A genome-wide search for susceptibility genes in human systemic lupus erythematosus sib-pair families

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune multisystem inflammatory disease characterized by the production of pathogenic autoantibodies. Previous genetic studies have suggested associations with HLA Class II alleles, complement gene deficiencies, and Fc receptor polymorphisms; however, it is likely that other genes contribute to SLE susceptibility and pathogenesis. Here, we report the results of a genome-wide microsatellite marker screen in 105 SLE sib-pair families. By using multipoint nonparametric methods, the strongest evidence for linkage was found near the HLA locus (6p11-p21) [D6S257, logarithm of odds (lod) = 3.90, P = 0.000011] and at three additional regions: 16q13 (D16S415, lod = 3.64, P = 0.000022), 14q21-23 (D14S276, lod = 2.81, P = 0.00016), and 20p12 (D20S186, lod = 2.62, P = 0.00025). Another nine regions (1p36, 1p13, 1q42, 2p15, 2q21-33, 3cent-q11, 4q28, 11p15, and 15q26) were identified with lod scores >/=1.00. These data support the hypothesis that multiple genes, including one in the HLA region, influence susceptibility to human SLE.

Figure 1

Nonparametric multipoint linkage analysis in 105 SLE sib-pair families. Shown are the analyses of chromosomes 1–22, plotting both Z_lr (solid line) and lod (dotted line) scores. Subjects were genotyped with 341 polymorphic markers at an average interval of 9.7 cM (longest, 26.4 cM; shortest, 0.5 cM). The average value of the information statistic, which is a measure of the percent inheritance information extracted at each marker (13), was 0.78, indicating that, overall, the markers were highly informative.