The HLA-DRB1 shared epitope is associated with susceptibility to rheumatoid arthritis in African Americans through European genetic admixture.

OBJECTIVE: To determine whether shared epitope (SE)-containing HLA-DRB1 alleles are associated with rheumatoid arthritis (RA) in African Americans and whether their presence is associated with higher degrees of global (genome-wide) genetic admixture from the European population. METHODS: In this multicenter cohort study, African Americans with early RA and matched control subjects were analyzed. In addition to measurement of serum anti-cyclic citrullinated peptide (anti-CCP) antibodies and HLA-DRB1 genotyping, a panel of >1,200 ancestry-informative markers was analyzed in patients with RA and control subjects, to estimate the proportion of European ancestry. RESULTS: The frequency of SE-containing HLA-DRB1 alleles was 25.2% in African American patients with RA versus 13.6% in control subjects (P = 0.00005). Of 321 patients with RA, 42.1% had at least 1 SE-containing allele, compared with 25.3% of 166 control subjects (P = 0.0004). The mean estimated percent European ancestry was associated with SE-containing HLA-DRB1 alleles in African Americans, regardless of disease status (RA or control). As reported in RA patients of European ancestry, there was a significant association of the SE with the presence of the anti-CCP antibody: 86 (48.9%) of 176 patients with anti-CCP antibody-positive RA had at least 1 SE allele, compared with 36 (32.7%) of 110 patients with anti-CCP antibody-negative RA (P = 0.01, by chi-square test). CONCLUSION: HLA-DRB1 alleles containing the SE are strongly associated with susceptibility to RA in African Americans. The absolute contribution is less than that reported in RA among populations of European ancestry, in which approximately 50-70% of patients have at least 1 SE allele. As in Europeans with RA, the SE association was strongest in the subset of African American patients with anti-CCP antibodies. The finding of a higher degree of European ancestry among African Americans with SE alleles suggests that a genetic risk factor for RA was introduced into the African American population through admixture, thus making these individuals more susceptible to subsequent environmental or unknown factors that trigger the disease.

Perinatal and early childhood risk factors associated with rheumatoid factor positivity in a healthy paediatric population.

OBJECTIVE: To examine perinatal and childhood risk factors for the presence of rheumatoid factor in healthy children. METHODS: The Diabetes Autoimmunity Study in the Young (DAISY) is a longitudinal study of children at increased risk of type 1 diabetes, based on possession of human leucocyte antigen (HLA)-DR4 and DR3 alleles or a family history of diabetes. 651 children who participated in DAISY, with an average age of 6.4 (range 1-15) years, were tested for the presence of rheumatoid factor in their most recent serum sample. 23 children were positive for rheumatoid factor. Exposure data were collected prospectively by interview. HLA-DR4 alleles were identified using polymerase chain reaction-based Class II genotyping. RESULTS: While exploring risk factors for rheumatoid factor positivity in a multivariate model, several important interaction terms involving HLA-DR4 status suggested the need to evaluate risk factors in HLA-DR4-positive and HLA-DR4-negative children separately. In HLA-DR4-negative children, rheumatoid factor-positive infants were less likely to have been breast fed for >3 months (odds ratio (OR) 0.18; 95% confidence interval (CI) 0.04 to 0.99), more likely to have been exposed to non-parental tobacco smoke (OR 5.38; 95% CI 0.93 to 31.27) and more likely to be a race/ethnicity other than non-Hispanic white (OR 6.94; 95% CI 1.10 to 43.88) compared with rheumatoid factor-negative children, after adjusting for age, sex and maternal education. In HLA-DR4-positive children, there were no significantly associated risk factors for rheumatoid factor positivity. CONCLUSIONS: Risk factors for rheumatoid factor positivity in children vary by HLA-DR4 genotype. In HLA-DR4-negative children, breast feeding may decrease the risk, and environmental tobacco smoke may increase the risk, of autoimmunity.

Rheumatoid factor seropositivity is inversely associated with oral contraceptive use in women without rheumatoid arthritis.

