Imputing Variants in HLA-DR Beta Genes Reveals That HLA-DRB1 Is Solely Associated with Rheumatoid Arthritis and Systemic Lupus Erythematosus

The genetic association of HLA-DRB1 with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) is well documented, but association with other HLA-DR beta genes (HLA-DRB3, HLA-DRB4 and HLA-DRB5) has not been thoroughly studied, despite their similar functions and chromosomal positions. We examined variants in all functional HLA-DR beta genes in RA and SLE patients and controls, down to the amino-acid level, to better understand disease association with the HLA-DR locus. To this end, we improved an existing HLA reference panel to impute variants in all protein-coding HLA-DR beta genes. Using the reference panel, HLA variants were inferred from high-density SNP data of 9,271 RA-control subjects and 5,342 SLE-control subjects. Disease association tests were performed by logistic regression and log-likelihood ratio tests. After imputation using the newly constructed HLA reference panel and statistical analysis, we observed that HLA-DRB1 variants better accounted for the association between MHC and susceptibility to RA and SLE than did the other three HLA-DRB variants. Moreover, there were no secondary effects in HLA-DRB3, HLA-DRB4, or HLA-DRB5 in RA or SLE. Of all the HLA-DR beta chain paralogs, those encoded by HLA-DRB1 solely or dominantly influence susceptibility to RA and SLE.

[1]  P. Gregersen,et al.  High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci. , 2015, Annals of the rheumatic diseases.

[2]  Y. Okada,et al.  The HLA-DRβ1 amino acid positions 11–13–26 explain the majority of SLE–MHC associations , 2014, Nature Communications.

[3]  S. Bang,et al.  Construction and Application of a Korean Reference Panel for Imputing Classical Alleles and Amino Acids of Human Leukocyte Antigen Genes , 2014, PloS one.

[4]  Y. Okada,et al.  Risk for ACPA-positive rheumatoid arthritis is driven by shared HLA amino acid polymorphisms in Asian and European populations. , 2014, Human molecular genetics.

[5]  Buhm Han,et al.  Imputing Amino Acid Polymorphisms in Human Leukocyte Antigens , 2013, PloS one.

[6]  Robert M. Plenge,et al.  Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis , 2011, Nature Genetics.

[7]  B. Browning,et al.  A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. , 2009, American journal of human genetics.

[8]  James Robinson,et al.  The IMGT/HLA database , 2008, Nucleic Acids Res..

[9]  Deric M. Park,et al.  HLA-DRB5*0101 and -DRB1*1501 expression in the multiple sclerosis-associated HLA-DR15 haplotype , 2005, Journal of Neuroimmunology.

[10]  E. Reinherz,et al.  Sequence variability analysis of human class I and class II MHC molecules: functional and structural correlates of amino acid polymorphisms. , 2003, Journal of molecular biology.

[11]  K. Tokunaga,et al.  Recent divergence of the HLA-DRB1*04 allelic lineage from the DRB1*0701 lineage after the separation of the human and chimpanzee species , 2003, Immunogenetics.

[12]  U. Reuter,et al.  Differential surface expression of HLA-DRB1 and HLA-DRB4 among peripheral blood cells of DR4 positive individuals. , 1999, Human immunology.

[13]  G. Andersson,et al.  Evolution of the human HLA-DR region. , 1998, Frontiers in bioscience : a journal and virtual library.

[14]  J. Klein,et al.  HLA-DRB intron 1 sequences: implications for the evolution of HLA-DRB genes and haplotypes. , 1996, Human immunology.

[15]  D. Larhammar,et al.  Simplifying genetic locus assignment of HLA-DRB genes. , 1994, Immunology today.

[16]  H. Charbonneau,et al.  mRNA abundance, rather than differences in subunit assembly, determine differential expression of HLA-DR beta 1 and -DR beta 3 molecules. , 1989, The Journal of biological chemistry.