Session Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis
Session Type: Abstract Submissions (ACR)
RA (RA [MIM 180300]) disproportionately affects women of reproductive age, implicating pregnancy-related factors. Fetal microchimerism (FMC), or the persistence of a small population of cells in the mother, is a natural consequence of pregnancy. FMC is present more often in RA cases than in controls. Mother-child histocompatibility could determine long-term FMC, possibly increasing risk of RA through exposure to fetal HLA-antigens. We hypothesized that RA cases are more likely to have histocompatible (HC) children compared to controls.
The MCIS included 5,000+ individuals; mothers with RA or SLE and controls (n=750), their children and fathers. RA cases with 1+ birth before diagnosis were recruited at UC San Francisco. Controls were primarily recruited from blood donors. Mothers provided information on their reproductive history, history of transfusion, transplant and infections. Comprehensive MHC region SNP genotyping was conducted using the Illumina MHC panel (n=1,783), ImmunoChip (n=8,842), and 660K (n=1,991) arrays. Four-digit genotype data for HLA-A, B, C, DPA1, DPB1, DQA1, DQB1 and DRB1 were imputed using the T1DGC reference panel and BEAGLE. We estimated ancestry proportions from 384 markers using STRUCTURE. A child was HC from the mother’s perspective if the paternal allele did not differ from the non-inherited maternal allele. Carrier status (+ or -) of any DRB1 allele associated with RA risk (Raychaudhuri, 2012) and corresponding to SE amino acid sequences QKRAA and QRRAA (01:01, 04:01, 04:04, 04:05, 04:08) and DERAA (01:03, 04:02, 11:02, 13:01, 13:02) was determined for mothers and children. We used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between RA and a) HC at each HLA locus and b) exposure to any SE+ and DERAA+ children, stratifying on maternal carrier status.
Increased HC among cases was only evident at DQB1 (25.3% vs. 17.4%, p=0.03). Having any SE+ children significantly increased risk of RA for SE- mothers (n=218) (OR 2.56; 95% CI, 1.43-4.58) but not SE+ mothers (n=248) (OR 1.48; 95% CI, 0.83-2.62). No association was found with DERAA+ children, regardless of maternal carrier status. Ancestry, parity, and history of transfusion did not impact results.
Exposure to SE+ children and DQB1 HC may contribute to RA etiology and could contribute to RA’s female-predominance. This is the largest study confirming the association between RA and SE+ children in SE- mothers.
L. A. Criswell,
H. L. Quach,
L. F. Barcellos,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/increased-risk-of-rheumatoid-arthritis-ra-among-shared-epitope-negative-se-mothers-with-shared-epitope-positive-se-children/