Evaluation of polymorphic variants in apoptotic genes and their role in susceptibility and clinical progression to systemic lupus erythematosus

Abstract

Background Systemic lupus erythematosus (SLE) is an autoimmune disease marked by the disruption of the immune homeostasis. Patients exhibit a wide range of clinical manifestations, and environmental and genetic factors are involved in SLE pathogenesis. Evidence suggests that abnormalities in the cellular and molecular events that coordinate apoptosis may favour the generation of autoantigens involved in autoimmunity. In this way, the apoptotic deregulation may be affected by polymorphic variants in apoptotic-related genes. Methods We analyzed FAS, FASL, BCL-2 and BAX polymorphisms in order to correlate to SLE susceptibility and clinical features. A total of 427 SLE patients from the Hospital de Clínicas de Porto Alegre and 543 controls from southern Brazil were evaluated. Results We observed higher frequencies of the FASL -844CC genotype and -844C allele, as well as of the FASL-844C/IVS2nt-124A haplotype in African-derived SLE patients when compared to controls ( P < 0.001). FASL -844C, which is related to high FasL expression, could contribute to increased apoptosis and to the breakdown of immunological tolerance, favouring autoantibody production and inflammation. On the other hand, the BAX -248GA genotype and the -248A allele , related to low protein expression, were observed as a protective factor against SLE in this same population. The rate of apoptosis and cell death was evaluated in peripheral lymphocytes, and SLE patients presented a higher percentage of dead lymphocytes (CD3Annexin V 7-AAD) compared to the control group. Conclusion Our data support a role for apoptosis in SLE susceptibility.

Associations between complement pathways activity, mannose-binding lectin, and odds of unprovoked venous thromboembolism

“…MBL deficiency is frequent in humans, ranging up to 20-30% when including those with levels below 400-500 ng/ml [21]. Plasma levels of MBL are independent of sex, remain stable throughout life, and varies mainly due to genotype [30,31].Whereas most individuals with low MBL are healthy, deficiency has been reported to be associated with various autoimmune [32,33] and infectious disorders [34,35]. Conflicting results have, however, been published regarding the association between MBL deficiency and risk of cardiovascular diseases.…”

New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond

“…Interaction of the FAS receptor with its ligand FASL plays a central role in programmed cell death, also called apoptosis. Autosomal dominant mutations of FAS or FASL genes result in decreased expression of FAS and FASL proteins and failure to remove autoreactive cells [110,147]. Defective FAS-FASL apoptotic pathway leads to a lymphoproliferative syndrome with autoimmune features (autoimmune lymphoproliferative syndrome; ALPS; OMIM 601859).…”

“…His SLE manifestations include malar rash, arthritis, serositis, renal disease, leukopenia, anti-DNA antibodies, and a positive ANA with generalized lymphadenopathy. Polymorphisms in FAS and FASL genes were shown to increase SLE susceptibility [95,147].…”

Monogenic Lupus: A Developing Paradigm of Disease

“…Apoptotic cell death results in increased DNA fragments, which if not properly processed can accumulate and result in autoimmunity. FAS gene polymorphisms have been shown to be associated with SLE ( 80 ) and variants in the FASL gene have been related to increase apoptosis ( 81 ). In this context, it is noteworthy that mice with deficiencies in Fas and FasL develop clinical features similar to SLE and ALPS, thus represent useful murine models to study the pathophysiology of both diseases.…”