Molecular Mechanism On The Association Between PI3K Signalling Pathway And Chinese Han Population With Primary Ovarian Insufficiency

Objective PI3K (phosphoinositide-3kinase) signalling pathway has been suggested toplay an essential role in the primordial follicles survival, activation, dormancy andapoptosis in animal models. The survival of primordial follicles is maintained by RPS6(Ribosomal protein S6). The completely disappeared follicles and ovarian failure wereobserved in Rps6gene knockout mice.The quiescence of primordial follicles aremaintained by PTEN (phosphatase and tensin homolog located on chromosome ten),TSC1(tuberous sclerosis complex1) and TSC2(tuberous sclerosis complex2). Thealmost premature activation and exhaustion of primordial follicles were observed inPTEN gene or TSC1gene or TSC2gene knockout mice. The aim of the study was to dothe association studies about SNPs (single nucleotide polymorphisms) in RPS6gene,PTEN gene, TSC1gene and TSC2gene between POI patients and healthy controls, andto investigate the possible relationship between PI3K signalling pathway and POI(primary ovarian insufficiency) in Chinese women.Methods In total,378Chinese women, including148POI patients and230controlswere recruited from the First Affiliated Hospital, Anhui Medical University, Chinabetween September2007and February2012. One tagging SNPs of RPS6gene(rs2277151), seven tagging SNPs of PTEN gene (rs1234219, rs1903858, rs2299939,rs35352882, rs17107001, rs2299941å'Œrs12572106), five tagging SNPs of TSC1gene(rs1050700, rs739441, rs2809244, rs1076160å'Œrs6597586) and four tagging SNPs of TSC2gene (rs2074969, rs8063461, rs8050755å'Œrs7187438) were chosen from theCHB (Han Chinese people in Beijing, China) HapMap database (http://www.hapmap.org). MALDI-TOF-MS (matrix-assisted laser desorption/ionisation time-of-flight massspectrometry) was used to detect the genotypes of these SNPs in the extracted samplesfrom POI patients and controls.Results The genotypic distributions of rs8050755in controls was not in accord withHardy-Weinberg equilibrium (p=2.23E-23). So we excluded rs8050755out the analysis.The genotypic distributions of other SNPs in controls were all in accord withHardy-Weinberg equilibrium. Compared to controls, there were significantly higherfrequencies of the rs1076160GG genotype (p=0.0195，OR=0.424，95%CI:0.251-0.717)and six haplotypes （C-A-T, A-C-T, A-A-T, A-C-T, A-C-A, A-A-A）（p<0.05） incases with POI. No differences were observed for the other SNPs of RPS6gene, PTENgene, TSC1gene and TSC2gene between POI cases and controls.Conclusions In summary, in the present study, we firstly observed a strong associationbetween polymorphisms of TSC1gene and the risk of POI in Chinese Han population,and the references analysis suggests that both TSC1gene and TSC2gene might be thenew candidate genes involved in POI. There were no association betweenpolymorphisms of RPS6gene, PTEN gene and the risk of POI, so maybe TSC1geneand TSC2gene regulate primordial follicles activation and dormancy through otherpathways rather than PI3K signaling pathway.