OBJECTIVES: To examine whether oral contraceptive use is associated with the presence of serum rheumatoid factor in women of reproductive age without rheumatoid arthritis. METHODS: 304 women selected from parents of children who were at increased risk of developing type 1 diabetes were studied, because they were enriched with the human leucocyte antigen-DR4 allele, a susceptibility marker for both type 1 diabetes and rheumatoid arthritis. Participants visited a clinic where blood was drawn for rheumatoid factor testing, and exposure data were collected via questionnaires. A medical history and joint examination were performed to rule out rheumatoid arthritis. Participants and examiners were unaware of the participants' rheumatoid factor status at the time of examination and questionnaire. RESULTS: Use of oral contraceptives at any time was inversely associated with rheumatoid factor positivity (adjusted odds ratio (OR) 0.2, 95% confidence interval (CI) 0.07 to 0.52) independent of age, education and smoking. Smoking > or = 20 pack-years was also associated with rheumatoid factor positivity (adjusted OR 56.38, 95% CI 4.31 to 736.98) compared with never smoking. Smoking 1-19 pack-years was not associated with a positive rheumatoid factor. CONCLUSIONS: Our results suggest that oral contraceptive use, and possibly cigarette smoking, act early in the development of the immune dysregulation that occurs in rheumatoid arthritis.

Antibodies against cyclic citrullinated peptide are associated with HLA-DR4 in simplex and multiplex polyarticular-onset juvenile rheumatoid arthritis.

OBJECTIVE: Anti-cyclic citrullinated peptide (anti-CCP) antibodies have been detected in patients with juvenile rheumatoid arthritis (JRA), particularly in those with polyarticular, rheumatoid factor (RF)-positive JRA. Our objectives were to determine whether anti-CCP antibodies are associated with HLA-DR4 in children with polyarticular JRA, whether anti-CCP antibodies are associated with clinical features of disease, and whether affected sibling pairs (ASPs) with JRA are concordant for this antibody. METHODS: Stored serum samples obtained from 230 HLA-typed patients with JRA (77 with polyarticular-onset disease and 153 with pauciarticular- or systemic-onset disease), 100 JRA ASPs, and 688 healthy children were tested for anti-CCP antibodies and RF. RESULTS: Thirteen percent of the patients with polyarticular-onset JRA and 2% of the other JRA patients exhibited anti-CCP antibodies, compared with only 0.6% of the controls. Fifty-seven percent of RF-positive patients with polyarticular-onset JRA had anti-CCP antibodies. HLA-DR4-positive patients with polyarticular-onset JRA were more likely to have anti-CCP antibodies than were those without HLA-DR4 alleles (odds ratio [OR] 5.20, 95% confidence interval [95% CI] 1.30-20.9). Anti-CCP antibodies were associated with polyarticular onset (OR 7.46, 95% CI 1.99-28.0), a polyarticular disease course (OR 9.78, 95% CI 1.25-76.7), and erosive disease (OR 14.3, 95% CI 3.01-67.9). Concordance rates for anti-CCP antibodies among ASPs were statistically significant. CONCLUSION: These data demonstrate increased anti-CCP antibody formation in HLA-DR4-positive patients with polyarticular-onset JRA. The overall prevalence of anti-CCP antibodies in JRA is low, but a substantial proportion of RF-positive patients with polyarticular-onset JRA have these antibodies. Anti-CCP antibodies in JRA are associated with polyarticular onset, a polyarticular course, and erosive disease.

Validation of a food frequency questionnaire in preschool children.

BACKGROUND: Support for the validity of food frequency questionnaires (FFQ) in preschool children using parental report is limited. METHODS: We obtained dietary information for 68 children age 1-3 years using three or four 24-hour recalls and a FFQ regarding the child's diet covering one year from families in Denver, CO from 1997 to 1999. FFQs were completed by the parents, and recalls were collected via interviews with the parents and alternate caregivers, where applicable. Nutrient biomarkers were measured in the plasma of 38 of the children. All nutrients were adjusted for energy intake using residuals, and log-transformed where necessary. RESULTS: Correlations (Pearson r) between the FFQ and the average of the recalls were 0.33 for protein, 0.41 for carbohydrate, 0.39 for fat, 0.42 for vitamin C, 0.27 for alpha-tocopherol, and 0.08 for total energy intake. We found no substantial changes in these correlations after stratification by whether or not meals and snacks were provided by caregivers other than the parents. The highest correlations (Spearman r) with biological measures were 0.51 between plasma ascorbic acid and FFQ vitamin C, and 0.48 between plasma and FFQ alpha-tocopherol. CONCLUSIONS: The FFQ shows mostly good agreements with multiple 24-hour recalls and biomarkers in preschool children. In addition, the validity of the FFQ using parental report does not appear to be compromised when there are meal providers in addition to the parents.