Genome screening in human systemic lupus erythematosus: Results from a second Minnesota cohort and combined analyses of 187 sib-pair families

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized b y a loss of immunologic tolerance to a multitude of self-antigens. Epidemio logical data suggest an important role for genes in the etiology of lupus, and previous genetic studies have implicated the HLA locus, complement gene s, and low-affinity IgG (Fc gamma) receptors in SLE pathogenesis. In an eff ort to identify new susceptibility loci for SLE, we recently reported the r esults of a genomewide microsatellite marker screen in 105 SLE sib-pair fam ilies. By using nonparametric methods, evidence for linkage was found in fo ur intervals: 6p11-21 (near the HLA), 16q13, 14q21-23, and 20p12.3 (LOD sco res greater than or equal to 2.0), and weaker evidence in another nine regi ons. We now report the results of a second complete genome screen in a new cohort of 82 SLE sib-pair families. In the cohort 2 screen, the four best i ntervals were 7p22 (LOD score 2.87), 7q21 (LOD score 2.40), 10p13 (LOD scor e 2.24), and 7q36 (LOD score 2.15). Eight additional intervals were identif ied with LOD scores in the range 1.00-1.67. A combined analysis of MN cohor ts 1 and 2 (187 sib-pair families) showed that markers in 6p11-p21 (D6S426, LOD score 4.19) and 16q13 (D16S415, LOD score 3.85) met the criteria for s ignificant linkage. Three intervals (2p15, 7q36, and 1q42) had LOD scores i n the range 1.92-2.06, and another 13 intervals had LOD scores in the range of 1.00-1.78 in the combined sample. These data, together with other avail able gene mapping results in SLE, are beginning to allow a prioritization o f genomic intervals for gene discovery efforts in human SLE.