reference panel was reported to yield concordance rates of 93.4 % for two-digit alleles and 89.3 % for four-digit alleles of HLA-B between imputed and actual data in East Asians [9]
Summary
The presence of the HLA-B*27 allele is a major risk factor for the development of ankylosing spondylitis (AS), which causes chronic inflammation of the spine and other sites. We investigated residual effects outside HLA-B within the major histocompatibility complex (MHC) region in the Korean population. The HLA-B*27 allele is found in approximately 90 % of patients [1], possibly explaining most of the genetic associations between AS and the major histocompatibility complex (MHC) locus on human chromosome 6. We conducted a similar fine-mapping study for the AS-MHC association by using both SNP and HLA variants (classic alleles and amino-acid residues) in Korean subjects to investigate the difference of secondary effects between the Asian and European populations and to identify novel functional variants conferring risk of AS in addition to HLA-B*27 in the Asian population
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