ARTHRITIS & RHEUMATISM Vol. 44, No. 12, December 2001, pp 2807–2818 © 2001, American College of Rheumatology Published by Wiley-Liss, Inc. Linkage Analysis of Human Systemic Lupus Erythematosus–Related Traits A Principal Component Approach Shaoqi Rao, 1 Jane M. Olson, 1 Kathy L. Moser, 2 Courtney Gray-McGuire, 1 Gail R. Bruner, 3 Jennifer Kelly, 3 and John B. Harley 4 Objective. To identify chromosomal regions con- taining genes involved in the susceptibility to human systemic lupus erythematosus (SLE)–related traits. Methods. In the context of a genome scan, we analyzed 101 SLE-affected sibpairs with respect to dermatologic, renal, immunologic, hematologic, neuro- logic, cardiopulmonary, and arthritic characteristics. Phenotypes were redefined in terms of principal com- ponents, which are synthetic variables composed of linear combinations of the original traits. Using 9 principal components obtained from these 7 traits plus age at SLE onset and race, we analyzed genome scan data with the multivariate version of the new Haseman- Elston regression model. Results. The largest linkage for an individual trait was on chromosome 2 at 228 cM (immunologic; P  0.00048). The most significant linkage to an individual principal component was on chromosome 4 at 208 cM (P  0.00007). The largest multivariate linkage was on chromosome 7 at 69 cM (P  0.0001). Of the individual organ systems, dermatologic involvement had the larg- est effect (P  0.0083) at this peak at 7p13 on chromo- some 7. Further analyses revealed that malar rash, a subtype of dermatologic involvement, was linked signif- icantly (P  0.00458) to this location. Conclusion. These results provide evidence of the presence and locations of genes that are involved in the genetic susceptibility to SLE-related traits in humans. Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterized by production of self-reactive autoantibodies. There may be multiple au- toantibody specificities that contribute to disease by either directly binding to self antigens or inducing inflammation following tissue deposition of antigen– antibody immune complexes (1,2). Hallmark features of SLE are the production of autoantibodies against nu- clear components, particularly anti-Sm and anti–double- stranded DNA (anti-dsDNA) (3) and the classic indu- rated and erythematous malar rash (4). The notion of a genetic contribution is supported by high heritability (66%) (5), familial aggregation (6), increased concor- dance rates among monozygotic twins compared with dizygotic twins and other full siblings (7,8), and genetic association to a number of candidate genes, including, among others, alleles in the HLA region, Fc receptors, and complement components (for review, see ref. 9). In addition, recent linkage analyses (10–14) suggest the presence of major genes. Environmental factors that are likely relevant to SLE pathogenesis may include infec- tious (Epstein-Barr virus), toxic (notably hydralazine and procainamide), and dietary agents (15–17). SLE is clinically heterogeneous, with consider- able variability of disease among patients. Classification of SLE requires that a patient meet any 4 of 11 criteria established by the American College of Rheumatology Supported in part by USPHS grants HG-01577, RR-03655, GM-28356, AR-42460, AR-45231, AI-24717, AI-31584, RR-15577, HL-07567, USPHS contract N01-AR-52221, and by the U.S. Depart- ment of Veterans Affairs. 1 Shaoqi Rao, PhD, Jane M. Olson, PhD, Courtney Gray- McGuire, MS: Case Western Reserve University, Cleveland, Ohio; 2 Kathy L. Moser, PhD: University of Minnesota, Minneapolis; 3 Gail R. Bruner, RN, BSN, Jennifer Kelly, BS: Oklahoma Medical Research Foundation, Oklahoma City; 4 John B. Harley, MD, PhD: Oklahoma Medical Research Foundation, University of Oklahoma, and Veterans Affairs Medical Center, Oklahoma City. Address correspondence and reprint requests to John B. Harley, MD, PhD, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104. Email: john-harley@ omrf.ouhsc.edu. Submitted for publication September 14, 2000; accepted in revised form July 6, 2001. 2807