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01.12.2017 | Research article | Ausgabe 1/2017 Open Access

Arthritis Research & Therapy 1/2017

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

Zeitschrift:
Arthritis Research & Therapy > Ausgabe 1/2017
Autoren:
Coline A. Gentil, Hilary S. Gammill, Christine T. Luu, Maureen D. Mayes, Dan E. Furst, J. Lee Nelson
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s13075-017-1253-9) contains supplementary material, which is available to authorized users.

Abstract

Background

Specific 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.

Methods

In 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.

Results

The 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.

Conclusions

SSc 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.
Zusatzmaterial
Additional file 1: Table S1. DRB1-DQA1-DQB1 common haplotypes in SSc patients and controls. (DOCX 44 kb)
13075_2017_1253_MOESM1_ESM.docx
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