Plasminogen activator inhibitor type 1 gene polymorphism and thromboses in patients with antiphospholipid syndrome

Abstract

AIM: To estimate the prevalence of plasminogen activator inhibitor type 1 (PAI-1) gene polymorphism in patients with antiphospholipid syndrome (APS) and its implication in vascular disorders/MATERIAL AND METHODS: The investigation enrolled 138 patients: 103 with APS, including 47 with systemic lupus erythematosus (SLE) + APS and 56 with primary APS (PAPS), 15 with SLE without APS, 20 with idiopathic thrombosis (IT), a control group (30 apparently healthy individuals). Thrombosis at various sites was recorded in 91 (88%) of the 103 patients with APS. The authors analyzed both the presence of thrombotic events in all the groups and the number of cases of thrombosis in each patient. Antiphospholipid antibodies, such as lupus anticoagulant, anticardiolipin antibodies, and anti-Β2-glycoprotein type 1 antibodies, were studied in all the patients. To diagnose a genotype in patients by the code encoding for PAI-1, DNA isolated from peripheral blood by standard methods was used and further investigated by real-time polymerase chain reaction/RESULTS: Out of 91 patients with APS and thrombosis, 27 (30%) had the 4G/4G genotype, which corresponded to homozygous mutation in the PAI-1 gene, 50 (55%) had the 4G/5G genotype (heterozygous mutation), and 14 (15%) had the 5G/5G (a normal genotype). The PAI-1 4G/5G genotype was present in 22 (70%) of 31 patients with SLE + APS and lower limb deep vein thrombosis versus 17 (47%) of 36 patients with PAPS (odds ratio (OR) 2.73; 95% confidence interval (CI), 0.89 to 8.59; р=0.08) and in 9 (90%) of 10 patients with SLE + APS and pulmonary artery thromboembolism versus 8 (40%) of 20 patients with PAPS (OR 13,5; 95% CI, 1.23 to 344.98; р=0,02). The incidence of thrombosis per 100 person-years was higher in the PAI-1 4G/4G and 4G/5G groups: 35.4 and 28.1 cases per 100 person-years, respectively. Thromboses were least often in the group of patients with the PAI-1 5G/5G genotype (18.6)/CONCLUSION: The prevalence of the PAI-1 5G/5G genotype in patients with APS and thrombosis was significantly lower than in those with SLE without APS or thrombosis. The 4G/5G polymorphism in APS in the presence of SLE was associated with venous thromboembolisms whereas in PAPS there was no relationship between the PAI-1 genotype, a history of thrombosis, and its localization.

Full Text

Полиморфизм гена ингибитора активатора плазминогена 1-го типа и тромбозы у больных с антифосфолипидным синдромом. - Резюме. Цель исследования. Оценка распространенности полиморфизма гена ингибитора активатора плазминогена 1-го типа (ИАП-1) у больных с антифосфолипидным синдромом (АФС) и его значение в сосудистых нарушениях. Материалы и методы. В исследование включили 138 больных. 103 с АФС: 47 - с системной красной волчанкой (СКВ) + АФС и 56 - с первичным АФС (ПАФС), 15 - с СКВ без АФС, 20 - с идиопатическими тромбозами (ИТ) и группа контроля (30 практически здоровых лиц). Тромбоз различной локализации регистрировался у 91 (88%) из 103 больных АФС. Проанализировали как наличие тромботических осложнений во всех группах, так и число случаев тромбоза у каждого пациента. У всех больных исследовали антифосфолипидные антитела (АФЛ): волчаночный антикоагулянт (ВА), антитела к кардиолипину (АКЛ) и антитела к Β2-гликопротеину 1-го типа (анти-Β2-ГП1). Для диагностики генотипа пациентов по гену, кодирующему ИАП-1 (PAI-1), использовали ДНК, выделенную из периферической крови стандартными методами, с последующим исследованием методом полимеразной цепной реакции в режиме реального времени. Результаты. У 27 (30%) из 91 больного АФС и с тромбозом имелся генотип 4G/4G, что соответствует гомозиготной мутации в гене PAI-1, у 50 (55%) - 4G/5G (гетерозиготная мутация) и у 14 (15%) - 5G/5G (нормальный генотип). Генотип PAI-1 4G/5G имелся у 22 (70%) пациентов из 31 с СКВ+АФС и тромбозом глубоких вен нижних конечностей против 17 (47%) из 36 - с АФС (отношение шансов - ОШ 2,73 при 95% доверительном интервале - ДИ от 0,89 до 8,59; р=0,08) и у 9 (90%) из 10 с СКВ+АФС и с тромбоэмболией легочной артерии против 8 (40%) из 20 - с ПАФС (ОШ 13,5 при 95% ДИ от 1,23 до 344,98; р=0,02). Частота случаев тромбозов на 100 человеко-лет была больше в группах с генотипом 4G/4G и 4G/5G гена PAI-1: 35,4 и 28,1 случая на 100 человеко-лет соответственно. Реже всего тромбозы встречались в группе больных с генотипом 5G/5G гена PAI-1: 18,6. Заключение. Распространенность генотипа 5G/5G гена PAI-1 у больных с АФС, имевших тромбозы, была достоверно ниже, чем у больных СКВ без АФС и тромбозов. Полиморфизм 4G/5G при АФС на фоне СКВ ассоциировался с венозными тромбоэмболиями, тогда как при ПАФС не отмечено взаимосвязи между генотипом PAI-1, тромбозом в анамнезе и его локализацией.
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