Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting the synovial membrane, cartilage and bone. PAI-1 is a key regulator of the fibrinolytic system through which plasminogen is converted to plasmin. The plasmin activates the matrix metalloproteinase system, which is closely related with the joint damage and bone destruction in RA. The aim of this study was to investigate the relationship between 4G/5G PAI-1 polymorphism with mRNA expression and PAI-1 plasma protein levels in RA patients. 113 RA patients and 123 healthy subjects (HS) were included in the study. The 4G/5G PAI-1 polymorphism was determined by polymerase chain reaction–restriction fragment length polymorphism method; the PAI-1 mRNA expression was determined by real-time PCR; and the soluble PAI-1 (sPAI-1) levels were quantified using an ELISA kit. No significant differences in the genotype and allele frequencies of 4G/5G PAI-1 polymorphism were found between RA patients and HS. However, the 5G/5G genotype was the most frequent in both studied groups: RA (42%) and HS (44%). PAI-1 mRNA expression was slightly increased (0.67 fold) in RA patients with respect to HS (P = 0.0001). In addition, in RA patients, the 4G/4G genotype carriers showed increased PAI-1 mRNA expression (3.82 fold) versus 4G/5G and 5G/5G genotypes (P = 0.0001), whereas the sPAI-1 plasma levels did not show significant differences. Our results indicate that the 4G/5G PAI-1 polymorphism is not a marker of susceptibility in the Western Mexico. However, the 4G/4G genotype is associated with high PAI-1 mRNA expression but not with the sPAI-1 levels in RA patients.
This work was supported by Grant No. 69235 to JFMV of the CONACYT (Fondo Sectorial Secretaria de Salud-IMSS-ISSSTE CONACYT, México-Universidad de Guadalajara) and Grant No. 147778 of the Fondo Mixto CONACYT-Gobierno del Estado de Guerrero 2010-01.
Conflict of interest
The authors declare that they do not have any conflict of interest.
Ha H, Oh EY, Lee HB (2009) The role of plasminogen activator inhibitor 1 in renal and cardiovascular diseases. Nat Rev Nephrol 5:203–211PubMedCrossRefGoogle Scholar
Ma Z, Paek D, Oh CK (2009) Plasminogen activator inhibitor-1 and asthma: role in the pathogenesis and molecular regulation. Clin Exp Allergy 39:1136–1144PubMedCrossRefGoogle Scholar
Eriksson P, Kallin PB, van’t Hooft FM et al (1995) Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA 92:1851–1855PubMedCrossRefGoogle Scholar
Wong TY, Poon P, Szeto CC et al (2000) Association of plasminogen activator inhibitor-1 4G/4G genotype and type 2 diabetic nephropathy in Chinese patients. Kidney Int 57:632–638PubMedCrossRefGoogle Scholar
Margaglione M, Cappucci G, Colaizzo D et al (1998) The PAI-1 Gene Locus 4G/5G polymorphism is associated with a family history of coronary artery disease. Arterioscler Thromb Vasc Biol 18:152–156PubMedCrossRefGoogle Scholar
Margaglione M, Cappucci G, d’Addedda M et al (1998) PAI-1 plasma levels in a general population without clinical evidence of atherosclerosis: relation to environmental and genetic determinants. Arterioscler Thromb Biol 18:562–567CrossRefGoogle Scholar
Morange PE, Henry M, Tregouët D et al (2000) The A −844 G polymorphism in the PAI-1 gene is associated with a higher risk of venous thrombosis in factor V Leiden Carriers. Arterioscler Thromb Vasc Biol 20:1387–1391PubMedCrossRefGoogle Scholar
van der Laan MH, Slagboom PE, Meulenbelt I et al (1998) A functional polymorphism in the promotor of plasminogen activator inhibitor-1 is associated with join destruction in RA. Arthritis Rheum 41:S60Google Scholar
Tàssies D, Espinosa G, Muñoz-Rodríguez FJ et al (2000) The 4G/5G polymorphism of the type-1 plasminogen activators inhibitor gene and thrombosis in patients with antiphospholipid syndrome. Arthritis Rheum 43:2349–2358PubMedCrossRefGoogle Scholar
McCormack LJ, Nagi DK, Stickland MH et al (1996) Promoter (4G/5G) plasminogen activator inhibitor-1 genotype in Pima Indians: relationship to plasminogen activator inhibitor-1 levels and features of the insulin resistance syndrome. Diabetologia 39:1512–1518PubMedCrossRefGoogle Scholar
Cardiel MH, Abello-Banfi M, Ruiz-Mercado R et al (1993) How the measure health status in rheumatoid arthritis in non-English speaking patients: validation of a Spanish version of the Health Assessment Questionnaire Disability Index (Spanish HAQ-DI). Clin Exp Rheumatol 11:117–121PubMedGoogle Scholar
Prevoo ML, van ‘t Hof MA, Kuper HH et al (1995) Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 38:44–48PubMedCrossRefGoogle Scholar
Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215PubMedCrossRefGoogle Scholar
Margaglione M, Grandone E, Cappucci G et al (1997) An alternative method for PAI-1 promoter polymorphism (4G/5G) typing. Thromb Haemost 77:605–606PubMedGoogle Scholar
Muñoz-Valle JF, Vázquez-Del Mercado M, García-Iglesias T et al (2003) T(H)1/T(H)2 cytokine profile, metalloprotease-9 activity and hormonal status in pregnant rheumatoid arthritis and systemic lupus erythematosus patients. Clin Exp Immunol 131:377–384PubMedCrossRefGoogle Scholar
Ruiz-Quezada S, Vázquez-Del Mercado M, Parra-Rojas I et al (2004) Genotype and allele frequency of PAI-1 promoter polymorphism in healthy subjects from the west of Mexico. Association with biochemical and hematological parameters. Ann Genet 47:155–162PubMedCrossRefGoogle Scholar
Lisker R, Ramírez E, González-Villalpando C et al (1995) Racial admixture in a mestizo population from Mexico City. Am J Hum Biol 7:213–216CrossRefGoogle Scholar
Rangel-Villalobos H, Muñoz-Valle JF, González-Martín A et al (2008) Genetic admixture, relatedness, and structure patterns among Mexican populations revealed by the Y-chromosome. Am J Phys Anthropol 135:448–461PubMedCrossRefGoogle Scholar
Nuño-Arana I, Páez-Riberos LA, Sando-val-Ramírez L et al (2005) High prevalence of 5G allele in Amerindian tribes and Mestizos from Mexico at 4G/5G PAI-I gene promoter polymorphism. Thromb Haemost 93:1005–1007PubMedGoogle Scholar
Torres-Carrillo N, Magdalena Torres-Carrillo N, Vázquez-Del Mercado M et al (2008) Distribution of–844 G/A and Hind III C/G PAI-1 polymorphisms and plasma PAI-1 levels in Mexican subjects: comparison of frequencies between populations. Clin Appl Thromb Hemost 14:220–226PubMedCrossRefGoogle Scholar