Polimorfismo do gene PDCD1 em pacientes da Amazônia com lúpus eritematoso sistêmico

Abstract

Systemic lupus erythematosus (SLE) is a complex disease with multiple clinical and physiological abnormalities held together by the production of a great number of auto-antibodies, most of them directed against nuclear material. Antigen-antibody complexes deposited upon endothelial surfaces prompt inflammation on target organs like the skin, kidneys, nervous system, blood, pleura and joints. Admittedly, many genes should act together, along with environmental factors, to launch disease pathways. Apoptosis is a central phenomenon in this scenario, with intrinsic incapacity to opsonise or digest nuclear debris. On the other hand, several abnormalities have been ascribed to regulatory and executive arms of the immune system which rend it over-reactive to antigenic challenge. Gain of function in stimulatory signaling pathways or loss of function in inhibitory ones may result in such over-reactivity. Linkage studies have identified a locus in chromosome 2q37.3 strongly linked with SLE. That is the locus of gene PDCD1 (programmed cell death-1), which codes for the membrane receptor PD-1, expressed in activated lymphocytes and macrophages, having an inhibitory action when contacting its ligands on antigen presenting cells and in other somatic tissues. Failure of this mechanism could result in autoimmunity, as long as a source of auto-antigens is provided. Mice knocked-out for the PDCD-1 gene present with a lupus-like syndrome and anti-nuclear antibodies. A haplotype containing the A allele on a G/A mutation at intronic position 7146 (rs11568821) of PDCD1 demonstrated strong association of with SLE in Scandinavian, Mexican and Euro-American patients, in another cohort from Sweden with renal disease, in patients from Philadelphia with anti-phospholipid antibodies and in patients from Mexico City with pediatric SLE. Otherwise, in Spain, 7146-A occurred significantly more in matched controls than in SLE patients. Intronic segment 7146 is a binding site for transcription factor RUNX1, so it is attractive to suppose that this SNP could play an important role in lupus pathogenesis. The above mentioned association studies call for replication and confirmation in other populations with diverse geographic provenience and different ancestry. We tested the association with SLE of allele A at 7146 position of PDCD1 in 207 patients attended at the University Hospital in Manaus, Amazonas, Brazil, fulfilling at least four of the 11 criteria of the American College of Rheumatology, and 202 matched controls from the same region. A DNA segment of 180 bp was amplified by polymerase chain reaction and then digested by restriction enzyme Pst-1. The frequency of allele A was 6,9% in controls and 8,2% in SLE patients, a difference with no statistical significance. SLE subgroups such as kidney disease, thrombotic disease, pediatric age and other features did not differ from controls in allele A frequency. Our findings, along with those of previous studies, support the view that PDCD1 gene may be indeed associated with SLE, but that 7146 position may not be the causal SNP, but could be in linkage disequilibrium with another putative SNP, the one to blame for functional derangement and disease.