Non-inherited maternal HLA alleles are associated with rheumatoid arthritis.
BACKGROUND
Rheumatoid arthritis (RA) is strongly associated with a series of HLA-DRB1 alleles that encode a conserved sequence of amino acids ((70)Q/R K/R R A A(74)) in the DRbeta1 chain, known as the shared epitope (SE). However 30% of patients are negative for DRB1*04 and 15% are SE-negative. Exposure to these alleles as non-inherited maternal antigens (NIMA) might explain this discrepancy. We undertook a family study to investigate the role of NIMA in RA.


METHODS
One hundred families, including the RA proband and both parents, were recruited. HLA-DRB1 genotyping was performed using an allele-specific polymerase chain reaction by standard methods. The frequencies of NIMA and non-inherited paternal antigens (NIPA) were compared using contingency tables and a two-tailed P test. We then reviewed four previously published studies of NIMA in RA and conducted an analysis of the combined data


RESULTS
We identified 36 families in which the proband was DRB1*04-negative and 13 in which the proband lacked the SE. There was an excess of DRB1*04 and SE NIMA (P=0.05) compared with NIPA. Combined analysis with previous studies showed that 53/231 mothers (23%) versus 25/205 fathers (12%) had a non-inherited DRB1*04 (P=0.003) and 30/99 mothers versus 18/101 fathers had a non-inherited SE allele (P=0.03).


CONCLUSIONS
A role for HLA NIMA in RA is suggested by these results.
Harney
S
S
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. sineadharney@hotmail.com
Newton
J
J
Milicic
A
A
Brown
M A
MA
Wordsworth
B P
BP
D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D015331:Cohort Studies; D018604:Epitope Mapping; D005220:Fathers; D005260:Female; D005787:Gene Frequency; D005802:Genes, MHC Class II; D005819:Genetic Markers; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D009035:Mothers; D016017:Odds Ratio
D005819:Genetic Markers; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains