Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Hierarchy of Risk Conferred by the HLA-DR Shared Epitope in Childhood Onset Rheumatoid Arthritis.

Prahalad3,  Sampath, Thompson2,  Susan D., Conneely6,  Karen, Jiang6,  Yunxuan, Prozonic6,  Jennifer, Brown6,  Milton, Angeles-Han5,  Sheila

Childrens Hospital Med Ctr, Cincinnati, OH
Stanford University Med Ctr, San Jose, CA
Texas Scottish Rite Hospital for Children, Dallas, TX
Texas Scottish Rite Hospital for Children
University of Utah, Salt Lake City, UT
University of Washington and Seattle Childerns's Hospital, Seattle, WA
Cincinnati Childrens Hospital Med Ctr, Cincinnati, OH
Emory Children's Center, Atlanta, GA
Emory Children's Center, Decatur, GA
Emory University, Atlanta, GA
Emory University
Emory University School of Medicine, Atlanta, GA
Mayo Clinic, Rochester, MN
Stanford University Med Ctr, Stanford, CA

Purpose:

Rheumatoid arthritis (RA) is an inflammatory arthritis with a peak age of onset ~50, although childhood cases occur. There is a strong association between certain HLA-DR alleles and RA. RA associated alleles encode DRb1 chains with conserved amino acid sequence in positions 70–74. The molecular structure encoding the susceptibility residues is termed the shared epitope (SE). While associations between SE and risk of RA is well established, some alleles (e.g. *0401) seem to confer a greater degree of risk than others (*0101). Tezenas Du Montcel et al proposed a classification in which some SE alleles conferred more susceptibility than others. While SE alleles have been evaluated in childhood cases of RA, most cohorts were small (n < 50), and used low resolution DNA typing. We sought to investigate possible hierarchy of SE alleles in the largest cohort assembled to date of RA in children.

Methods:

Cases were 189 children with JIA who had one or more positive tests for rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide (CCP) antibodies. Controls were 100 healthy Non-Hispanic White (NHW) adults. High resolution sequence based HLA-DRB1 genotypes were determined on cases and controls. In addition DRB1 genotypes were available on 273 healthy NHW controls. Per Tezenas Du Montcel et al, SE alleles were classified as follows: S2: (KRAA at amino acid positions 71–74) *0401, *1303; S3P: (QRAA) *0101, *0102, *0404, *0405, *0408, *1001, *1402. All other alleles were designated as low-risk (L) alleles. Logistic regression was performed using NHW cases and controls to calculate the odds ratio of various combinations of SE alleles (L/L, S3P/L, S2/L, S3P/S3P, S2/S2, S3P/S2).

Results:

The mean age of onset of RA was 10.7 years. Of 87 children tested for anti-CCP antibodies, 72% were positive. Of 21 African-American (AA) cases 48% carried 1 or 2 SE alleles. Of 25 Hispanic children 76% carried 1 or 2 SE alleles. Of the 134 NHW cases, 76% carried 1 or 2 SE alleles compared to 54% of controls (OR = 2.73, p <0.00001). A significantly greater proportion of cases carried 2 copies of SE alleles compared to controls (31.3% vs. 5.4%, OR 8.1, p <1 ×10-7). The effect of the number of risk alleles (SE) was very significant (OR = 2.5 (95% C.I.: 1.5–4.2) for each additional risk allele, p = 0.0003). There was a greater risk for S3P/S2 individuals beyond that expected based on the number of risk alleles alone (OR = 2.9 (95% C.I.: 1.1–7.4), p = 0.025). Genotype-specific risk estimates with L/L as reference group suggested a hierarchy of risk, with highest risk among those who had a S2 and a S3P allele (Table).

Conclusions:

This is the largest described cohort of children with RA. We confirm the association between SE alleles and susceptibility to RA in children. The excess risk conferred by individuals who carry the combination of S2/S3P risk alleles suggests that children with DRb1 chains containing KRAA/QRAA might be especially prone to RA.

 Number (%) of controlsNumber (%) of RA patientsComparison to L/L genotype
Genotype(N = 373)(N = 134)OR (95% CI)P
S2/S3P9 (2.4)28 (20.9)19.5 (8.4–45.2)<0.0001
S2/S23 (0.8)4 (2.9)8.4 (1.8–39.2)0.0069
S3P/S3P8 (2.1)10 (7.5)7.8 (2.9–21.4)<0.0001
S2/L60 (16.1)22 (16.4)2.3 (1.2–4.3)0.0078
S3P/L92 (24.7)38 (28.4)2.6 (1.5–4.4)0.0004
L/L201 (53.9)32 (23.9)1.0 (referent) 

To cite this abstract, please use the following information:
Prahalad, Sampath, Thompson, Susan D., Conneely, Karen, Jiang, Yunxuan, Prozonic, Jennifer, Brown, Milton, et al; Hierarchy of Risk Conferred by the HLA-DR Shared Epitope in Childhood Onset Rheumatoid Arthritis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :255
DOI: 10.1002/art.28024

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