OP0053 HLA DRB1 Amino Acid Position 11 is Strongly Associated with Seropositive Rheumatoid Arthritis in Black South Africans

Objective.To investigate the association of specific amino acid positions, residues, and haplotypes of HLA-DRB1 in black South Africans with autoantibody-positive rheumatoid arthritis (RA).Methods.High-resolutionHLA-DRB1genotyping was performed in 266 black South Africans with autoantibody-positive RA and 362 ethnically and geographically matched controls. The alleles were converted to specific amino acid residues at polymorphic sites for downstream analyses. Logistic regression models were used to test whether variability at site, specific amino acid residues, and haplotypes (constructed from positions 11, 71, and 74) were associated with RA.Results.Of the 29 amino acid positions examined, positions 11, 13, and 33 (permutation p = 3.4e-26, 1.2e-27, and 2.1e-28, respectively) showed the strongest association with RA. Univariate analyses of individual amino acid residues showed valine at position 11 (OR 5.1, 95% CI 3.7–7.0) and histidine at position 13 (OR 6.1, 95% CI 4.2–8.6) conferred the highest risk. The valine containing haplotypes of position 11, 71, 74, V_K_A conferred the most risk (OR 4.52, 95% CI 2.68–7.61) and conversely the haplotype with serine at this position, S_K_R, conferred the most protection (OR 0.83, 95% CI 0.61–1.15).Conclusion.Autoantibody-positive RA in black South Africans is associated with histidine at position 13 and valine at position 11 of HLA-DRB1, and haplotypes with valine at position 11 conferred the highest risk; conversely, serine at position 11 conveyed protection.

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Brief Report: Main Contribution of DRB1*04:05 Among the Shared Epitope Alleles and Involvement of DRB1 Amino Acid Position 57 in Association With Joint Destruction in Anti-Citrullinated Protein Antibody-Positive Rheumatoid Arthritis

Arthritis & Rheumatology ◽

10.1002/art.39105 ◽

2015 ◽

Vol 67 (7) ◽

pp. 1744-1750 ◽

Cited By ~ 15

Author(s):

Chikashi Terao ◽

Koichiro Yano ◽

Katsunori Ikari ◽

Moritoshi Furu ◽

Noriyuki Yamakawa ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Amino Acid ◽

Shared Epitope ◽

Joint Destruction ◽

Amino Acid Position ◽

Citrullinated Protein

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HLA-DRB1 Analysis Identified a Genetically Unique Subset within Rheumatoid Arthritis and Distinct Genetic Background of Rheumatoid Factor Levels from Anticyclic Citrullinated Peptide Antibodies

The Journal of Rheumatology ◽

10.3899/jrheum.170363 ◽

2018 ◽

Vol 45 (4) ◽

pp. 470-480 ◽

Cited By ~ 3

Author(s):

Ryosuke Hiwa ◽

Katsunori Ikari ◽

Koichiro Ohmura ◽

Shuichiro Nakabo ◽

Keitaro Matsuo ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Amino Acid ◽

Rheumatoid Factor ◽

Genetic Background ◽

Linear Regression Analysis ◽

Amino Acid Position ◽

Genetic Associations ◽

Genetic Characteristics ◽

Important Amino Acid ◽

Group 2

Objective.HLA-DRB1 is the most important locus associated with rheumatoid arthritis (RA) and anticitrullinated protein antibodies (ACPA). However, fluctuations of rheumatoid factor (RF) over the disease course have made it difficult to define fine subgroups according to consistent RF positivity for the analyses of genetic background and the levels of RF.Methods.A total of 2873 patients with RA and 2008 healthy controls were recruited. We genotyped HLA-DRB1 alleles for the participants and collected consecutive data of RF in the case subjects. In addition to RF+ and RF− subsets, we classified the RF+ subjects into group 1 (constant RF+) and group 2 (seroconversion). We compared HLA-DRB1 alleles between the RA subsets and controls and performed linear regression analysis to identify HLA-DRB1 alleles associated with maximal RF levels. Omnibus tests were conducted to assess important amino acid positions.Results.RF positivity was 88%, and 1372 and 970 RF+ subjects were classified into groups 1 and 2, respectively. RF+ and RF− showed similar genetic associations to ACPA+ and ACPA− RA, respectively. We found that shared epitope (SE) was more enriched in group 2 than 1, p = 2.0 × 10−5, and that amino acid position 11 showed a significant association between 1 and 2, p = 2.7 × 10−5. These associations were independent of ACPA positivity. SE showed a tendency to be negatively correlated with RF titer (p = 0.012). HLA-DRB1*09:01, which reduces ACPA titer, was not associated with RF levels (p = 0.70).Conclusion.The seroconversion group was shown to have distinct genetic characteristics. The genetic architecture of RF levels is different from that of ACPA.

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