Instituto de Investigacion Sanitaria and Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain.
Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Granada, Spain.
Arthritis Rheumatol. 2021 Jun;73(6):963-969. doi: 10.1002/art.41630. Epub 2021 Apr 23.
Previously, only the HLA-DRB1 alleles have been assessed in rheumatoid arthritis (RA). The aim of the present study was to identify the key major histocompatibility complex (MHC) susceptibility factors showing a significant association with anti-carbamylated protein antibody-positive (anti-CarP+) RA.
Analyses were restricted to RA patients who were anti-cyclic citrullinated peptide antibody negative (anti-CCP-), because the anti-CCP status dominated the results otherwise. Therefore, we studied samples from 1,821 anti-CCP- RA patients and 6,821 population controls from Spain, Sweden, and the Netherlands. The genotypes for ~8,000 MHC biallelic variants were assessed by dense genotyping and imputation. Their association with the anti-CarP status in RA patients was tested with logistic regression and combined with inverse-variance meta-analysis. Significance of the associations was assessed according to a study-specific threshold of P < 2.0 × 10 .
The HLA-B08 allele and its correlated amino acid variant Asp-9 showed a significant association with anti-CarP+/anti-CCP- RA (P < 3.78 × 10 ; I = 0). This association was specific when assessed relative to 3 comparator groups: population controls, anti-CarP-/anti-CCP- RA patients, and anti-CCP- RA patients who were positive for other anti-citrullinated protein antibodies. Based on these findings, anti-CarP+/anti-CCP- RA patients could be separated from other antibody-defined subsets of RA patients in whom an association with the HLA-B08 allele has been previously demonstrated. No other MHC variant remained associated with anti-CarP+/anti-CCP- RA after accounting for the presence of the HLA-B08 allele. Specifically, the reported association of HLA-DRB103 was observed at a level comparable to that reported previously, but it was attributable to linkage disequilibrium.
These results identify HLA-B*08 carrying Asp-9 as the MHC locus showing the strongest association with anti-CarP+/anti-CCP- RA. This knowledge may help clarify the role of the HLA in susceptibility to specific subsets of RA, by shaping the spectrum of RA autoantibodies.
先前，仅对类风湿关节炎（RA）中的 HLA-DRB1 等位基因进行了评估。本研究的目的是确定与抗瓜氨酸化蛋白抗体阳性（抗-CarP+）RA 显著相关的关键主要组织相容性复合体（MHC）易感因素。
分析仅限于抗环瓜氨酸肽抗体阴性（抗-CCP-）的 RA 患者，因为抗-CCP 状态否则会主导结果。因此，我们研究了来自西班牙、瑞典和荷兰的 1821 名抗-CCP-RA 患者和 6821 名人群对照者的样本。通过密集基因分型和内插评估了约 8000 个 MHC 双等位基因变异体的基因型。使用逻辑回归测试它们与 RA 患者抗-CarP 状态的关联，并结合逆方差荟萃分析。根据特定研究的 P < 2.0×10-8 阈值评估关联的显著性。
HLA-B08 等位基因及其相关的天冬氨酸-9 变异体与抗-CarP+/抗-CCP-RA 显著相关（P < 3.78×10-8；I = 0）。当相对于 3 个比较组进行评估时，这种关联是特异性的：人群对照者、抗-CarP-/抗-CCP-RA 患者和抗-CCP-RA 患者，他们对其他瓜氨酸化蛋白抗体呈阳性。基于这些发现，可以将抗-CarP+/抗-CCP-RA 患者与其他先前已证明与 HLA-B08 等位基因相关的抗体定义的 RA 患者亚组区分开来。在考虑 HLA-B08 等位基因存在的情况下，没有其他 MHC 变体与抗-CarP+/抗-CCP-RA 相关。具体来说，先前报道的 HLA-DRB103 与 HLA-B*08 相关联的报道水平与先前报道的水平相当，但归因于连锁不平衡。
这些结果确定 HLA-B*08 携带天冬氨酸-9 为与抗-CarP+/抗-CCP-RA 最强相关的 MHC 基因座。通过塑造 RA 自身抗体的谱，这些知识可能有助于阐明 HLA 在易感性特定 RA 亚群中的作用。
