Date: Monday, October 22, 2018
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of skin and internal organs and has a predilection for women. The strongest genetic contribution to SSc is from the Human Leukocyte Antigen (HLA) class II region. Previous studies have reported increased DRB1*11, especially DRB1*1101 and *1104, and decreased DRB1*07 and DRB1*15 in Caucasian women with SSc.(1) The third hypervariable region (HV3), corresponding to amino acid sequences from positions 67 to 74 of the DRβ1 molecule, forms the primary T-cell recognition site.(2) Peptide and T-cell interactions are influenced by charge and SSc risk evaluation according to HV3 charge could provide insight into the immunological basis of HLA associations with SSc. We therefore asked whether SSc patients differ from healthy individuals for HV3 amino-acid charge.
High resolution HLA–DRB1 genotyping was conducted for 420 adult females, 157 SSc and 263 healthy controls. Alleles were classified into 4 groups based on the 67‒74 amino acid sequence charge: −2, 0, +1, and +2 (no individual had a -1 charge). Odds Ratios (OR) were calculated for 9 of 10 possible genotypic combinations accounting for 99% of subjects. P-values were calculated by Fisher Exact test.
In 9 comparisons, the genotypic OR of SSc risk according to HV3 charge ranged from 0.42 to 2.14. Risk was statistically significant when both alleles encoded for HV3 with a charge of 0, OR [and 95% confidence interval] 2.14 [1.33-3.37], 30/157 SSc vs. 77/263 controls; p = 0.0016, p = 0.014 after correcting for 9 comparisons. Protection from SSc was significant for the combination of 0 charge encoded by one allele and +1 charge by the other allele, OR 0.57 [0.35-0.92], 49/157 in SSc vs. 46/263 in controls; p = 0.028, however this was not significant after correcting for 9 comparisons p = 0.25. The most frequent alleles with a 0 charge in our population were DRB1*07:01 (23% of cases and 25% of controls), DRB1*15:01 (18% of cases and 25% of controls), and DRB1*11:01/4 (31% of cases and 13% of controls); the latter was significantly increased in cases (p < 0.0001; OR 2.88 [1.75-4.67] as expected, consistent with previous studies. Homozygosity for these 3 alleles (5/157 SSc and 10/263 controls) did not explain the observation of SSc risk when both alleles encode 0 charge HV3. Furthermore, having a single “dose” of 0 charge did not differ in cases vs. controls (71% vs. 70%, respectively).
SSc risk is associated with inheritance of a 0 charge DRβ1 molecule for positions 67‒74 encoded by both parental haplotypes, independent of the allelic identity of the DRB1 gene. Inheritance of one allele encoding a 0 charge and the other a +1 charge was associated with protection but was not significant after correction for multiple comparisons. The amino-acid sequence of the HV3 is thought to be particularly important in the HLA-peptide-Tcell interaction. The current observation regarding HV3 charge on both haplotypes points to an aspect of that interaction that may help elucidate the role of HLA molecules in SSc pathogenesis.
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To cite this abstract in AMA style:Sensoy O, Kanaan SB, Nelson JL. Risk of Systemic Sclerosis According to Charge of the HLA-DRβ1 Third Hypervariable Region [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/risk-of-systemic-sclerosis-according-to-charge-of-the-hla-dr%ce%b21-third-hypervariable-region/. Accessed January 20, 2021.
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