Session Title: Genetics and Genomics of Rheumatic Disease II
Session Type: Abstract Submissions (ACR)
HLA class II genes are associated with a wide spectrum of autoimmune diseases. Specific alleles at the DRB1, DQA1 and DQB1 loci are associated with systemic sclerosis (SSc) risk and/or clinical characteristics such as autoantibody profile. HLA nomenclature, particularly for the HLA-DRB1 locus, evolved utilizing serological typing reagents resulting in “a language of HLA” with initial grouping based primarily on antibody recognition of the HLA molecule. However, the third hypervariable region (3rd HVR) is the important site for T cell recognition, and the T cell perspective may be more important for autoimmune diseases including SSc. We therefore conducted an analysis based on the different amino acid sequences of the 3rd HVR (aa 67-74) irrespective of the HLA allele group. We sought to test the hypotheses that 1) overall charge of the amino acids in the 3rd HVR (positive, neutral or negative) differs for SSc patients compared to controls and 2) 3rd HVR charge differs for maternally-inherited vs. paternally-inherited HLA-DRB1 alleles.
We studied 254 control women and 133 women with SSc. HLA genotyping for DRB1 was performed by a PCR sequence-specific oligonucleotide probe method. Family studies were conducted to determine which HLA haplotype was maternally- or paternally-inherited. The data were then categorized according to which of 24 different 3rd HVR sequences was encoded by each allele. Next the 3rd HVR sequences were grouped according to whether they resulted overall in a positive, neutral or negative charge. Analyses were done by chi square.
The overall distribution of the 3rd HVR sequences was significantly different in the SSc compared to the control population (p=0.0005), a difference primarily driven by enrichment of the FLED sequence present in the DRB1*1104 allele among the SSc population (p=0.001). No difference was observed for the overall 3rd HVR charge comparing the two populations. However, interestingly, among SSc patients, 3rd HVR charge differed by maternal vs. paternal haplotype (p=0.0001), a difference not seen among controls.
We observed a significant difference in the distribution of HLA-DRB1 alleles when classified according to the 3rd HVR, and especially an enrichment of the FLED sequence among SSc patients compared to controls. This result indicates a possible role for 3rd HVR amino acid sequences in SSc. Polymorphism of amino acid sequences in the 3rd HVR can result in overall differences in charge. Our surprising observation of a significantly skewed distribution of 3rd HVR charge in maternal vs. paternal HLA haplotype in SSc patients but not in controls suggests a potential epigenetic effect that could contribute to SSc pathogenesis.
Acknowledgement: We are very grateful for support of this work from the Scleroderma Foundation.
C. A. Gentil,
H. S. Gammill,
C. T. Luu,
J. L. Nelson,
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