Sequencing of the MHC region defines<i>HLA-DQA1</i>as the major genetic risk for seropositive rheumatoid arthritis in Han Chinese population

Guo, Jianping; Zhang, Tao; Cao, Hongzhi; Li, Xiaowei; Hao, Linlin; Liu, Mengru; Zou, Yundong; Zhang, Yuanwei; Wang, Yuxuan; Sun, Xiaolin; Hu, Fanlei; Du, Yan; Mo, Xiao‐Dong; Liu, Xu; Yang, Yue; Yang, Huangming; Wu, Xinyu; Zhang, Xuewu; Jia, Huijue; Jiang, Hui; Hou, Yong; Liu, Xin; Su, Yin; Zhang, Ming‐Rong; Yang, Huanming; Wang, Jian; Sun, Liangdan; Liu, Liang; Padyukov, Leonid; Lai, Luhua; Yamamoto, Kazuhiko; Zhang, Xuejun; Klareskog, Lars; Xu, Xun; Li, Zhanguo

doi:10.1136/annrheumdis-2018-214725

Cited by 32 publications

(30 citation statements)

References 54 publications

(76 reference statements)

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“…Another recent study applied deep sequencing in order to identify novel genetic risks and identified two novel factors. One of them, that is, HLA‐DQα1:160 D, conferred strong susceptibility to ACPA‐positive RA and another one, HLA‐DRβ1:37N appeared to be protective . By using computational modeling, the authors suggested a possible role of these factors in antigen recognition by respective HLA‐typed T cells and their subsequent activation.…”

Section: Hypotheses Elucidating Mechanisms Of Autoimmunity In Ramentioning

confidence: 99%

Autoantibodies and B Cells: The ABC of rheumatoid arthritis pathophysiology

Volkov

Schie

Woude

2019

Immunological Reviews

112

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Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation. In the last few decades, new insights into RA‐specific autoantibodies and B cells have greatly expanded our understanding of the disease. The best‐known autoantibodies in RA—rheumatoid factor (RF) and anti‐citrullinated protein antibodies (ACPA)—are present long before disease onset, and both responses show signs of maturation around the time of the first manifestation of arthritis. A very intriguing characteristic of ACPA is their remarkably high abundance of variable domain glycans. Since these glycans may convey an important selection advantage of citrulline‐reactive B cells, they may be the key to understanding the evolution of the autoimmune response. Recently discovered autoantibodies targeting other posttranslational modifications, such as anti‐carbamylated and anti‐acetylated protein antibodies, appear to be closely related to ACPA, which makes it possible to unite them under the term of anti‐modified protein antibodies (AMPA). Despite the many insights gained about these autoantibodies, it is unclear whether they are pathogenic or play a causal role in disease development. Autoreactive B cells from which the autoantibodies originate have also received attention as perhaps more likely disease culprits. The development of autoreactive B cells in RA largely depends on the interaction with T cells in which HLA “shared epitope” and HLA DERAA may play an important role. Recent technological advances made it possible to identify and characterize citrulline‐reactive B cells and acquire ACPA monoclonal antibodies, which are providing valuable insights and help to understand the nature of the autoimmune response underlying RA. In this review, we summarize what is currently known about the role of autoantibodies and autoreactive B cells in RA and we discuss the most prominent hypotheses aiming to explain the origins and the evolution of autoimmunity in RA.

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Section: Hypotheses Elucidating Mechanisms Of Autoimmunity In Ramentioning

confidence: 99%

Autoantibodies and B Cells: The ABC of rheumatoid arthritis pathophysiology

Volkov

Schie

Woude

2019

Immunological Reviews

112

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“…The GAsP reference panel showed higher imputation accuracy (93%-95%) compared with 1000 Genome Asian panel (<90%). 30 Four SNPs within known GWAS associations with RA were included: rs9268839 (HLA-DRB9), 31 32 rs9275376 (HLA-DQB1), [33][34][35][36] rs4947332 (tag-SNP for HLA-DRB1*04:07) and rs7752903 (TNFAIP3). 31 32 In addition, a panel of five ancestry informative markers (negative control) were selected to estimate the potential effects of population stratification: rs174583 (11q12.2), rs11745587 (5q31.1), rs521188 (1p31.3) and rs7740161 (6q23.2).…”

Section: Dna Extraction Snp Selection and Genotypingmentioning

confidence: 99%

MicroRNA variants and HLA-miRNA interactions are novel rheumatoid arthritis susceptibility factors

