The Association Between VCAM-1,ICAM-1and PECAM-1Single Nucleotide Polymorphisms And Preeclampsia

BackgroundPreeclampsia is a complication specifically occurred in pregnancy, a syndrome that is characterized by hypertension, proteinuria, vascular endothelin cells disfunction and excessive inflammatory responses, the incident of which is about9.4%-10.4%. It is an important obstetrical disease leading to the maternal and perinatal death in clinical, and the second leading cause of maternal death in China. If the condition is serious, patients will die of seizures, coma, heart cerebrovascular accident, heart failure, pulmonary edema, liver and kidney disfunction or diffuse vascular hemorrhage; and perinatal will occur severe complications such as fetal growth restriction, fetal distress, fetal intrauterine death, premature birth and neonatal asphyxia. Researchers have tried to elucidate the pathogenesis of preeclampsia from different angles over the past half-century, hoping to find effective methods of prediction, prevention and treatment. However, its etiology has not been determined yet till now, so it’s still difficult to predict and prevent. Among various theories of the cause that have been widely recognized, genetic susceptibility may play an important role in the pathogenesis of preeclampsia. The susceptibility genes of preeclampsia that the current research focuses on are:(1) susceptibility genes involved in the injury of endothelial cells and the change of the tension of vessels;(2) susceptibility genes involved in blood coagulation;(3) susceptibility genes involved in lipid metabolism;(4)human leukocyte antigen genes(HLA-DR4);(5)mitochondrial genes and so on. However, due to the heterogeneity of preeclampsia, genetic susceptibility is distribution differentiation between different peoples and different areas, with the addition of the interaction between genes and genes, genes and environment, which make the search for susceptibility genes a great challenge.Adhesion molecules are cell surface receptors mediated the combination between cells and cells or cells and extracellular matrix, participating in recognition of the cell, the activation and signal transduction, which plays an important role in immune response, inflammation and thrombosis. Vascular cellular adhesion molecule-1(VCAM-1), intercellular adhesion molecule-1(ICAM-1) and platelet endothelial cell adhesion molecule-1(PECAM-1) are immunoglobulin superfamily members of adhesion molecules. Abnormal cell surface adhesion molecules may have an important effect on preeclampsia. Studies found that the level of VCAM-1, ICAM-land PECAM-1in preeclampsia patients’ blood were significant different than the controls. The mechanism may be related to the injury of endothelial cells. VCAM-1, ICAM-1and PECAM-1have many gene polymorphisms, and whether these gene polymorphisms would influence the expression of VCAM-1, ICAM-1and PECAM-1in plasma of patients with preeclampsia and affect the occurrence and development of preeclampsia are not clear. At present, the studies of the association between preeclampsia and VCAM-1, ICAM-1and PECAM-1are limited to the protein level, however, the studies of the association on the genetics, except that Kwon’s and Tabatabai’s reports, are rarely reported. Furthermore, as the racial differences and regional differences of genetic polymorphisms, the results may also be different. ObjectiveWe aim to examine whether the distributions of genotypic and allelic frequencies of VCAM-1gene rs3181092and1041163, ICAM-lgene rs5498and PECAM-1gene rs281865545polymorphisms in patients with preeclampsia are different from those of a control group and to explore the susceptibility genes of preeclampsia of Han Chinese in southern China to get a better understanding of the pathogenesis of preeclampsia, thus providing the basis for the prevention and symptomatic treatment of preeclampsia.MethodsChoose110patients with preeclampsia who were hospitalized in Nanfang hospital between December2011and October2013, and choose110healthy pregnant women during the same period as the controls. All entrants are single pregnancy, Han Chinese and sporadic cases without blood relationship, excluding assisted reproductive technology of pregnancy, chronic hypertension disease, diabetes, premature rupture of membranes, gestational diabetes and immune history of systemic disease. Collect clinical indexes including age, height, body weight before pregnancy, gravidities, parities, blood pressure on admission to hospital, the illness gestational weeks, white blood cell counts, platelet counts and urine protein in24hours. Candidate gene method was used to select SNPs of rs1041163, rs3181092, rs5498and rs281865545, and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing were used for the detection of these SNPs. Single factor Logistic regression analysis was used to analyze the risk factors of preeclampsia, and multivariable Logistic regression analysis was used to adjust the effect of these risk factors on the association of preeclampsia and