Abstract
Genetic variations of human leukocyte antigen (HLA) genes within the major histocompatibility complex (MHC) locus are strongly associated with disease susceptibility and prognosis for many diseases, including many autoimmune diseases. In this study, we developed a Korean HLA reference panel for imputing classical alleles and amino acid residues of several HLA genes. An HLA reference panel has potential for use in identifying and fine-mapping disease associations with the MHC locus in East Asian populations, including Koreans. A total of 413 unrelated Korean subjects were analyzed for single nucleotide polymorphisms (SNPs) at the MHC locus and six HLA genes, including HLA-A, -B, -C, -DRB1, -DPB1, and -DQB1. The HLA reference panel was constructed by phasing the 5,858 MHC SNPs, 233 classical HLA alleles, and 1,387 amino acid residue markers from 1,025 amino acid positions as binary variables. The imputation accuracy of the HLA reference panel was assessed by measuring concordance rates between imputed and genotyped alleles of the HLA genes from a subset of the study subjects and East Asian HapMap individuals. Average concordance rates were 95.6% and 91.1% at 2-digit and 4-digit allele resolutions, respectively. The imputation accuracy was minimally affected by SNP density of a test dataset for imputation. In conclusion, the Korean HLA reference panel we developed was highly suitable for imputing HLA alleles and amino acids from MHC SNPs in East Asians, including Koreans.
Highlights
There is a well-characterized high degree of genetic variability in human leukocyte antigen (HLA) genes located at the major histocompatibility complex (MHC) locus on chromosome 6 [1]
Diverse genetic variations and heterozygosity of HLA molecules allow the immune system to defend against a wide range of foreign molecules and pathogens [2], various classical alleles of HLA genes have been found to be associated with susceptibility to or prognosis of multiple inflammatory disorders and other complex traits [3,4]
The 4-digit alleles of the 6 HLA genes (HLA-A, -B, -C, -DRB1, -DPB1 and -DQB1) typed using NGS methods were assigned to 233 HLA alleles, which results in 1,025 polymorphic amino acid positions in the study subjects (Table 1)
Summary
There is a well-characterized high degree of genetic variability in human leukocyte antigen (HLA) genes located at the major histocompatibility complex (MHC) locus on chromosome 6 [1]. SNP2HLA uses a specialized HLA reference panel that encodes SNPs within the MHC region along with HLA classical alleles and amino acid residues [5]. This method has not been used in HLA association studies in non-European populations because the HLA reference panel was generated from European genetic information. To overcome this limitation, the first Asian HLA reference panel was very recently constructed mostly from Southeast Asian subjects [11,12]. We developed an HLA reference panel for East Asians, including Koreans, for use with SNP2HLA
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