Ethnic Variation in the Clinical Manifestations of Rheumatoid Arthritis: Role of HLA–DRB1 Alleles INMACULADA DEL RINCO ´ N, 1 DANIEL F. BATTAFARANO, 2 RAMO ´ N A. ARROYO, 3 FREDERICK T. MURPHY, 2 MICHAEL FISCHBACH, 4 AND AGUSTI ´ N ESCALANTE 1 Objective. To assess the extent of ethnic variation in the clinical expression of rheumatoid arthritis (RA) and the role of HLA–DRB1 alleles in this variation. Methods. We assessed consecutive RA patients for joint findings, subcutaneous nodules, laboratory and radiographic findings, and treatment. We typed HLA–DRB1 alleles to identify those that contain the shared epitope (SE). We adjusted ethnic comparisons for age and sex, and tested for ethnic heterogeneity in the effect of the SE. Results. We studied 777 RA patients, 498 of whom were women (64%), 432 were Hispanic (56%), 272 were non-Hispanic white (NHW; 35%), 53 were African American (AA; 7%), and 20 were Asian (3%). Compared with NHW, Hispanics had significantly more tender joints (17 versus 11), more swollen joints (8 versus 7), more frequent rheumatoid factor (RF) positivity (93% versus 84%), higher erythrocyte sedimentation rate (ESR; 45 versus 36 mm/hr), and a lower number of lifetime disease-modifying antirheumatic drugs (1.9 versus 2.5). AA were older at onset (46 versus 44 years), had less frequent subcutaneous nodules (18% versus 28%), and higher ESR (42 versus 36 mm/hour) than did NHW. Hispanics and AA were more likely than NHW to be null for the SE (odds ratio [OR]  4.59 for AA; and OR  1.61 for Hispanics), and less likely to have 2 SE-carrying alleles (OR  0.59 for Hispanics and OR  0.25 for AA). The number of SE copies was associated with subcutaneous nodules, ESR, RF, and radiographic changes. Ethnic heterogeneity in the effect of the SE was modest. Conclusions. There is ethnic variation in the clinical expression of RA and in both the frequency and types of SE-carrying HLA–DRB1 alleles. Some ethnic variation in clinical findings is associated with differences in SE frequency. However, we found that the effect of the SE on the clinical features of RA varies little between ethnic groups. KEY WORDS. Rheumatoid arthritis; African Americans; Hispanic Americans; Ethnic groups; HLA–DRB1; Shared epitope. INTRODUCTION The HLA–DRB1 alleles associated with rheumatoid arthri- tis (RA) vary among ethnic groups. Although DRB1*04 is associated with RA in northern European populations (1– 3), the RA-associated markers in Mediterranean people and blacks are DRB1*01 and *10 (4 – 8); and in North American natives, RA is linked to DRB1*14 (9,10). RA- associated alleles share amino acid sequences between positions 70 and 74 of the DRB1 molecule, the shared epitope (SE) (11). Among persons of Mexican origin, who comprise a population with considerable admixture from 3 races, no single HLA–DRB1 predominates as an RA marker (12,13). However, a double dose of the SE in mem- bers of this ethnic group is associated with more than 20-fold increase in the risk of RA (12,13). Three SE se- quences have been implicated: QKRAA, which occurs in HLA–DRB1 subtypes *0401 and *0409; QRRAA, which occurs in *0101, *0102, *0404, *0405, *0408, *0410, *1402, and *1406; and RRRAA, which occurs in *1001. QKRAA is found in populations of northern European ancestry, whereas the QRRAA and RRRAA occur in other ethnic groups (4 – 8). The SE sequences may also influence disease expression (14 –16). The sequence QKRAA has been found to be as- sociated with more severe disease and a greater frequency of extraarticular manifestations (14,15). A gene-dose effect Supported in part by a Clinical Science Grant and an Arthritis Investigator Award from the Arthritis Foundation; NIH grants RO1-HD37151, K23-HL004481, K24-AR47530, and MO1-RR1346; and Beginning Grant-in-Aid 0060044Y from the American Heart Association, Texas Affiliate. 1 Inmaculada del Rinco ´n, MD, Agustı´n Escalante, MD: The University of Texas Health Science Center at San Antonio; 2 Daniel F. Battafarano, DO, Frederick T. Murphy, DO: Brooke Army Medical Center, San Antonio, Texas; 3 Ramo ´n A. Arroyo, MD: Wilford Hall Air Force Medical Center, San Antonio, Texas; 4 Michael Fischbach, MD: The University of Texas Health Science Center at San Antonio and South Texas Veterans Administration Health System, San Anto- nio, Texas. Address correspondence to Agustı ´n Escalante, MD, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-7874. Submitted for publication December 26, 2001; accepted in revised form June 11, 2002. Arthritis & Rheumatism (Arthritis Care & Research) Vol. 49, No. 2, April 15, 2003, pp 200 –208 DOI 10.1002/art.11000 © 2003, American College of Rheumatology ORIGINAL ARTICLE 200