Genome scan stratified by the presence of anti-double-stranded DNA (dsDNA) autoantibody in pedigrees multiplex for systemic lupus erythematosus (SLE) establishes linkages at 19p13.2 (SLED1) and 18q21.1 (SLED2).
Anti-double-stranded DNA (anti-dsDNA) is arguably one of the most specific autoantibodies in systemic lupus erythematosus (SLE). This antibody is associated with more severe SLE and with glomerulonephritis. From 196 pedigrees multiplex for SLE, we selected those that had any SLE affected positive for anti-dsDNA by the Crithidia luciliae kinetoplast imunofluorescence assay. This stratification strategy tested the hypothesis that anti-dsDNA would identify a more genetically homogeneous group of pedigrees, in which previously undetected linkage effects could be established. A genome screen data for linkage to SLE was available at 307 microsatellite markers for this selected group of 71 pedigrees: 37 European-American, 29 African-American, and five others. The most significant results were obtained at 19p13.2 (LOD(max) = 4.93), named SLED1, in the 37 European-American pedigrees using a dominant model with mixed penetrances (92% for females and 49% for males) at 100% homogeneity (theta = 0). A second linkage effect, SLED2, was established in the 29 African-American pedigrees at 18q21.1 (LOD(max) = 3.40) using a recessive model with 100% penetrance (theta = 0.1). Parametric and non-parametric multipoint analyses were performed, which provided further evidence and support of susceptibility genes residing in these regions. In conclusion, two powerful linkages have been detected with SLE based on the presence of anti-dsDNA. These findings show SLE to be a richly complicated disease phenotype that is now ripe for important new discovery through a genetic approach.
Namjou
B
B
Arthritis and Immunology Research Program, Oklahoma Medical Research Foundation, OK 73104, USA.
Nath
S K
SK
Kilpatrick
J
J
Kelly
J A
JA
Reid
J
J
Reichlin
M
M
James
J A
JA
Harley
J B
JB
D000818:Animals; D000906:Antibodies / Q000097:blood; D001323:Autoantibodies / Q000276:immunology*; D002887:Chromosomes, Human, Pair 18; D002888:Chromosomes, Human, Pair 19; D003421:Crithidia / Q000276:immunology; D004247:DNA / Q000276:immunology*; D005260:Female; D005455:Fluorescent Antibody Technique; D008040:Genetic Linkage; D006801:Humans; D008126:Lod Score; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D008297:Male; D010375:Pedigree
D000906:Antibodies; D001323:Autoantibodies; D004247:DNA