ARTHRITIS & RHEUMATISM Vol. 46, No. 9, September 2002, pp 2320–2329 DOI 10.1002/art.10485 © 2002, American College of Rheumatology HLA–DRB1 Genotype Associations in 793 White Patients From a Rheumatoid Arthritis Inception Cohort Frequency, Severity, and Treatment Bias James F. Fries, 1 Frederick Wolfe, 2 Raymond Apple, 3 Henry Erlich, 3 Teodorica Bugawan, 3 Tyson Holmes, 1 and Bonnie Bruce 1 Objective. The HLA–DRB1 “shared epitope” (SE) genotypes are associated with rheumatoid arthritis (RA), but it remains controversial whether the associa- tion is with incidence, severity, or both, whether there are associations in seronegative patients, and whether different DRB1 alleles that contain the SE have similar effects on RA susceptibility and/or severity. The present study was undertaken to study these issues in a large cohort of patients with RA. Methods. White patients with RA of <6 months’ duration (n  793) were enrolled in an inception cohort. HLA–DRB1 typing was performed, and patients were categorized into 21 DRB1 genotype groups. The disabil- ity index of the Health Assessment Questionnaire was the primary outcome measure. Results. DRB1 associations in seronegative RA patients closely resembled those in controls. Of seropos- itive patients, 21% had 2 copies of the epitope, 52% had 1 copy, and 27% had none. However, not all genotypes with 1 copy were associated with increased susceptibil- ity; for example, frequencies of DRB1*0404/X and *01/X did not differ from those in controls. Absolute differ- ences between seropositive RA patients and controls were greatest for DRB1*0401 homozygosity (3.8% ver- sus 0.8%, respectively) and *0401/0404 heterozygosity (4.7% versus 1.0%). DRB1*0404 was increased in fre- quency in seropositive RA but, unlike *0401, an in- creased frequency was seen only with 2 epitope copies. The relatively rare DRB1*10 had an unexpected associ- ation with seropositive RA, being present in 1.7% of seropositive RA patients and 0.7% of controls, and also showed a trend toward association with greater disease severity. The presence of 2 epitope copies was associated with increased frequency of seropositivity and younger age at disease onset, not with disease severity. Treat- ment indication bias was substantial and may have accounted for some of these effects. HLA–DRB1*0401/ 0404 was found much more frequently in men and in patients with a lower age at disease onset, and there was a trend toward a higher frequency of *0404/0401 in women. Conclusion. This large inception cohort study confirms previously identified major associations and provides additional insights. Only one dominant asso- ciation was found: *0401, which differs from other SE alleles in a single Lys-for-Arg substitution. The associ- ation of the rare DRB1*10 allele has not previously been postulated. Sex associations were confirmed. Associa- tions with seronegative RA were not seen. Not all genotypes containing an SE copy showed increased susceptibility to RA. The association of SE genotypes found in this study related to disease susceptibility rather than severity. The association of the DRB1 shared epitope (SE) genotypes with rheumatoid arthritis (RA) has been extensively reported (1–16). However, it is less certain whether they predict severity or susceptibility, whether they are associated with seronegative RA, whether the associations differ between sexes, and whether there are additional unrecognized associations between genotype Supported by NIH grant AR-43584 to the Arthritis, Rheuma- tism, and Aging Medical Information System. 1 James F. Fries, MD, Tyson Holmes, PhD, Bonnie Bruce, PhD: Stanford University School of Medicine, Palo Alto, California; 2 Frederick Wolfe, MD: Wichita Arthritis Center, Wichita, Kansas; 3 Raymond Apple, PhD, Henry Erlich, PhD, Teodorica Bugawan, BS: Roche Molecular Systems, Oakland, California. Address correspondence and reprint requests to James F. Fries, MD, 1000 Welch Road, Suite 203, Palo Alto, CA 94304. Submitted for publication December 17, 2001; accepted in revised form May 13, 2002. 2320