Uncovering specific genetic-respiratory disease endotypes for rheumatoid arthritis risk.

IF 20.3 1区医学 Q1 RHEUMATOLOGY Annals of the Rheumatic Diseases Pub Date : 2024-11-01 DOI:10.1136/ard-2024-226391

Vanessa L Kronzer, Katrina A Williamson, Keigo Hayashi, Elizabeth J Atkinson, Cynthia S Crowson, Xiaosong Wang, Jing Cui, James R Cerhan, Jennifer A Sletten, Gregory C McDermott, Elena K Joerns, Robert Vassallo, John M Davis, Jeffrey A Sparks

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Abstract

Objective: We aimed to identify specific genetic-respiratory disease endotypes for rheumatoid arthritis (RA) risk.

Methods: This case-control study used the Mass General Brigham (MGB) and Mayo Clinic (MC) Biobanks for discovery and replication, respectively. We matched criteria-confirmed incident RA cases to four non-RA controls on age, sex and health record history. Genetic exposures included the top 11 RA risk alleles, and a validated human leucocyte antigen (HLA) genetic risk score (GRS). We identified seven respiratory diseases by codes. Using logistic regression models adjusting for potential confounders, we estimated Rs with 95% CIs for the interactions between genetic and respiratory exposures for RA risk.

Results: We identified 653 RA cases and 2607 controls in MGB, and 428 incident RA cases and 1712 non-RA controls in MC (mean age 64, 69% female). Respiratory diseases were associated with an increased risk of RA (OR 1.34, 95% CI 1.05, 1.71). Six out of 11 non-HLA RA risk alleles interacted strongly with specific respiratory diseases for RA risk, including NFKBIE and sinusitis (OR 5.49, 95% CI 1.56, 19.4 MGB; 5.26, 95% CI 2.00, 13.86 MC) and FAM167A and acute sinusitis for seronegative RA (OR 6.00, 95% CI 2.09, 17.24 MGB; 4.90, 95% CI 1.71, 14.1 MC). The RA HLA GRS interacted synergistically with interstitial lung disease for RA risk (OR 5.41, 95% CI 2.71, 10.8 in MC), with DPB1*02:01, DRB1*16:01 and DRB1*04:04 best predicting RA (positive predictive value 61%).

Conclusion: Several genetic-respiratory disease interactions strongly drive RA onset. If confirmed, these novel associations may reflect RA endotypes that can facilitate individualised prevention, diagnosis and treatment.

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揭示类风湿性关节炎风险的特定遗传-呼吸系统疾病内型。

目的：我们旨在确定类风湿性关节炎（RA）风险的特定遗传-呼吸系统疾病内型：我们旨在确定类风湿性关节炎（RA）风险的特定遗传-呼吸系统疾病内型：这项病例对照研究分别利用麻省总布里格姆医院（MGB）和梅奥诊所（MC）的生物库进行发现和复制。我们根据年龄、性别和健康记录史将标准确诊的RA病例与4名非RA对照者进行了配对。遗传风险包括前 11 个 RA 风险等位基因和经过验证的人类白细胞抗原（HLA）遗传风险评分（GRS）。我们通过代码确定了七种呼吸系统疾病。利用调整潜在混杂因素的逻辑回归模型，我们估算了遗传和呼吸系统暴露对 RA 风险的交互作用的 Rs 值及 95% CIs：我们在 MGB 中发现了 653 例 RA 病例和 2607 例对照，在 MC 中发现了 428 例 RA 病例和 1712 例非 RA 对照（平均年龄 64 岁，69% 为女性）。呼吸系统疾病与 RA 风险增加有关（OR 1.34，95% CI 1.05，1.71）。在 11 个非 HLA RA 风险等位基因中，有 6 个与特定呼吸系统疾病的 RA 风险有强烈的相互作用，包括 NFKBIE 与鼻窦炎（OR 5.49，95% CI 1.56，19.4 MGB；5.26，95% CI 2.00，13.86 MC），以及血清阴性 RA 的 FAM167A 与急性鼻窦炎（OR 6.00，95% CI 2.09，17.24 MGB；4.90，95% CI 1.71，14.1 MC）。RA HLA GRS与间质性肺病对RA风险有协同作用（OR 5.41，95% CI 2.71，10.8，MC），其中DPB1*02:01、DRB1*16:01和DRB1*04:04对RA的预测效果最好（阳性预测值为61%）：结论：几种遗传与呼吸系统疾病的相互作用强烈地推动了 RA 的发病。如果得到证实，这些新的关联可能反映出 RA 的内型，有助于个体化预防、诊断和治疗。

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来源期刊

Annals of the Rheumatic Diseases 医学-风湿病学

CiteScore

35.00

自引率

9.90%

发文量

3728

审稿时长

1.4 months

期刊介绍： Annals of the Rheumatic Diseases (ARD) is an international peer-reviewed journal covering all aspects of rheumatology, which includes the full spectrum of musculoskeletal conditions, arthritic disease, and connective tissue disorders. ARD publishes basic, clinical, and translational scientific research, including the most important recommendations for the management of various conditions.