PubMed · 7663502
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1995. Predictions for polycystin.. https://doi.org/10.1038/ng0695-123
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A genetic contribution to the development of systemic lupus erythematosus (SLE) is well established. Several genome-wide linkage scans have identified a number of putative susceptibility loci for SLE, some of which have been replicated in independent samples. This study aimed to identify the regions showing the most consistent evidence for linkage by applying the genome scan meta-analysis (GSMA) method. The study identified two genome-wide suggestive regions on 6p21.1-q15 and 20p11-q13.13 (P-value=0.0056 and P-value=0.0044, respectively) and a region with P-value<0.01 on 16p13-q12.2. The region on chromosome 6 contains the human leukocyte antigen cluster, and the chromosome 16 and 20 regions have been replicated in several cohorts. The potential importance of the identified genomic regions are also highlighted. These results, in conjunction with data emerging from dense single nucleotide polymorphism typing of specific regions or future genome-wide association studies will help guide efforts to identify the actual predisposing genetic variation contributing to this complex genetic disease.
Activity of Janus kinase 2 (JAK2) in the JAK2/STAT5 signaling pathway is critically controlled by suppressor of cytokine signaling-1 (SOCS-1). We have previously shown that SOCS-1 is biallelically mutated in the primary mediastinal B-cell lymphoma (PMBL) cell line MedB-1, resulting in impaired JAK2 degradation and sustained phospho-JAK2 action. SOCS-1 is frequently mutated in PMBL tumor primaries. Here, we report that the PMBL cell line Karpas1106P has a biallelic deletion of the SOCS-1 region on chromosome 16p13.13. By fluorescence in situ hybridization and microsatellite analysis, this deletion was narrowed down to a range of 650 kb to 1.48 Mb. Like MedB-1, Karpas1106P harbors gains of the JAK2 gene on chromosomal region 9p24 and elevated levels of JAK2 mRNA. Nevertheless, JAK2 protein was not increased but constitutively phosphorylated in Karpas1106P cells. In analogy to MedB-1 cells, Karpas1106P cells exhibited a retarded degradation of de novo synthesized JAK2 protein revealed by pulse/chase experiments. Therefore, we conclude that loss of SOCS-1 function either by mutation or by the complete deletion of the gene plays an important role in the dysregulation of JAK/STAT signaling in Karpas1106P and PMBL.
The presence of systemic lupus erythematosus (SLE) susceptibility genes on chromosome 20 is suggested by the observation of genetic linkage in several independent SLE family collections. To further localize the genetic effects, we typed 59 microsatellites in the two best regions, as defined by genome screens. Genotypes were analyzed for statistical linkage and/or association with SLE, by use of a combination of nonparametric linkage methods, family-based tests of association (transmission/disequilibrium and pedigree disequilibrium tests), and haplotype-sharing statistics (haplotype runs test), in a set of 230 SLE pedigrees. Maximal evidence for linkage to SLE was to 20p12 (LOD = 2.84) and 20q13.1 (LOD = 1.64) in the white pedigrees. Subsetting families on the basis of evidence for linkage to 16q12 significantly improved the LOD scores at both chromosome 20 locations (20p12 LOD = 5.06 and 20q13 LOD = 3.65), consistent with epistasis. We then typed 162 single-nucleotide polymorphism markers across a 1.3-Mb candidate region on 20q13.1 and identified several SNPs that demonstrated significant evidence for association. These data provide additional support for linkage and association to 20p12 and 20q13.1 in SLE and further refine the intervals of interest. These data further suggest the possibility of epistatic relationships among loci within the 20q12, 20q13, and 16q12 regions in SLE families.