Integrin alpha2bbeta3 gene polymorphism and the microvascular system in scleroderma

Background: Activated integrin alpha2bbeta3 mediates platelet aggregation through the interaction with von Willebrand factor, fibronectin and fibrinogen. When codified by the P1A2 allele (corrisponding to C to T replacement at nucletide 1565 in the alpha2bbeta3 gene), this integrin has demonstrated to bind more tightly to immobilized fibrinogen and to enhance platelet reactivity. Therefore the A2 allele might predispose to an easier vascular damage and to a more severe prognosis with the involvement of internal organs. Objectives: To study the severity of microvascular damage in a retrospective cohort of consecutively referred scleroderma patients with respect to integrin alpha2bbeta3 gene polymorphism. Methods: 80 italian patients with SSc (22 with diffuse (dcSSc) and 58 with limited (lcSSc) skin involvement phenotype-according to LeRoy classification (1)) and 128 healthy blood donors (HBDs) entered this study. The DNA, extracted by salting-out method from venous blood of patients and controls, was genotyped for the integrin alpha2bbeta3 gene polymorphism (P1A1/A2), using the polymerase chain reaction and the restriction enzymes Msp1(2). In vivo morphologic evaluation of skin capillares was performed in each patient, using the technique of naifold video capillaroscopy. The internal organ involvement was determined using the severity scores validated by Medsger et al. (3). Results: In our cohort of subjects, the alpha2bbeta3 gene polymorphism (P1A1/A2) polymorphism didn't associate with the SSc disease. The genotype distribution didn't differ when we divided the patients according to the skin involvement phenotype (dcSSc or lcSSc). Analysing the naifold capillaroscopic pattern to evaluate the microvascular involvement, we found that the SSc patients with the A2 allele were more prone to develop avascular areas with extensive dissappearence of capillaries with respect to SSc patients with A1A1 genotype (73% vs 40%, respectively; OR (CIs 95%) = 4.06 (1.38-11.90)). Moreover, the presence of the allele A2 was associated with an higher probability of developing digital necrosis with respect to the patients with A1A1 genotype (41% vs 19%, respectively; OR (CIs 95%) = 2.96 (1.01-8.66)). There were no differences in the frequency of giant capillaries and hemorrhages in the two subgroup of patients. Looking at the organ specific involvement in SSc, we found that patients carrying the allele A2 had an increased probability to have a mild-moderate cardiac disease (47% vs 26% in A1A1 genotype, OR (CIs 95%) = 2.90 (1.03-8.00)) with respect to those carrying the A1A1 genotype. None of the patients had severe disease. Conclusion: The presence of allele A2 in position 1565 in the gene of integrin alpha2bbeta3 may be a marker of microvascular damage and severity of heart involvement. References: 1. LeRoy EC et al., J Rheumatol 1988; 15: 202-52. Weiss EJ et al., N Engl J Med 1996, 334: 1090-943. Medsger TA et al., J Rheumatol 1999, 26: 2159-67.