Study Of The Association Of Fgf1 And Fgf2 Snps With The Risk Of Endometriosis And Adenomyosis

Objective : Endometriosis (EMs) and adenomyosis are common gynecological diseases, which can bring chronic pelvic pain and infertility for women of reproductive age, are produced by multiple gene loci interacting with each other and with the environment. It is the widely accepted that endometriosis is caused by the blood of menstruate countercurrented, while adenomyosis is caused by the endomembrane intrude into the muscular of the uterus. Their aetiology and pathogenesis are not completely understood to date. However, the endometrial cells implant either outside the uterine cavity or within the myometrial wall of the uterus, one of the preconditions must be the angiogenesis if implantation of these cells intends to be successful, in which the fibroblast growth factors (FGFs) play important roles. FGFs are potent factors during the proliferation and differentiation of endothelial cells. As two prototype factors, FGF1 (acidic FGF,aFGF) and FGF2 (basic FGF, bFGF) are the most extensively studied members because of their basic type in the FGFs. The single nucleotide polymorphisms (SNPs) of FGF1 and FGF2 may modify the transcriptional activity and protein expression of FGF1 and FGF2, and further contribute to the development of some diseases. We suppose that SNPs of FGF1 and FGF2 may influence the risk of developing endometriosis and adenomyosis by modifying their protein expression. The aim of the present study was to investigate association of the two SNPs, FGF1 -1385A/G (C/T, rs:34011) in the promoter and FGF2 754C/G (rs:2922979) in the intron 1, with the risk of endometriosis and adenomyosis in North Chinese women by case–control studies.Methods:This case-contral study included 690 patients (421 with endometriosis and 269 with adenomyosis) and frequency-matched healthy control women. Five milliliter of venous blood from each subject was drawn in Vacutainer tubes containing EDTA. The genomic DNA was extracted using proteinase K digestion followed by a salting out procedure. Genotypes of the FGF1 and FGF2 genes were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.Statistical analysis was performed using SPSS13.0 software package. A probability level of 5% was considered significant. The age difference of cases and frequency-matched controls was analyzed by the t-test. Hardy-Weinberg analysis was performed during the controls to analysis whether they can represent the whole population with the probability level of 5%. Comparison of the genotype and allelotype distribution of FGF1 and FGF2 respectively in patients and healthy controls was performed by means of Chi-square test. The combination genotype of FGF1 and FGF2 were analysed by two-sided contingency tables using Chi-square test. The odds ratio (OR) and 95% confidence Interval (CI) were calculated using an unconditional logistic regression model.Results:1 Age among endometriosis, adenomyosis and control women had no significant difference (P>0.05). The genotype frequencies of FGF1 and FGF2 in healthy controls did not significantly deviate from that expected for a Hardy-Weinberg equilibrium (P>0.05).2 The distribution of the FGF1 -1385A/A, A/G and G/G genotypes between endometriosis patients (7.8%, 36.3% and 55.8%, respectively) and controls (10.9%, 41.1% and 48.0%, respectively) had no significant difference (P>0.05). But the frequency of the A allelotype in endometriosis patients (26.0%) was significantly lower than that in the controls (31.5%) (P<0.05). Contrast to the -1385G/G genotype, the A/A+A/G allelotype could significantly decrease the risk of developing endometriosis significantly (OR=0.730; 95%CI=0.557~0.958).3 No significant difference about the FGF1 -1385A and G allele distribution was shown between adenomyosis patients (28.4% and 71.6%) and controls (33.1% and 66.9%) (P>0.05). Genotype frequencies of the FGF1 -1385A/A, A/G and G/G in the adenomyosis group were 9.7%, 37.5%, 52.8%, and 13.4%, 39.4%, 47.2% in the controls, respectively. There was not statistical difference between the two groups either (P>0.05). The -1385A/G and A/A genotype could not modify the risk of developing adenomyosis compared to the G/G genotype, the odds ratio was 0.852 (95%CI=0.593~1.225) and 0.646 (95%CI=0.370~1.129).4 The frequencies of the FGF2 754C and G allele among endometriosis patients and healthy controls were 94.1%, 5.9% and 90.1%, 9.9%, respectively; Significant difference about the two alleles distribution was shown between endometriosis patients and controls (P<0.05). The frequencies of the 754C/C, C/G and G/G genotypes among endometriosis patients (88.8%, 10.5% and 0.7%, respectively) were significantly different from those in healthy controls (81.9%, 16.4% and 1.7%, respectively) (P<0.05). Contrast to the C/C genotype, the C/G+G/G genotype could significantly decrease the risk of developing endometriosis (OR=0.570; 95%CI=0.385~0.844).5 The frequencies of the FGF2 754C and G allele among adenomyosis patients were 92.0% and 8.0%, which was statistical difference with the healthy controls (87.7% and 12.3%) (P<0.05). There was no difference about FGF2 754C/C, C/G, G/G genotypes between adenomyosis patients (85.9%, 12.3% and 1.9%) and healthy controls (78.1%, 19.3% and 2.6%) (P>0.05). However, compared with the C/C genotype, the C/G+G/G genotype could significantly decrease the risk of developing adenomyosis(OR=0.586; 95%CI=0.374~0.917).6 The combined analysis of FGF1 -1385A/G and FGF2 754C/G genotypes showed that the -1385G/G﹡754C/C was the most frequent combined genotypes in the population. There was statistical difference about the combined genotypes between endometriosis patients and healthy controls (P<0.05). Compared with the -1385G/G﹡754C/C genotype, -1385AA﹡754CG,-1385AA﹡754GG,-1385GA﹡754GG and -1385GA﹡754CG could significantly decrease the risk of developing endometriosis, the odds ratio were 0.601 (95%CI=0.441~0.821), 0.610 (95%CI=0.393~0.946), 0.778 (95%CI=0.610~0.993) and 0.731 (95%CI=0.586~0.912), respectively. In spite of no difference was shown about the combined genotypes between adenomyosis patients and healthy controls (P>0.05), but compared with -1385G/G﹡754C/C genotype, the -1385AA﹡754CG could significantly decrease the risk of developing adenomyosis, the odds ratio was 0.606 (95%CI=0.422~0.869). The other combined genotypes could not modify the risk of developing endometriosis and adenomyosis.Conclusions:1 The FGF1 -1385A/G SNP in the promoter region might be related to the risk of endometriosis development. The carriers of the A allelotype could significantly decreased the risk of developing endometriosis.2 No association was shown between the FGF1 -1385A/G SNP and the risk of developing adenomyosis.3 The FGF2 754C/G SNP in the intron 1 might be related to the risk of both endometriosis and adenomyosis development. The C/G+GG genotype might be one of the potential protective factors to the development of endometriosis and adenomyosis development.4 The combined analysis of FGF1 and FGF2 genotypes indicated that the -1385G/G﹡754C/C was the most frequent combined genotypes in the population. Compared with the -1385G/G﹡754C/C genotype, -1385AA﹡754CG, -1385AA﹡754GG, -1385GA﹡754GG and -1385GA﹡754CG could significantly decrease the risk of the endometriosis development. And the -1385A/A﹡754C/G combined genotype could significantly decrease the risk of developing adenomyosis too. The other genotypes could not modify the risk of developing endometriosis and adenomyosis.