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Renal disease occurs in 40-75% of systemic lupus erythematosus (SLE) patients and significantly contributes to morbidity and mortality. We used two pedigree stratification strategies to explore the impact of the ACR renal criterion for SLE classification upon genetic linkage with SLE. In both we used SLE as the phenotype. First, we evaluated genome scan data from > 300 microsatellite markers in the 75 pedigrees that had at least one SLE affected with the SLE renal criterion. A maximum-likehood parametric model approach produced a maximum screening LOD score of 3.16 at 10q22.3 in the European-American (EA) pedigrees. The African-American (AA) pedigrees obtained a maximum screening LOD score of 2.58 at 11p15.6. A multipoint sib-pair regression analysis produced P = 0.0000008 in EA at 10q22.3 (SLEN1) and P = 0.000001 in AA at 2q34-35 (SLEN2). A second stratification strategy explored the renal criterion in 35 pedigrees with two or more SLE patients with renal disease and produced a LOD score of 3.34 at 11p15.6 in AA (SLEN3). Sib-pair analysis in these 35 pedigrees revealed P = 0.00003 at 4q13.1 in EA, P = 0.00003 at 11p13 and 0.00007 at 3q23 in AA. Thus, multiple genetic linkages are related to the renal criterion in SLE. Of the significant genetic linkages with SLE described herein, those at 10q22.3 in the EA pedigrees (SLEN1) and at 2q34-35 in the AA pedigrees (SLEN2) have not been previously described. [ABSTRACT FROM AUTHOR]