Evidence for linkage of a candidate chromosome 1 region to human systemic lupus erythematosus.

Abstract

Genetic susceptibility confers significant risk for systemic lupus erythematosus (SLE). The MHC region and other polymorphic loci have been associated with SLE. Because more compelling evidence for an involvement of a genetic locus includes linkage, we tested a candidate region homologous to a murine SLE susceptibility region in 52 SLE-affected sibpairs from three ethnic groups. We analyzed seven microsatellite markers from the human chromosome 1q31-q42 region corresponding to the telomeric end of mouse chromosome 1, the region where specific manifestations of murine lupus, including glomerulonephritis and IgG antichromatin, have been mapped. Comparing the mean allele sharing in affected sibpairs of each of these seven markers to their expected values of 0.50, only the five markers located at 1q41-q42 showed evidence for linkage ( P ϭ 0.0005-0.08). Serum levels of IgG antichromatin also showed evidence for linkage to two of these five markers ( P ϭ 0.04), suggesting that this phenotype is conserved between mice and humans. Compared to the expected random distribution, the trend of increased sharing of haplotypes was observed in affected sibpairs from three ethnic groups ( P Ͻ 0.01). We concluded that this candidate 1q41-q42 region probably contains a susceptibility gene(s) that confers risk for SLE in multiple ethnic groups. ( J. Clin. Invest. 1997. 99:725-731.)

Screening the genome for rheumatoid arthritis susceptibility genes: A replication study and combined analysis of 512 multicase families

“…The 1p13 region has been linked to SLE (28). The 1q43 region containing the D1S235 marker was first linked to susceptibility to SLE using a candidate approach (29), and this linkage was subsequently confirmed in 3 separate genome-wide screens (28)(29)(30). The 18q21 locus has shown evidence for linkage with type I insulin-dependent diabetes mellitus (31)(32)(33), SLE (34), and Grave's disease (35) in humans, and the orthologous region in rodents has been implicated in animal models of SLE (36), multiple sclerosis (37), and experimental allergic encephalomyelitis (38).…”

Analysis of gene expression profiles in human systemic lupus erythematosus using oligonucleotide microarray

“…[4][5][6] Several whole-genome linkage studies have also been reported suggesting about 20 SLE susceptibility loci. [7][8][9][10] Together, these studies suggest that SLE is a polygenic disorder with contributions from multiple genes, each one of which has a modest effect.…”

Genetic linkage and association studies of Type I diabetes: challenges and rewards

“…Recent research indicates that several of the non-HLA regions linked to Type I diabetes also show linkage to other autoimmune diseases, suggesting common pathogenic pathways shared by Type I diabetes and these other disorders [127,128]. For example, the IDDM3 region on chromosome 15q26 has been reported to be linked to coeliac disease [129,130], the IDDM6 region on chromosome 18q21 has been reported to be linked to Graves disease [131] as well as multiple sclerosis and rheumatoid arthritis [69], the IDDM8 region on chromosome 6q27 has been reported to be linked to rheumatoid arthritis [132], the IDDM12 (CTLA4) region on chromosome 2q33 has been reported to be linked to coeliac disease [133,134], Graves disease [78,135], multiple sclerosis [136] and rheumatoid arthritis [137,138], the IDDM16 region on chromosome 14q32 has been reported to be linked to multiple sclerosis [139], and the chromosome 1q42 region containing an unnamed diabetes locus has been reported to be linked to systemic lupus erythematosus [140,141] (for additional examples, see [128]). Although some of these co-localizations could be coincidental, the possibility remains that at least a few IDDM loci would be more accurately called autoimmunity susceptibility loci.…”