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To identify additional sex‐specific and epistatic quantitative trait loci (QTL) regulating collagen‐induced arthritis (CIA) severity overall, as well as within different stages during the disease course, in an intercross between major histocompatibility complex–identical inbred rat strains DA/Bkl (susceptible) and ACI/Hsd (resistant). Arthritic male (DA × ACI)F2 intercross offspring (n = 143) were analyzed separately from the females (n = 184). Phenotypic extremes (maximum arthritis scores [MAS]) were genotyped and used for QTL analysis. All 327 rats were genotyped with the simple sequence‐length polymorphism (SSLP) markers closest to the peak of Cia7 and Cia10, the major loci previously identified in this intercross, and with SSLPs covering chromosomes 12 and 18. Phenotypes studied were disease onset, arthritis severity scores on days 14–39, MAS, mean and cumulative arthritis scores, delayed‐type hypersensitivity, and antibody responses to rat type II collagen. A new female‐specific arthritis‐severity recessive locus was identified on rat chromosome 12 (Cia25), with a maximum effect observed on day 28 (logarithm of odds [LOD] 4.7). The homozygous DA genotype at Cia25 was associated with a 45% higher median arthritis score in females. Sequencing analyses of the Cia25 candidate gene Ncf1 revealed polymorphisms between DA and ACI. The previously identified locus, Cia10, was found to be male‐specific. A 2‐locus interaction model analysis identified a novel recessive chromosome 18 QTL, Cia26, which was dependent on Cia7, with its maximum effect observed at later stages during the disease course (peak LOD score of 3.6 for arthritis scores on day 39). This study identified 2 novel female‐specific loci, and 1 male‐specific locus. Cia25 regulates MAS and disease severity during the mid‐to‐late stages of the disease course and may be accounted for by Ncf1 polymorphisms. Cia26 is in epistasis with Cia7 and regulates later stages of disease, suggesting an involvement in disease perpetuation and/or chronicity. [ABSTRACT FROM AUTHOR]

To examine the association between HLA–DRB1 alleles and the production of anti–cyclic citrullinated peptide (anti‐CCP) and rheumatoid factor (RF) autoantibodies in patients with rheumatoid arthritis (RA).We studied 1,723 Caucasian RA patients enrolled in the North American Rheumatoid Arthritis Consortium (NARAC) family cohort and the Study of New Onset Rheumatoid Arthritis (SONORA) cohort. All patients were tested for anti‐CCP antibodies (by enzyme‐linked immunosorbent assay), RF (by nephelometry), and HLA–DR genotype (by polymerase chain reaction and sequence‐specific oligonucleotide hybridization).When controlled for the presence of RF, anti‐CCP positivity was strongly associated with the HLA–DRB1 shared epitope (SE). In RF+ patients, the presence of the SE was very significantly associated with anti‐CCP positivity, with an odds ratio (OR) of 5.8 and a 95% confidence interval (95% CI) of 4.1–8.3. This relationship was also seen in RF– patients (OR 3.1 [95% CI 1.8–5.3]). In contrast, RF positivity was not significantly associated with presence of the SE independently of anti‐CCP antibodies. Strikingly, HLA–DRB1*03 was strongly associated with reduced anti‐CCP titers, even after controlling for the presence of the SE and restricting the analysis to anti‐CCP+ patients. HLA–DR3 was also associated with anti‐CCP– RA in our population.The HLA–DRB1 SE is strongly associated with the production of anti‐CCP antibodies, but not RF. In contrast, HLA–DR3 alleles are associated with anti‐CCP– disease and with lower levels of anti‐CCP antibodies, even when controlling for the SE. These data emphasize the complexity of the genetic effects of the major histocompatibility complex on the RA phenotype. [ABSTRACT FROM AUTHOR]