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Non-inherited maternal human leukocyte antigen alleles in susceptibility to familial rheumatoid arthritis
  1. K A Guthrie1,
  2. N R Tishkevich2,
  3. J L Nelson2,3
  1. 1
    Clinical Statistics, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
  2. 2
    Department of Medicine, Rheumatology, University of Washington, Seattle, Washington, USA
  3. 3
    Immunogenetics, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
  1. K A Guthrie, Clinical Statistics D5-360, Fred Hutchinson Cancer Research Center 1100 Fairview Ave. N, Seattle, Washington 98109-1024, USA; kguthrie{at}


Objectives: Some patients with rheumatoid arthritis (RA) lack RA-associated human leukocyte antigen (HLA) alleles. Prior studies investigated non-inherited maternal HLA alleles (NIMA) in RA risk with conflicting results.

Methods: We examined NIMA in a large cohort of families from the North American Rheumatoid Arthritis Consortium (NARAC).

Results: Among 620 patients with 1 or both parents having a HLA genotype, patients with RA informative for analysis included 176 without HLA-DRB1*04 and 86 without the HLA shared epitope (SE). The frequency of NIMA encoding HLA-DR4 or the SE was compared to the non-inherited paternal allele (NIPA). DR4-encoding NIMA vs NIPA revealed no significant difference (27% vs 20%). However, parity is known to modulate RA risk and analyses stratified by sex and age of onset showed significant variation among women. Interestingly, among women with onset <45 years DR4-encoding NIMA was increased compared to NIPA; among women ⩾45 years at onset the reverse was observed (31% vs 16% compared to 10% vs 60%, p = 0.008). DR4 encoding NIMA vs NIPA did not differ in men. The SE did not differ in men or women.

Conclusions: Risk of RA was associated with HLA-DR4 encoding NIMA in younger-onset women but not in older-onset women or men. These observations could help explain conflicting prior results of NIMA in RA.

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  • Competing interests: None declared.

  • Funding: This study was supported by US National Institutes of Health grants NO1 AR22263, AI45659 and AI41721.

  • Ethics approval: Ethics approval was obtained.