Characterization of the HLA-DRβ1 third hypervariable region amino acid sequence according to charge and parental inheritance in systemic sclerosis

Abstract

BackgroundSpecific HLA class II alleles are associated with systemic sclerosis (SSc) risk, clinical characteristics, and autoantibodies. HLA nomenclature initially developed with antibodies as typing reagents defining DRB1 allele groups. However, alleles from different DRB1 allele groups encode the same third hypervariable region (3rd HVR) sequence, the primary T-cell recognition site, and 3rd HVR charge differences can affect interactions with T cells. We considered 3rd HVR sequences (amino acids 67–74) irrespective of the allele group and analyzed parental inheritance considered according to the 3rd HVR charge, comparing SSc patients with controls.MethodsIn total, 306 families (121 SSc and 185 controls) were HLA genotyped and parental HLA-haplotype origin was determined. Analysis was conducted according to DRβ1 3rd HVR sequence, charge, and parental inheritance.ResultsThe distribution of 3rd HVR sequences differed in SSc patients versus controls (p = 0.007), primarily due to an increase of specific DRB1*11 alleles, in accord with previous observations. The 3rd HVR sequences were next analyzed according to charge and parental inheritance. Paternal transmission of DRB1 alleles encoding a +2 charge 3rd HVR was significantly reduced in SSc patients compared with maternal transmission (p = 0.0003, corrected for analysis of four charge categories p = 0.001). To a lesser extent, paternal transmission was increased when charge was 0 (p = 0.021, corrected for multiple comparisons p = 0.084). In contrast, paternal versus maternal inheritance was similar in controls.ConclusionsSSc patients differed from controls when DRB1 alleles were categorized according to 3rd HVR sequences. Skewed parental inheritance was observed in SSc patients but not in controls when the DRβ1 3rd HVR was considered according to charge. These observations suggest that epigenetic modulation of HLA merits investigation in SSc.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1253-9) contains supplementary material, which is available to authorized users.

Association Between HLA-DRB1 Alleles and Gravesʼ Disease in Asian Populations: A Meta-Analysis

“…It corresponds with our findings that DRB1*0101 is a protective allele for GD and that DRB1*1502 has a tendency to decrease the risk of GD. Although how charges and polarities promote or impede the binding of thyroid antigens to pocket conformations have not been fully elucidated, it has been found in studies of type 1 diabetes, Sjögren's syndrome, systemic sclerosis and Hashimoto's thyroiditis(HT) that the polarity and charge of amino acids on the DRb chain could promote or avoid disease progression [4,32,40,41]. A study of the relationship between HLA-DR pockets and HT found that DRb1-Arg74, in contrast to protective DRb1-Glu74, creates a narrower pocket that makes the thyroid peptide more susceptible to binding to the T-cell receptor, which leads to autoimmune thyroiditis [39].…”

Updates on genetics in systemic sclerosis

“…One of the most extensive studies enrolling 1300 SSc patients and 1000 controls with Caucasian, African, and Hispanic American backgrounds found that the associated HLA class II alleles were different among ethnic groups, and all associations were not robust [ 94 ]. The associations between susceptibility of SSc and the third hypervariable region (HVR) sequences of the DRB1 gene were also investigated but were again borderline [ 95 ]. On the other hand, the HLA region (6p21.3), especially the HLA-DPB1 and DPB2 , was consistently identified as the gene region most strongly associated with SSc by GWAS, and this association was most prominent in SSc patients with anti-topo I antibody [ 45 ], but it remains controversial if the primarily associated genes were located within HLA or non-HLA genes.…”

HLA Association among Thai Patients with Diffuse and Limited Cutaneous Systemic Sclerosis

“…Several studies have determined the contribution of HLA Class II molecules to the development of SSc. The charge of amino acid motifs at the 67–74 position on the third hypervariable region of HLA-DRB1 affected their association with SSc [ 17 ]. The uncharged polar residue tyrosine at 30, and amino acid sequence of 71 TRAELDT 77 on the first domain of the HLA-DQ β chain have been reported in SSc patients, being anti-topoisomerase antibody (ATA) positive [ 18 ].…”