Family Association Study Between Tumournecrosis Factor-αGene And MIF Gene Polymorphisms And PCOS In Han Chinese

Background:Polycystic ovary syndrome (PCOS) is a complex disease involving genetic and environmental components. Chronic low-grade inflammation has emerged as a key contributor to the pathogenesis of PCOS. Tumournecrosisfactor-a(TNF-a) is a proinflammatory cytokine in the pathogenesis of PCOS. The genetic association between polymorphisms ofTNF-agene and PCOS was investigated. The results from case-control studies, however, were inconsistent.Macrophage migration inhibitory factor (MIF) was one of the first of the pro-inflammatory cytokines to be described and is widely expressed in numerous types of tissue. A previous case-control study identified MIF-173G/CSingleNucleotide Polymorphisms (SNP) rs755622which were independently associated with PCOS in Han Chinese.Objective:To overcome population stratification, a family-based analysis was conducted to validate whether these SNPs are associated with PCOS.Methods:A family based study was conducted with216family trios (648participants) having a probandwith PCOS. Transmission disequilibrium test (TDT) was used to analyse the association between two SNPs(rs1799964、rs1799724) of TNF-agene and rs755622ofMIF gene and PCOS. Women with PCOS were divided into two groups based on body mass index (BMI):group A (BMI<25kg/m2) and group B (BMI>25kg/m2). Parents of women with PCOS were accordingly categorized into group C and D (fathers) and group E and F (mothers).Results:After categorizing women with PCOS by BMI, we found significant differences in weight (P<0.001), waist circumference (P<0.001), hip circumference (P<0.001), waist-hip ratio (P<0.001), systolic blood pressure (P<0.001), diastolic blood pressure (P<0.001), prolactin (P=0.009), triglycerides (P=0.006), fasting insulin (P<0.001) and2-h insulin (P=0.001) between groups A and group B. In fathers (group C and D), weight (P<0.001), waist circumference (P<0.001), hip circumference (P<0.001), waist-hip ratio (P<0.001), systolic blood pressure (P<0.001), diastolic blood pressure (P<0.001), fasting insulin (P<0.001), triglycerides (P<0.001) and low-density lipoprotein (P=0.025) were statistically different. Height (P=0.023), weight (P<0.001), waist circumference (P<0.001), hip circumference (P<0.001), waist-hip ratio (P<0.001), systolic blood pressure (P=0.005), diastolic blood pressure (P<0.001), fasting insulin (P<0.001) and triglycerides (P<0.001) were higher in group F compared with group E.No significant differences were found in the genotype frequencies of rs1799964、rs1799724-. rs755622in all obese and lean women with PCOS and their parents.Minor allele frequencies of the SNPs were0.178(rs1799964),0.118(rs1799724) and0.191(rs755622). The threeSNPs were in Hardy-Weinberg equilibrium; TDT was only conducted when one parent was heterozygous. Of216trios,112trios of rs1799964and76trios of rs1799724and129trios of rs755622were tested.A significant difference in transmission was found for rs1799964(transmitted:non-transmitted=73:39;χ2=10.321; P=0.0013). rs1799724showed no evidence of an association with PCOS; riskalleles were over transmitted (transmitted:non-transmitted=43:33;χ2=1.316). No significant transmission disequilibrium between the alleles of rs755622and PCOS was found (χ2=0.938; p=0.3328).Conclusions:Transmission disequilibrium of the three SNPs indicatedthat rs1799964may participate in the pathogenesis of PCOS in Chinese women. These data provide a basis for further studiesof TNF-αin the cause of PCOS. The MIF rs755622may not participate in the pathogenesy of PCOS.