Y 染色体的镶嵌缺失是晚发类风湿性关节炎的特征,与基于发病年龄的多基因风险评分的关联形成鲜明对比。

Shunsuke Uchiyama, Yuki Ishikawa, Katsunori Ikari, Suguru Honda, Keiko Hikino, Eiichi Tanaka, Yoichiro Kamatani, Takahisa Gono, Giulio Genovese, Masataka Kuwana, Chikashi Terao
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In each dataset, we evaluated the effect sizes of mosaic loss of Y (mLOY) and polygenic risk score (PRS) of RA in males and subsequently performed a meta-analysis. The interaction between mLOY and PRS was assessed. These models were applied separately to RA, LORA, and young-onset RA (YORA).\nResults: mLOY increased significantly in LORA (OR=1.43, P=0.0070). We observed a negative association between mLOY and YORA (OR=0.66, P=0.0034). On the other hand, we found consistently negative associations of autosomal mCAs or mosaic loss of X (mLOX) with RA, LORA, and YORA. The effect sizes of PRS were lower for LORA than for YORA. mLOY with a high cell fraction strengthened the association between PRS and LORA (P=0.0036), whereas the association with YORA was independent of mLOY.\nConclusion: LORA was characterised by the presence of a high burden of mLOY. 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引用次数: 0

摘要

目的:镶嵌染色体改变(mCAs)会随着年龄的增长而增加,并与年龄相关疾病有关。方法:从两个独立的日本数据集(数据集 1:2107 例 RA 病例和 86998 例对照;数据集 2:2359 例 RA 病例和 86998 例对照)的外周血样本中检测 mCAs。我们使用逻辑回归模型和荟萃分析评估了每个数据集中 mCA 与 RA 之间的关联。在每个数据集中,我们都评估了Y染色体马赛克缺失(mLOY)和男性RA多基因风险评分(PRS)的效应大小,随后进行了荟萃分析。评估了 mLOY 和 PRS 之间的交互作用。结果:mLOY 在 LORA 中显著增加(OR=1.43,P=0.0070)。我们观察到 mLOY 与 YORA 呈负相关(OR=0.66,P=0.0034)。另一方面,我们发现常染色体 mCA 或镶嵌性 X 缺失(mLOX)与 RA、LORA 和 YORA 一直呈负相关。高细胞分数的 mLOY 增强了 PRS 与 LORA 的关联(P=0.0036),而与 YORA 的关联与 mLOY 无关:结论:LORA 的特征是存在大量的 mLOY。在 LORA 中观察到 mLOY 与 PRS 之间的相互作用,而在 YORA 中则未观察到,这表明这两个亚群之间存在不同的基因-环境相互作用。这些数据表明,不同的病理生理机制是 LORA 和 YORA 发展的基础。
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Mosaic loss of chromosome Y characterizes late-onset rheumatoid arthritis and contrasting associations of polygenic risk score based on age at onset.
Objectives: mosaic chromosomal alterations (mCAs) increase with age and are associated with age-related diseases. The association between mCAs and rheumatoid arthritis (RA), particularly late-onset rheumatoid arthritis (LORA), has not been explored. Methods: mCAs were detected in peripheral blood samples from two independent Japanese datasets (Set 1:2,107 RA cases and 86,998 controls; Set 2:2,359 RA cases and 86,998 controls). The associations between mCAs and RA were evaluated in each dataset using logistic regression models and meta-analysis. In each dataset, we evaluated the effect sizes of mosaic loss of Y (mLOY) and polygenic risk score (PRS) of RA in males and subsequently performed a meta-analysis. The interaction between mLOY and PRS was assessed. These models were applied separately to RA, LORA, and young-onset RA (YORA). Results: mLOY increased significantly in LORA (OR=1.43, P=0.0070). We observed a negative association between mLOY and YORA (OR=0.66, P=0.0034). On the other hand, we found consistently negative associations of autosomal mCAs or mosaic loss of X (mLOX) with RA, LORA, and YORA. The effect sizes of PRS were lower for LORA than for YORA. mLOY with a high cell fraction strengthened the association between PRS and LORA (P=0.0036), whereas the association with YORA was independent of mLOY. Conclusion: LORA was characterised by the presence of a high burden of mLOY. The observed interaction between mLOY and PRS in LORA, but not in YORA, supports different gene-environment interactions between the subsets. These data suggest that distinct pathophysiological mechanisms underlie the development of LORA and YORA.
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