Current advances in the human lupus genetics

Abstract

Genetic predisposition has been firmly established as a key element in susceptibility to systemic lupus erythematosus (SLE). During the past three decades, association studies have assessed many genes for potential roles in predisposing to SLE. These studies have identified a few risk factors including hereditary deficiency of complement components, major histocompatibility complex class II alleles, and allelic variants for the Fc portion of IgG (FCGR) genes. In recent years, a few groups have completed linkage analyses in data sets from families containing multiple members affected with SLE. Results from these initial genome scans are encouraging; approximately eight chromosomal regions have been identified exhibiting evidence for significant linkage to SLE and have been confirmed using independent cohorts (1q23, 1q25-31, 1q41-42, 2q35-37, 4p16-15.2, 6p11-21, 12q24, and 16q12), suggesting the high likelihood of the presence of one or multiple SLE susceptibility genes at each locus. Another approach of linkage analyses conditioned on pedigrees where one affected member manifesting a particular clinical condition has also identified many chromosomal regions linked to SLE. Within several established susceptibility loci, evidence for association of positional candidate genes is emerging. Within 2q35-37, an intronic single nucleotide polymorphism (SNP) of the positional candidate gene program cell death 1 gene has been associated with SLE susceptibility. The SLE-associated SNP affects a transcription factor, RUNX1, binding site. Recently, SNPs of novel positional candidate genes that influence RUNX1 binding motifs have also been associated with other autoimmune diseases, suggesting the possibility of a common theme shared among susceptibility genes for autoimmune diseases. In the coming years, susceptibility genes responsible for the observed linkage will be identified, and will lead to further delineating genetic pathways involved in susceptibility to SLE.

The proapoptotic and antimitogenic protein p66SHC acts as a negative regulator of lymphocyte activation and autoimmunity

“…27,[29][30][31]36 Our findings implicate p66Shc not only as a regulator of apoptosis, but as an important participant in the inhibitory circuitry responsible for fine-tuning of the signals emanated from AgRs. Of note, human ShcA has been mapped to chromosome 1q21, where a susceptibility locus for SLE, 50 as well as for other autoimmune pathologies, including multiple sclerosis 51 and type-2 diabetes, 52 has been identified. The mouse syntenic region on chromosome 3 also displays susceptibility loci in multiple autoimmune disease models, including Eae3, Idd10, and Idd17.…”

Is FCRL3 a New General Autoimmunity Gene?

“…The chromosome 1q21-q23 was found to harbor a susceptibility locus for several autoimmune diseases including SLE [10], psoriasis, and atopic dermatitis [11]. However, because of the clustering of Fc␥R II/III and FCRL genes and extended blocks of linkage disequilibrium (LD) within the gene clusters, it is difficult to resolve a true disease-associated gene variant(s) in this genomic region.…”

Expression and function of the P2X7 purinergic receptor in patients with systemic lupus erythematosus and rheumatoid arthritis

“…Regions of genetic linkage have been detected on several chromosomes, suggesting the contribution of different genes, common or specific for some human populations [3]. The chromosomal regions that exhibit a significant linkage with SLE are 1q23, 1q25-31, 1q41-42, 2q35-37, 4p16 -15.2, 6p11-21, 12q24, and 16q12, and information regarding candidate genes is emerging [4]. Similar to SLE, rheumatoid arthritis (RA) is an autoimmune systemic inflammatory disease [5], and its etiology remains elusive, although genetic factors appear to be also involved.…”