Mosaic loss of chromosome Y characterizes late-onset rheumatoid arthritis and contrasting associations of polygenic risk score based on age at onset.

Objectivesmosaic 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. MethodsmCAs 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). ResultsmLOY 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. ConclusionLORA 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. Key messagesO_ST_ABSWhat is already known about this subject?C_ST_ABS{square} The prevalence of late-onset rheumatoid arthritis (LORA) in aging societies is increasing worldwide. {square}LORA has unique clinical characteristics, including higher prevalence in males, acute onset of the disease, and lower proportion of seropositivity compared with young-onset RA (YORA), suggesting distinct genetic and environmental components between the RA subsets. {square}Mosaic chromosomal alterations (mCAs) accumulate with age and are associated with age-related disorders. mCAs occur in both autosomes and sex chromosomes and would reflect the clonal expansion of dysregulated immune cells. What does this study add?{square} Mosaic loss of Y (mLOY) is increased in male patients with LORA. {square}While mLOY is positively associated with LORA, mLOY is negatively associated with YORA. {square}The association of the RA-polygenic risk score (PRS) with LORA was more apparent in the presence of mLOY, while the association with YORA was independent of mLOY. How might this impact clinical practice or future developments?{square} mLOY plays an acquired risk for RA in males by modifying the contribution of the genetic risk to RA development depending on age at onset. {square}Further investigation of the different effects of mLOY on LORA and YORA would lead to a better understanding of the pathological basis of RA influenced by aging and sex.