Guo

Jin

Zhou

et al. 2020

Preprint

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ObjectiveAlthogh Genome-wide association studies have identified >100 variants for rheumatoid arthritis (RA),the reported genetic variants only explain <40% of RA heritability. We conducted a systemic association study between common East-Asian miRNA SNPs with RA in a large Han Chinese cohort to explain missing heritability and identify miRNA epistatic interactions.Methods4 HLA SNPs (HLA-DRB1, HLA-DRB9, HLA-DQB1 and TNFAIP3) and 225 common SNPs located in miRNA which might influence the miRNA target binding or pre-miRNA stability were genotyped in 1,607 rheumatoid arthritis and 1,580 matched normal individuals. A meta-analysis with previous GWAS studies (4,873 RA cases and 17,642 controls) was performed to discovery another novel miRNA RA-associated SNPs.Results2 novel SNPs including rs1414273 (miR-548ac, OR=0.84, P=8.26×10-4) and rs2620381 (miR-627, OR=0.77, P=2.55×10-3) conferred significant association with RA. Individuals carried 8 risk alleles showed 15.38 (95%CI: 4.69-50.49, P<1.0×10-6) times more risk to be affected by RA. In addition, rs5997893 (miR-3928) showed significant epistasis effect with rs4947332 (HLA-DRB1, OR=4.23, P=0.04) and rs2967897 (miR-5695) with rs7752903 (TNFAIP3, OR=4.43, P=0.03). Finally, we demonstrated targets of the significant miRNAs showed enrichment in immune related genes (P=2.0×10-5) and FDA approved drug target genes (P=0.014).Conclusions6 novel miRNA SNPs including rs1414273 (miR-548ac, P=8.26×10-4), rs2620381 (miR-627, P=2.55×10-3), rs4285314 (miR-3135b, P=1.10×10-13), rs28477407 (miR-4308, P=3.44×10-5), rs5997893 (miR-3928, P=5.9×10-3) and rs45596840 (miR-4482, P=6.6×10-3) were confirmed to be significantly associated with RA in a Chinese population. Our study suggests that miRNAs might be interesting targets to accelerate the understanding of the pathogenesis and drug development for rheumatoid arthritis.

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“…We read with great interest the paper by Guo et al 1 addressing the HLA association with seropositive rheumatoid arthritis (RA) in Han Chinese. The authors reported that aspartic acid at position 160 of HLA-DQα1 (HLA-DQα1:160D) was the major risk factor.…”

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confidence: 99%

Questions on ‘Sequencing of the MHC region definesHLA-DQA1 as the major genetic risk for seropositive rheumatoid arthritis in Han Chinese population’ by Guoet al

Regueiro

González

2020

Ann Rheum Dis

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We read with great interest the paper by Guo et al 1 addressing the HLA association with seropositive rheumatoid arthritis (RA) in Han Chinese. The authors reported that aspartic acid at position 160 of HLA-DQα1 (HLA-DQα1:160D) was the major risk factor. It was accompanied by asparagine at position 37 of HLA-DRβ1 (HLA-DRβ1:37N), which was protective. These results were obtained by targeted sequencing in 961 cases and 1812 controls distributed in discovery and validation stages. The underlying assumption is that sequencing had uncovered new susceptibility HLA alleles. Specifically, HLA-DQα1 has not previously been associated with RA, whereas the most associated HLA alleles and amino acids were those included in the shared epitope (SE) of HLA-DRB1. 2-4 SE alleles that have been associated with increased RA risk in all the ethnic groups analysed including the Han Chinese and other Asian ethnicities. 2-5 The new results are, therefore, of an extraordinary novelty and need to be considered with attention. A careful analysis shows reasons for concern due to internal inconsistencies in the Guo et al study. 1 These inconsistencies include amino acids at DQα1:160 that do not sum up: the frequencies of the three amino acids (D, A and S) were 0.20, 0.22 and ≈0.02 in controls and 0.36, 0.37 and ≈0.01 in patients with RA, respectively (table 1). The three amino acids did not add up to 1.0 as required given that they are the only amino acids at this position. Also, the OR in cases/controls of the DQα1:160 amino acids was inconsistently described: two of the amino acids were described as increased in patients with RA, DQα1:160D with OR=2.36 and DQα1:160A with OR=2.27 (table 1). These ORs are impossible considering the low frequency of the third (DQα1:160S) amino acid. None of these inconsistencies can be attributed to a typographical error because they appear in multiple places. In addition, the DRβ1:37N amino acid was reported as associated with protection from RA with OR=0.49 and p=5.81×10-16 , but its frequency was identical in patients with RA and controls (table 1). This puzzling result is unlikely to be a typographical error because the equality between patients and controls is reported in three supplementary tables and because the omnibus test performed by Guo et al did not find DRβ1:37N among the DRB1 amino acids associated with RA (supplementary table 10 in Guo et al). On the contrary, the most associated DRB1 amino acids (page 776 and supplementary table 10 in Guo et al) were the same reported in other studies that correspond to the SE, which are the 11 and 13 amino-acid positions and the DRB1*04:05 allele. 2-5 Besides these internal inconsistencies, the frequency of the DQA1 alleles containing the DQα:160A amino acid was much lower in Guo et al than in other studies including those done in Asians (table 1). 6 These inconsistencies are worrisome and ask for clarification.

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Sequencing of the MHC region definesHLA-DQA1as the major genetic risk for seropositive rheumatoid arthritis in Han Chinese population

Cited by 32 publications

References 54 publications

Autoantibodies and B Cells: The ABC of rheumatoid arthritis pathophysiology

Autoantibodies and B Cells: The ABC of rheumatoid arthritis pathophysiology

MicroRNA variants and HLA-miRNA interactions are novel rheumatoid arthritis susceptibility factors

Questions on ‘Sequencing of the MHC region definesHLA-DQA1 as the major genetic risk for seropositive rheumatoid arthritis in Han Chinese population’ by Guoet al

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