gene polymorphism. Compare the differences of illness during gestational weeks, blood pressure, proteinuria, white blood cell counts and platelets counts between genotypes which are related to preeclampsia.Results1. Comparing the clinical indexes with the two groups and found that maternal age, gravidities, parities and BMI before pregnancy were significantly different. Advanced maternal age (age>35yr), primigravida and primipara in preeclampsia group were more than the controls; the BMI before pregnancy were larger than the controls.2. The observed and expected genotype counts of rs1041163, rs3181092, rs5498and rs281865545were consistent with Hardy Weinberg equilibrium (p>0.05),which showed that the research objects were from the same group.3.The frequency of AA genotype(40.3%) and AA+AG genotype(91%) of rs3181092of VCAM-1in late-onset preeclampsia group were higher than the control group(22.7%and78.2%), the distribution in two groups had significant different (p<0.05). The relative risk suffered from late-onset preeclampsia of AA genotype and AA+AG genotype were4.320folds (OR=4.320,95%CI:1.516-12.308) and2.837folds (OR=2.837,95%CI:1.094-7.357) of the CC genotype carriers. The frequency of A allele (65.7%) in late-onset preeclampsia group was significantly higher than the controls. The relative risk suffered from late-onset preeclampsia of A allele was1.879folds of G allele carriers(OR=1.879,95%CI:1.205-2.928).4. The frequency of CG genotype(65.1%) of rs281865545of PECAM-1in early-onset preeclampsia group was higher than the control group(45.5%), the distribution in two groups had significant different (p<0.05). The relative risk suffered from early-onset preeclampsia of CG genotype was2.240folds (OR=2.240,95%CI:1-5.018) of the CC genotype carriers. The frequency of CG+GG genotype (74.4%) and G allele (41.9%) in early-onset preeclampsia group were higher than the controls, but the distribution in two groups didn’t have significant different(p> 00.05).5. The distribution of frequencies of the genotypes and alleles of rs1041163of VCAM-1in preeclampsia group and the control group were not significantly different(p>0.05). The frequency of AG genotype(49.1%) and G allele (27.3%)of rs5498of ICAM-1in preeclampsia group were higher than the control group(41.8%and24.5%), but the distribution in two groups didn’t have significant different(p>0.05).6. It was found that advanced maternal age, primigravida, primipara and BMI before pregnancy were the risk factors of preeclampsia and would increase the risk of the onset to preeclampsia by performing single factor Logistic regression analysis. The AA genotype of rs3181092of VCAM-1was an independent influencing factor of late-onset preeclampsia after adjusted advanced maternal age, primigravida primipara and BMI before pregnancy by using multivariable Logistic regression analysis(p<0.05). The relative risk suffered from late-onset preeclampsia of AA genotype were3.927folds (OR=3.927,95%CI:1.159-12.905) of the CC genotype carriers.The CG genotype of rs281865545of PECAM-1was an independent influencing factor of early-onset preeclampsia after adjusted advanced maternal age, primigravida, primipara and BMI before pregnancy by using multivariable Logistic regression analysis(p<0.05).The relative risk suffered from early-onset preeclampsia of CG genotype was4.193folds (OR=4.193,95%CI:1.456-12.079) of the CC genotype carriers.7. The white blood cell counts and platelet counts between genotypes of rs3181092of VCAM-1in preeclampsia group were significantly different(p<0.05), which of AA genotype carriers were lower than those of GG genotype carriers and AG genotype carriers. However, the illness during gestational weeks, blood pressure and proteinuria between genotypes of rs3181092were not significantly different(p> 0.05) and these clinical indexes between genotypes of rs281865545also were not significantly different(p>0.05).Conclusions1. Our study found for the first time that AA genotype and AA+AG genotype of rs3181092of VCAM-1were association with the pathogenesis of preeclampsia, especially late-onset preeclampsia. AA genotype may be the susceptible genotype of late-onset preeclampsia in Han Chinese in southern China. A allele carriers of rs3181092may have more genetic predisposition to preeclampsia.2. Our study found for the first time that CG genotype of rs281865545of PEC AM-1was association with the pathogenesis of preeclampsia, especially early-onset preeclampsia. CG genotype may be the susceptible genotype of early-onset preeclampsia in Han Chinese in southern China. CG genotype carriers of rs281865545may have more genetic predisposition to preeclampsia.3. There were not association between preeclampsia in Han Chinese in southern China and rs1041163of VCAM-1and rs5498of ICAM-1.4. AA genotype of rs3181092of VCAM-1may affect the counts of white blood cells and platelets in preeclampsia patients.5. Age, body max index (BMI) before pregnancy, gravidities and parities are also the risk factors of preeclampsia; All factors influence and interact with each other.